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Seminars in Fetal & Neonatal Medicine (2007) 12, 54e63

Iron in fetal and neonatal nutrition

Raghavendra Rao a,*, Michael K. Georgieff a,b

a Division of Neonatology, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USAb Institute of Child Development, Center for Neurobehavioral Development,University of Minnesota, Minneapolis, MN, USA

KEYWORDSInfant;Iron deficiency;Iron overload;Iron;Newborn

Summary Both iron deficiency and iron excess during the fetal and neonatal period bodepoorly for developing organ systems. Maternal conditions such as iron deficiency, diabetes mel-litus, hypertension and smoking, and preterm birth are the common causes of perinatal irondeficiency. Long-term neurodevelopmental impairments and predisposition to future irondeficiency that are prevalent in infants with perinatal iron deficiency require early diagnosis,optimal treatment and adequate follow-up of infants at risk for the condition. However, due tothe potential for oxidant-mediated tissue injury, iron overload should be avoided in the peri-natal period, especially in preterm infants.ª 2006 Elsevier Ltd. All rights reserved.

Introduction

Iron and iron-containing compounds play vital roles incellular function in all organ systems. The requirementfor iron is greater in rapidly growing and differentiatingcells. Iron deficiency during the fetal and neonatal (peri-natal) period can result in dysfunction of multiple organsystems, some of which might not recover despite ironrehabilitation. However, the presence of excess iron duringthe perinatal period can also be detrimental to developingorgans. Preterm infants with immature antioxidant systemsare particularly vulnerable. Maintaining iron homeostasisthat avoids both iron deficiency and toxicity is essential foroptimal development and function. This paper discussesthe iron balance in the fetus and the neonate, the clinical

* Corresponding author. Mayo Medical Code 39, 420 DelawareStreet SE, Minneapolis, MN 55455, USA. Tel.: þ1 612 626 0644;fax: þ1 612 624 8176.

E-mail address: raoxx017@umn.edu (R. Rao).

1744-165X/$ - see front matter ª 2006 Elsevier Ltd. All rights reservedoi:10.1016/j.siny.2006.10.007

spectrum of iron deficiency and iron overload disordersduring this period, their pathophysiology and currentmanagement strategies.

Determinants of iron status in the fetus andneonate

The total body iron content of a newborn infant born duringthe third trimester is approximately 75 mg/kg; approxi-mately 60% of this is accreted during the third trimesterof gestation.1 The distribution of the body iron is 75e80%in red blood cells (RBC) as hemoglobin (Hb), approximately10% in tissues as iron-containing proteins (e.g. myoglobinand cytochromes), and the remaining 10e15% as storageiron (e.g. ferritin and hemosiderin). The storage iron con-tent progressively increases and is reflected by cord serumferritin concentrations >60 mg/L at full term.

The iron requirements after birth are influenced by thetime of onset of postnatal erythropoiesis and the rate of bodygrowth. The iron endowment at birth and iron from external,

d.

Iron in fetal and neonatal nutrition 55

usually dietary, sources meet this need. The period soonafter birth is characterized by a 30e50% decrease in Hbsecondary to cessation of erythropoiesis, lysis of senescentfetal RBC and expansion of the vascular volume. During this‘physiologic anemia’ the Hb can reach 100e110 g/L between6 and 8 weeks of age. In preterm infants, the Hb nadir can beas low as 60e80 g/L, occur 1e4 weeks earlier than full-terminfants and is called ‘anemia of prematurity’. An element ofdisordered or ineffective erythropoiesis might contribute tothe earlier, more severe Hb nadir in preterm infants. The ironreleased during lysis of senescent RBCs (3.47 mg/g of Hb) isstored for future use and is reflected by a transient increasein serum ferritin concentration during the first month of life.2

In full-term infants, this stored iron supports the iron needsof the ensuing erythropoiesis and growth until 4e6 monthsof age. In preterm infants, earlier iron supplementation isnecessary (see below).

Common factors that affect iron homeostasis during theperinatal period are listed in Box 1. As with other agegroups, iron deficiency is more common than iron excess.

Perinatal iron-deficiency conditions

Certain gestational conditions associated with decreasedfetal iron delivery and/or increased fetal iron demandbeyond the placental transport capacity can result inperinatal iron deficiency. As in other ages, available iron

is prioritized to support erythropoiesis in perinatal irondeficiency. When maternalefetal iron delivery is inade-quate for this purpose, depletion of storage and non-storage tissue iron occurs.

The prevalence of iron deficiency is greater in women ofreproductive age, even in developed countries. Pregnancyrequires approximately 1000 mg of additional iron to sup-port the expanding maternal RBC and plasma volumes andthe growth of the fetaleplacental unit.3,4 Maternal iron de-ficiency affects 30e50% of pregnancies3,5,6 and is the mostcommon cause of perinatal iron deficiency worldwide. Morethan 80% of pregnant women in developing countries are es-timated to be affected.6 In addition to inadequate dietaryiron intake, iron loss due to parasitic infestations, chronicgastrointestinal hemorrhage and high dietary fiber contentcontribute to iron deficiency in these mothers. In theUnited States, iron-deficiency anemia has been demon-strated in 27% of pregnant ethnic minority women duringthe third trimester.3 Teenagers, recent immigrants from de-veloping countries, women from socially disadvantagedpopulations and multiparous women with short interpreg-nancy intervals are particularly affected. Despite iron sup-plementation, 30% of pregnant women have a low serumferritin concentration at the end of pregnancy.7

Maternal iron deficiency, with or without associatedanemia, adversely affects fetal iron status. A maternal Hbconcentration <85 g/L is associated with decreased fetaliron stores (cord serum ferritin <60 mg/L). More severe

Box 1. Factors that influence body iron status during the perinatal period

Factors that have a negative effect:

� Maternal iron deficiency� Maternal diabetes mellitus� Maternal smoking� Intrauterine growth restriction� Multiple gestationa

� Preterm birth� Acute and chronic fetal hemorrhage, e.g. umbilical cord accidents and fetofetal (donor twin) transfusions� Immediate clamping of the umbilical cord after birth� Exchange transfusion� Restrictive transfusion practiceb

� Uncompensated phlebotomy lossesb

� Recombinant erythropoietin useb

� Delayed and inadequate iron supplementationb

� Exclusive breast milk usebc

� Ingestion of cow’s milk

Factors that have a positive effect:

� Maternal iron supplementd

� Fetofetal transfusion (recipient twin)� Delayed clamping of the umbilical cord� Liberal transfusion practiceb

� Early and adequate iron supplementationb

� Use of iron-fortified formulab

a Iron deficiency is more likely if mother is iron deficient during pregnancy.b The risk of iron deficiency is greater in preterm infants than full-term infants.c Exclusive breastfeeding meets the iron needs of full-term infants during the first 4e6 months of life.d Routine iron supplementation of mothers with adequate iron stores is controversial.

56 R. Rao, M.K. Georgieff

maternal anemia (Hb <60 g/L) is associated with lower cordHb concentration, as well as cord serum ferritin concentra-tion <30 mg/L, a level suggestive of severe depletion ofstorage iron and potential brain iron deficiency (see be-low).8 A maternal ferritin concentration <12 mg/L appearsto be the threshold below which fetal iron accretion isaffected6; 14% of full-term infants born to iron-deficientmothers have a serum ferritin concentration <30 mg/L atbirth. Finally, even when iron endowment appears to beadequate at birth, infants of mothers with mild to moder-ate iron deficiency anemia are at risk for iron deficiencythroughout infancy, especially between 6 and 12 monthsof age.5,9

Intrauterine growth restriction (IUGR), maternal smok-ing and poorly controlled diabetes mellitus during preg-nancy are important causes of perinatal iron deficiency indeveloped countries. All three gestational conditions arecharacterized by intrauterine fetal hypoxia and augmentederythropoiesis that requires additional iron. Approximately10% of all pregnancies are complicated by IUGR. Whereasmaternal malnutrition is likely responsible in developingcountries, pre-existing or pregnancy-induced maternalhypertension is responsible for IUGR in developed coun-tries. In pregnancies associated with IUGR due to maternalhypertension, placental iron transport is decreased due toplacental vascular disease and impaired uteroplacentalblood flow. Approximately 50% of IUGR infants are irondeficient at birth, as suggested by cord serum ferritinconcentration <60 mg/L.10 The liver and brain iron concen-trations are decreased in IUGR infants without a significanteffect on Hb at birth. In severe cases, brain iron concentra-tion could be decreased by 33%.11

Maternal smoking during gestation is associated withfetal hypoxia due to carbon monoxide and decreaseduteroplacental blood flow due to nicotine and catechol-amine-induced vasoconstriction. The augmented erythro-poiesis stimulated by fetal hypoxia results in depletion ofiron stores in the offspring of these mothers.12e14 Cord Hb isincreased and ferritin concentrations in cord blood and theplacenta are decreased 40% and 20%, respectively, ininfants of mothers who smoked during pregnancy.12 Toour knowledge, the tissue iron concentration in this infantpopulation has not been assessed.

Between 5% and 10% of pregnancies are complicated bymaternal diabetes mellitus. Poorly controlled diabetesmellitus during gestation is associated with maternal andfetal hyperglycemia, fetal hyperinsulinemia, increasedfetal metabolic rate and oxygen consumption. The in-creased fetal oxygen consumption in a relatively hypoxicintrauterine environment stimulates erythropoiesis andexpands the fetal RBC mass. The additional iron requiredfor the augmented erythropoiesis cannot be met by in-creasing maternalefetal transport. Whereas placentaltransferrin receptor expression is increased in pregnanciescomplicated by diabetes mellitus, the affinity of thereceptor to maternal transferrin is decreased, probablydue to hyperglycosylation of the oligosaccharides present inthe binding domain.15 Furthermore, placental vascular dis-ease might be present in mothers with longstanding, poorlycontrolled diabetes mellitus, further limiting iron transportacross the placenta. Tissue iron is depleted to support theiron needs of augmented erythropoiesis under these

situations. Nearly 65% of infants of diabetic mothers (IDM)have perinatal iron deficiency, as suggested by cord serumferritin concentration <60 mg/L. In approximately 25% ofthese infants cord serum ferritin is <35 mg/L, suggestingsignificant depletion of tissue iron, including brain iron.16,17

Preterm birth is another important cause of iron de-ficiency during the perinatal period. Between 25% and 85%of preterm infants with a birth weight <1500 g are at risk ofiron deficiency during infancy, depending on their diet andiron supplementation.18 Preterm birth deprives the fetus ofthe significant iron accretion that occurs beyond 32 weeksof gestation. The total body and tissue iron contents, Hband serum ferritin concentration are lower in the preterminfant.2,19,20 Early onset of postnatal erythropoiesis,greater postnatal growth velocity, uncompensated phlebot-omy losses, exclusive use of breast milk and delayed or in-adequate iron supplementation predispose the preterminfant to iron deficiency until 24 months of age. Birthweight <1000 g (extremely low birth weight, ELBW), associ-ated IUGR and use of recombinant human erythropoietin(rHuEpo) without adequate iron supplementation are addi-tional risk factors. Without an external source of iron, ironstores in non-transfused preterm infants will sustain effec-tive erythropoiesis only until they have doubled their birthweight, i.e. until approximately 2 months of age.21 Withoutiron supplementation, ELBW infants might be in negativeiron balance during the first month.22

Effects of perinatal iron deficiency

The most well-described effect of iron deficiency isanemia. However, anemia as a consequence of iron de-ficiency is extremely rare during the perinatal period.Before the appearance of anemia, the storage form ofiron in the reticuloendothelial system, specifically in theplacenta and liver, is depleted, followed by decreasedtissue iron in the heart and brain. Autopsy studies havedemonstrated that liver iron is decreased by 90%, heart ironby 55% and brain iron by 40% in infants of mothers withpoorly controlled diabetes mellitus.17 Serum ferritin con-centration <35 mg/L at birth suggest a >70% decrease ofstorage pools in the liver and the likelihood of brain iron de-ficiency (see Siddappa et al.23 for details). Such low serumferritin concentrations at birth are present in approxi-mately 25% of IDM and 14% of infants born to motherswith iron deficiency.6,16

Perinatal iron deficiency adversely affects the growthand functioning of multiple organ systems, including heart,skeletal muscle, the gastrointestinal tract and brain.24e27

Altered immune function and temperature instability arealso attributed to perinatal iron deficiency.28 The most sig-nificant adverse effects of perinatal iron deficiency areneurodevelopmental impairments and predisposition toearlier onset of postnatal iron deficiency.

Effects of perinatal iron deficiency onneurodevelopmentIron deficiency between 6 and 24 months of age is associ-ated with long-term neurocognitive abnormalities that arenot reversed, despite adequate iron supplementation.29

Iron is essential for neurotransmission, energy metabolism

Iron in fetal and neonatal nutrition 57

and myelination in the developing brain. The exact mecha-nisms through which iron deficiency affects brain develop-ment and function are not completely understood, althoughboth direct and indirect mechanisms have been proposed.29

Iron deficiency during the perinatal period also appears tobe detrimental to the developing brain. Research from ourlaboratory has demonstrated neurometabolic, structural,electrophysiological and behavioral alterations in develop-ing rats subjected to perinatal iron deficiency.30e32 Brainregions involved with cognitive processing, such as the hippo-campus and striatum, appear to be particularly vulnerable.Although iron rehabilitation corrects some deficits, structuraland functional abnormalities persist into adulthood.

In contrast to the literature on postnatal iron deficiency,few studies have assessed the role of perinatal irondeficiency on neurodevelopment in human infants. Newborninfants with low cord blood Hb and iron have alteredtemperament during the first week of life.33 Preterm infantswith iron-deficiency anemia have abnormal reflexes at36 weeks postconceptional age.34 Electrophysiological stud-ies from our laboratory have demonstrated that IDM withserum ferritin concentration <35 mg/L at birth have abnor-mal recognition memory processing soon after birth,23 whichpersists in infancy,35 despite complete repletion of ironstores by 9 months.36 Tamura et al.37 have described im-paired language ability, fine-motor skills and tractability at5 years in childrenbornwithcord serum ferritin concentration<76 mg/L. Thus, perinatal iron deficiency appears to have im-mediate and long-term adverse effect on neurodevelopment.

Predisposition to future iron deficiencyInfants with perinatal iron deficiency are at risk of irondeficiency during infancy. Use of cow’s milk and inadequateiron supplementation can increase the risk. In developingcountries, full-term infants with lower Hb and serum ferritinconcentration at birth are at risk of developing iron de-ficiency at 6 months of aged3 months earlier than thosewith adequate iron endowment at birth.5 Even in developedcountries, full-term infants with low cord ferritin concentra-tions have low serum ferritin concentration at 9 months ofage.36 Infants born to mothers who smoked during gestationare at risk for iron deficiency at 12 and 24 months.38 How-ever, whether these infants had poor iron endowment atbirth is not known. Finally, preterm birth as a risk factorfor postnatal iron deficiency has been discussed above.

Perinatal conditions associated with ironexcess

Certain congenital and iatrogenic conditions are associatedwith excessive tissue iron deposition during the perinatalperiod.

Neonatal hemochromatosis is a congenital conditioncharacterized by severe liver injury with iron depositionin intrahepatic and extrahepatic tissues, such as theexocrine pancreas, myocardium, mucosal glands of theoropharynx, and the thyroid39; the reticuloendothelialsystem is spared. Neonatal hemochromatosis is a distinctdisorder from adult-onset and juvenile-onset hemochroma-tosis.40 The etiopathogenesis of the condition is not com-pletely known. Abnormal fetoplacental iron homeostasis,

fetal liver injury, maternal autoimmune disorders and anautosomal recessive transmission have been considered. Ithas also been postulated that the condition might be analloimmune disorder.39

Neonatal hemochromatosis begins during the fetal periodand is often characterized by IUGR, oligohydramnios andpreterm birth. The presenting features are acute hepato-cellular failure and multiorgan failure that mimics neonatalsepsis. Serum aminotransferase concentrations are modestlyelevated, whereas concentration of alpha-fetoprotein ismarkedly increased. Iron indices are abnormal with in-creased serum ferritin concentrations (>800 mg/L; range1200e40,000 mg/L), hypotransferrinemia and hypersatura-tion of transferrin. The prognosis is poor; death occurs withinweeks in the majority.39,41

Multiple RBC transfusions could potentially result in ironexcess during the perinatal period. Preterm infants whohave received multiple RBC transfusions have increasedserum ferritin (>500 mg/L) and liver iron (>40 mmol/g,a value that reflects iron overload in adults) concentra-tions.42e44 Iron overload also potentially results from exces-sive enteral dietary iron supplementation,45 but has yet tobe demonstrated in human infants.

Effects of iron excess during the perinatal period

Full-term infants with high cord serum ferritin concentra-tions are at greater risk for lower full-scale intelligencequotient at 5 years of age.37 However, it is not clear whetherfetal iron load was responsible for the increased cord serumferritin in them. Accumulation of protein-bound iron (ferritinand hemosiderin) is not harmful to the tissues per se; it is in-creased non-protein-bound iron (NPBI), which promotes thegeneration of reactive oxygen species, that is responsiblefor the organ dysfunction in iron overload conditions.Because of their poorly developed antioxidant systems,preterm infants are particularly vulnerable. It has beenpostulated that iron-mediated oxidant stress plays a role incommon perinatal conditions, such as bronchopulmonarydysplasia and retinopathy of prematurity. An increasedconcentration of NPBI and decreased antioxidant defenseshave been demonstrated after RBC transfusions in preterminfants.46 Approximately 25% of full-term infants undergoingcardiopulmonary bypass exhibit evidence of iron overloadduring and after cardiopulmonary bypass, due to potentialhemolysis during the procedure.47 Finally, it is not knownwhether enteral iron supplementation could result in oxida-tive stress during the perinatal period. Iron supplementationin doses as high as 12 mg/kg per day is not associated withevidence of oxidative stress in stable preterm infants.48

However, ELBW infants, who have poorly regulated ironabsorption during the first month of life,22 might be at riskfor iron overload. Developing mice that were fed a formulawith iron content similar to that used in human infants(12 mg/L) develop neurodegeneration in the midbrain.45

Management of perinatal iron-deficiencyconditions

Avoidance of iron deficiency during pregnancy assuresoptimal perinatal iron nutrition. Accordingly, all pregnant

58 R. Rao, M.K. Georgieff

women should be screened for iron deficiency, preferablybefore pregnancy. Universal screening of infants at birth isnot recommended unless they are considered at risk foriron deficiency.

Screening for perinatal iron deficiency

No single, currently available laboratory test will assess ironstatus in all compartments (RBC, transport, functional andstorage). Assessment is further complicated in preterminfants because normative values do not exist for many tests.

Decreased Hb and mean corpuscular volume, and widerRBC distribution width (RDW) used for diagnosing irondeficiency in older age groups49 are not helpful in the new-born. These are late signs of iron deficiency and do not ac-curately reflect the iron status of the tissues. For example,despite depleted tissue iron stores, IDM and IUGR infantscan have normal or higher Hb because of the preferentialrouting of limited amount of iron into fetal RBC mass.

Free erythrocyte protoporphyrin and zinc protopor-phyrin (ZnPP), either alone or as a ratio of hemoglobin(ZnPP/H), is increased when iron supply is insufficient tosupport erythropoiesis. The ZnPP:H ratio varies inverselywith gestation, and gestation-specific normative values areavailable.50,51 Levels are increased in conditions that areassociated with fetal hypoxia and perinatal iron deficiency,such as IDM, IUGR and maternal smoking. Despite theseobservations, it is not clear whether increased ZnPP:H atbirth represents the normally occurring, enhanced intra-uterine erythropoiesis or perinatal iron deficiency.52

Finally, ZnPP:H is also increased in other conditions atbirth, such as in maternal chorioamnionitis.50

Measurement of serum transferrin receptor (sTfR),a truncated form of membrane transferrin receptor (TfR),has been used to assess iron status during the perinatalperiod. Increased sTfR or its ratio to log-serum ferritin (TfR-F index) reflects tissue iron deficiency in children andadults. Cord blood sTfR levels vary inversely with gesta-tional age and are higher in maternal iron deficiency andsmoking.53,54 However, as with ZnPP:H, it is not knownwhether sTfR or the TfR-F index are reliable measures oftissue iron deficiency or a reflection of the enhanced eryth-ropoiesis during the perinatal period.55 Ferritin is the majorform of storage iron in the body. Serum ferritin concentra-tion has been used as a proxy of body iron stores. A defini-tive ratio between cord serum ferritin and neonatal ironstores has not been established. The ratio is estimated tobe lower in newborn infants (1 mg/L of serum ferritin beingequivalent to 2.7 mg of stored iron) than in adults (1 mg/Lserum ferritin being equivalent to 8e10 mg stored iron).56

The gestational-age-specific cord serum ferritin concentra-tions range from a mean concentration of 63 mg/L at23 weeks to a mean value of 171 mg/L at 41 weeks.57 In pre-term and full-term infants, the 5th percentile cord serumferritin concentrations are 35 mg/L and 40 mg/L, respec-tively. As with other age groups, low serum ferritin concen-trations are seen only in conditions of iron deficiency in theperinatal period. However, serum ferritin is increased in in-flammatory conditions, following erythrocyte transfusionsand in neonatal hemochromatosis.

Serum iron and transferrin saturation are other measuresutilized in the assessment of iron status, although neither

measure is sensitive for this purpose during the perinatalperiod. The utility of newer biomarkers, such as pro-hepcidin and hepcidin in cord blood or urine has not beenadequately studied in the perinatal period.49

In summary, there are no stand-alone biomarkers for themeasurement of iron status in all compartments during theperinatal period. Combination of multiple markers is likely toprovide better information on the body iron status. Serumferritin measurement soon after birth may help to identifythoseat risk forperinatal irondeficiencyand its consequences.

Screening for iron deficiency beyond theperinatal period

The American Academy of Pediatrics (AAP) recommendsscreening full-term infants for iron deficiency between 9and 12 months of age, with a second screen 6 months later,i.e. at 15e18 months.58 Full-term infants at risk for iron de-ficiency are preferably screened earlier (e.g. at 6 months).Routine screening beyond 24 months is currently not rec-ommended, except in children who are at risk of iron defi-ciency due to dietary and environmental factors.

The optimal screening test for iron deficiency beyondthe perinatal period has yet to be determined. Currentrecommendation is to screen for anemia using age-,gender- and population-specific Hb or hematocrit, witha confirmatory second laboratory measurement if thevalues are <5th percentile.58 Increased erythrocyte proto-porphyrin (>35 mg/dL whole blood or >3 mg/g Hb) can alsobe used as a screening test. An improvement in Hb (>10 g/L)or hematocrit (>3%) after 1 month of enteral iron supple-mentation (3e6 mg/kg per day) is then used for establishingiron deficiency as the cause of anemia. If there is no responseto iron supplementation, other tests, such as microcytosis(RBC volume <70 fL), low RBC count (<4.0 � 1012/L), wid-ened RDW (>17%) and lower serum ferritin concentration(<15 mg/L) are used to further differentiate iron deficiencyfrom anemia due to other causes.58

Preterm infants are likely to benefit from early screeningfor iron deficiency after discharge from the hospital. Eventhough there are no special recommendations for preterminfants from the AAP, it is considered prudent to screen theiron status of these infants at 4 months of age.58 Unfortu-nately, many preterm infants develop iron deficiencybefore this age,59 depending on the number of RBCtransfusions, the growth velocity and iron supplementation.A low serum ferritin concentration (<50 mg/L) at 2 monthsportends the risk of subsequent iron deficiency in preterminfants with birth weight of <1700 g.60 Therefore, assess-ment of Hb and serum ferritin at 2 months, and thereafterevery 2 months until 6 months of age, might be advanta-geous in preterm infants. Measurement of ZnPP:H may beuseful for detecting iron-deficient erythropoiesis at andafter discharge in preterm infants.52

Beyond 6 months of age, serum ferritin does not corre-late well with measures of erythropoiesis in preterminfants.52 Additional tests of iron deficiency, such as Hb,mean corpuscular volume, red cell distribution width,ZnPP:H ratio and transferrin saturation are necessary.Finally, the establishment of reticulocytosis following ironsupplementation can also be considered diagnostic of pre-existing iron deficiency in this population.

Iron in fetal and neonatal nutrition 59

Prevention and treatment of perinatal irondeficiency conditions

Recommendations for iron nutrition for pregnant womenand full-term and preterm infants are available.1,58 Therecommended dietary allowance for pregnant women is27 mg/day of iron.1 A recent study found that daily ironsupplementation in a dose of 40 mg/day starting at18 weeks of gestation prevents iron deficiency during preg-nancy and postpartum in >90% of women in developedcountries.61 Doses as high as 100 mg/day might be neces-sary in areas with a high prevalence of iron deficiency.62

Full-term newborn infants with no risks for neonatal irondeficiency will maintain adequate iron status during theinitial 4e6 months of life on breast milk that contains<1 mg of iron/L or on infant formula that contains 4e12 mg/L. The current AAP recommendation is to beginiron supplementation in all breastfed full-term infants at4e6 months through iron-containing complementary foods.If iron cannot be provided through dietary sources, elemen-tal iron at 1 mg/kg/day should be used after 6 months.58

However, commencing iron supplementation at 1 monthof age results in higher Hb, a decrease in the incidenceof iron deficiency at 6 months of life, and an improvementin neurodevelopmental indices at 13 months of age inbreastfed infants.63 Thus, early supplementation can bebeneficial in a select group of breastfed infants. Preterm in-fants require more iron than full-term infants as discussedbelow.

Absorption and retention of enterally administered irondepends on a variety of factors. Absorption is increased iniron-deficiency states and with increasing gestational andpostnatal ages, and is decreased with larger doses and aftera recent RBC transfusion.64 The dietary source also has asignificant effect. The iron content of breast milk variesbetween 0.2 and 0.8 mg/L. Between 20 and 50% of breastmilk iron is absorbed and retained by the infant.65 Theretention of iron from formula milk is much lower, rangingfrom 4 to 20%.

Between 7 and 54% of iron administered betweenfeedings is retained by the infant65; 30e40% is probablya true representative value. Retention is better in infantswho are fed breast milk than in formula-fed infants, inthose with iron deficiency and if supplementation is begunafter postnatal erythropoiesis has commenced. The per-centage retained varies inversely with the dosage adminis-tered, except in ELBW infants <1 month of age.22,65 Unlikeadults, only a portion (12e55%) of absorbed iron is promptlyincorporated into erythrocytes in infants.65

Unless there is a need for long-term parenteral nutrition(e.g. total bowel resection), parenteral iron administrationis rarely used in infants. The dose in such situations is100e200 mg/day.66 RBC transfusion is another method ofdelivering iron parenterally, but exposes the infant totransfusion-related complications.

Maternal iron deficiencyMost gestational iron supplementation studies have focusedon the beneficial effect of such supplementation in re-ducing the risk of preterm birth and low birth weight.3

Treatment of the iron-deficient mother with additional die-tary iron results in increased iron transport to the fetus,

even at the expense of maternal iron status.67 The serumferritin concentration is increased at birth and at 3 monthsin infants of iron-deficient mothers who received iron sup-plementation during gestation.6,62 An additional benefit ofmaternal iron supplementation is prevention of pretermbirth, which allows additional time for the fetus to accreteiron. To be effective, iron supplementation should bestarted earlier, preferably pre-pregnancy.3 Oral supple-mentation is more effective than parenteral supplementa-tion67 and is also safer.

Another method of enhancing neonatal iron status isdelayed clamping of the umbilical cord at birth. Theinfant can receive a transfusion of 20e30 mL/kg of blood,depending on the time of clamping and the position of theinfant in relation to the mother. This translates to approx-imately 15e25 mg/kg of additional iron endowment. A30e120-s delay in clamping of the cord improves theiron status during the initial 2e3 months of life in full-term and preterm infants.68 This practice is particularlybeneficial for infants born to mothers with iron deficiency,those with birth weight <3000 g and those not given iron-fortified formula.69 The role of delayed umbilical cordclamping in ELBW infants, IUGR infants and in populationswith adequate maternal iron endowment has not beenstudied.

Infants with iron deficiency have altered temperamentand cognition and are at risk for earlier onset of postnataliron deficiency. Breastfed infants who are supplementedwith iron in a dose of 7.5 mg/day from 1 month of age per-form better in neurodevelopmental tests at 1 year of age.63

Additional studies are necessary to determine the role ofsuch supplementation.

Maternal diabetes mellitusThe abnormalities in iron metabolism in IDM are a functionof maternal glycemic control. Maternal iron supplementa-tion is unlikely to improve fetal iron status, as the majorityof mothers with diabetes mellitus are iron sufficient.Adequate maternal transferrin saturation will impedeabsorption of supplemented iron from her gastrointestinaltract. Furthermore, placental iron transport will also bepartially dependent on the degree of saturation of maternaltransferrin. It is possible that iron supplementation afterbirth might more rapidly replete the depleted iron stores iniron-deficient IDM. However, the efficacy of such therapy innormalizing the iron status and in correcting neurobeha-vioral impairments has not been studied. Therefore, rou-tine iron supplementation beyond what is available fromhuman milk and infant formula is not recommended.

IUGR due to maternal hypertensionIUGR due to maternal malnutrition can benefit from ironsupplementation during gestation, as malnourished womenare also likely to be iron deficient. Iron supplementation ofhypertensive mothers with IUGR fetuses is not likely to besuccessful for reasons similar to cases of IDM discussedabove. However, screening for and treatment of maternalhypertension could potentially reduce placental vasculardisease and normalize iron transport. Furthermore, ade-quate oxygenation of the fetus through improved placentalblood flow will reduce fetal iron needs for augmentederythropoiesis.

60 R. Rao, M.K. Georgieff

Overall, newborn infants with IUGR have low total bodyiron and are at risk of earlier postnatal iron deficiency.Thus, earlier screening (at 6 months instead of 9 months)for iron deficiency is prudent. Currently, there are no spe-cial recommendations to increase iron delivery to full-term IUGR infants beyond what is considered adequatein appropriate-for-gestation infants. However, it mightbe prudent to dose these infants in a manner similar topremature infants of similar birth weights (2e4 mg/kgper day).

Maternal smokingCessation of smoking is the most effective way to preventiron abnormalities in the fetus and neonate. No recom-mendations exist for additional iron supplementation ofappropriate-for-gestation newborn infants whose motherssmoked during pregnancy. However, heavy smoking canresult in IUGR, presumably with attendant reductions intotal body iron. Moreover, infants born to mothers whosmoked during gestation are at risk of iron deficiency until24 months of age.38 Therefore, it might be advisable to sub-ject the infants of mothers who smoked during gestation toearly screening for iron deficiency and to supplement themwith additional iron.

Preterm infantsPreterm infants exhibit a wide range of iron status atdischarge, depending on their degree of prematurity,amount of phlebotomy losses, number of red cell trans-fusions, bouts of infection, and timing and dosing of ironsupplementation. Limiting phlebotomy losses and startingiron therapy at 2 weeks (as opposed to 2 months) of postna-tal age might be effective preventative strategies againstsubsequent iron deficiency.70 The AAP recommends thatpreterm infants receive 2e4 mg of enteral iron/kg perday.58 Infants receiving rHuEpo therapy should receiveat least 6 mg/kg per day. Intravenous iron, althoughextremely effective in supporting erythropoiesis, mightconfer an increase of oxidative stress.71

It is not possible to provide dosing recommendationsfor preterm infants with altered iron distribution char-acterized by anemia and high serum ferritin concentra-tions because their total body iron status is unknown. Itremains unclear whether and when iron sequestered intheir livers will be released for utilization by the bonemarrow. Furthermore, it appears that enterally dosediron might be sequestered in the liver before becomingavailable for erythropoiesis,71 potentially further exa-cerbating their hyperferremia without improvingerythropoiesis.

After discharge, premature infants continue to haveincreased iron needs because of the rapid growth rateduring the first postnatal year. There is a high rate of irondeficiency in preterm infants fed low-iron formulas orbreast milk.72 Current preterm discharge formulas provideapproximately 1.8e2.2 mg of iron/kg per day, assuminga typical consumption of 150e160 mL/kg per day. Recentdata suggest that preterm infants with low serum ferritinconcentrations might require additional iron supplementa-tion.57 It might be prudent to supplement formula-fed pre-term infants with iron in a dose of 1 mg/kg per day.58

Management of iron-overload conditionsduring the perinatal period

Neonatal hemochromatosis

There is an 80% probability that this condition will recur insubsequent pregnancies.39 As an alloimmune mechanism isthought to be involved in the pathogenesis of the condition,intravenous immunoglobulin administration during subse-quent pregnancies might improve perinatal outcome.39,73

Newborn infants with hemochromatosis are extremely illand require intensive care. Relatively asymptomatic new-born infants with hyperferremia have been described andmight represent heterozygotes of the more severe form ofhemochromatosis. Iron chelation combined with a cocktailof antioxidants started soon after birth and continued untilserum ferritin levels are <500 mg/L is successful in some pa-tients.41 Liver transplant might be necessary but is oftennot feasible because of the smaller size of these infants;the results are not encouraging.41 It seems prudent to placeinfants with hemochromatosis or hyperferremia on low-irondiets once they recover.

Other perinatal conditions associated withiron overload

Infants undergoing cardiopulmonary bypass might benefitfrom iron chelation.47 Infants with potential iron-induceddamage from reperfusion following hypoxiceischemic in-jury have not been studied with respect to iron dosing.For the most part, the reperfusion injury occurs whenthey are ill and are not receiving enteral or parenteraliron. Animal models demonstrate that administration ofthe iron chelator, desferoxamine, before the ischemicevent reduces neurologic morbidity.74 It is unclear whetherpost-event chelation would be effective in reducing theamount of damage. Similarly, it is not known whether de-laying iron supplementation improves neurologic outcome.Finally, iron supplementation might be delayed in preterminfants who have increased serum ferritin concentrationsdue to multiple RBC transfusions.

Conclusions and future directions

Most of the perinatal iron deficiency conditions can beprevented through optimal management of gestationalconditions in their mothers. Ensuring maternal iron suffi-ciency during gestation is probably the most cost-effectivemethod of preventing perinatal iron deficiency. However,iron excess during gestation also appears to increase the riskof perinatal complications in the fetus and the mother.Additional studies are necessary to determine the role ofroutine iron supplement in iron-adequate mothers. Addi-tional research is also necessary to assess the effects of irondeficiency on tissue iron status and organ function in variousperinatal iron deficiency conditions. To be meaningful, thesestudies should be long term and should include remedialmeasures in a randomized controlled fashion. Comprehen-sive laboratory methods that are sensitive and specific fordiagnosing abnormal iron homeostasis and their long-term

Iron in fetal and neonatal nutrition 61

effects have to be developed. Finally, research is necessaryto develop nutritional and non-nutritional interventionsthat complement iron supplementation and prevent orreverse the long-term adverse sequelae of perinatal irondeficiency.

Acknowledgements

The editorial assistance of Ann Fandrey is gratefullyacknowledged.

Practice points

� Both iron deficiency and iron excess during theperinatal period are detrimental.� Reduced iron delivery from the mother and/or in-

creased fetal iron demand beyond the placentaltransport capacity result in perinatal irondeficiency.� A serum ferritin concentration <35 mg/L at birth

indicates significant depletion of storage and tis-sue iron.� Long-term neurodevelopmental impairments and

predilection for early postnatal iron deficiencyare the principal sequelae of perinatal irondeficiency.� Maternal intervention is the best way to prevent

iron deficiency in the newborn infant.� Infants with perinatal iron deficiency should be

screened for iron deficiency early during infancy.� Exclusive breastfeeding and avoidance of cow’s

milk and low-iron formula are effective in prevent-ing postnatal iron deficiency in full-term infants.� Limiting phlebotomy losses and early iron supple-

mentation are effective in preventing iron defi-ciency in preterm infants.� Due to the potential for oxidative stress, indis-

criminate iron supplementation should be avoidedin preterm infants.

Research directions

� The role of routine iron supplementation inmothers with adequate iron stores.� Assessment of tissue iron status in maternal iron

deficiency, maternal smoking and preterm infantsand their relationship to long-term sequelae.� Development of biomarkers for diagnosing iron

status in different compartments and for predict-ing neurodevelopmental outcome.� Development of complementary nutritional and

non-nutritional strategies to counter the adverseeffects of perinatal iron deficiency.

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