Randomized Trial of Iron Supplementation versus Routine Iron Intake in VLBW Infants Effects of Iron Supplementation of LBW Infants on Cognition and Behavior at 3 Years Effects of iron supplementation of low-birth-weight infants on cognition and behavior at 7 years: a randomized controlled trial Impact of maternal, antenatal and birth-associated factors on iron stores at birth: data from a prospective maternal–infant birth cohort Reduced Erythrocyte Superoxide Dismutase Activity in Low Birth Weight Infants Given Iron Supplements 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 Growth, Efficacy, and Safety of Feeding an Iron-Fortified Human Milk Fortifier Hematologic and selenium status of low-birth-weight infants fed formulas with and without iron. The Premature Infants in Need of Transfusion (PINT) study: a randomized, controlled trial of a restrictive (low) versus liberal (high) transfusion threshold for extremely low birth weight infants. Early versus late enteral prophylactic iron supplementation in preterm very low birth weight infants: a randomised controlled trial Iron Supplements Reduce the Risk of Iron Deficiency Anemia in Marginally Low Birth Weight Infants Iron nutritional status in preterm infants fed formulas fortified with iron High iron status in very low birth weight infants is associated with an increased risk of retinopathy of prematurity. Iron sulfate supplementation decreases zinc protoporphyrin to heme ratio in premature infants. Blood transfusion increases radical promoting non-transferrin bound iron in preterm infants Oxidative stress markers and antioxidant status after oral iron supplementation to very low birth weight infants. Prospective Randomized Trial of Early Versus Late Enteral Iron Supplementation in Infants With a Birth Weight of Less Than 1301 Grams Haematological effect of iron supplementation in breast fed term low birth weight infants Effects of Iron Supplementation on Auditory Brainstem Response in Marginally LBW Infants A randomized trial of two levels of iron supplementation and developmental outcome in low birth weight infants. Feeding iron-fortified premature formula during initial hospitalization to infants less than 1800 grams birth weight. Iron supplementation in premature infants using the zinc protoporphyrin to heme ratio: short- and long-term outcomes Iron Supplementation Until 6 Months Protects Marginally Low-Birth-Weight Infants From Iron Deficiency During Their First Year of Life
OBJECTIVE : To determine if iron supplementation of 2 mg/kg per day , in addition to routine iron-fortified formula or mother 's milk , increased the hematocrit ( Hct ) at 36 weeks ' postmenstrual age ( PMA ) . METHODS : : Infants with a birth weight < 1500 g who reached 120 mL/kg per day of feedings before 32 weeks ' PMA were r and omly assigned to iron ( multivitamin with iron ) or control ( multivitamin ) from enrollment until 36 weeks ' PMA ( or discharge , if sooner ) . Investigators and caregivers were masked . Transfusion guidelines were used . The primary outcome was Hct at 36 weeks ' PMA . A nonparametric rank sum analysis was performed so that infants who died before 36 weeks and infants who were transfused could be included in an intention-to-treat analysis . Infants were ranked by death ( lowest rank ) then by number of transfusions ( next lowest ranks ) . For infants who survived and were not transfused , the 36-week PMA Hct was used for the rank . RESULTS : One hundred fifty infants were enrolled ( 76 iron , 74 controls ) . There were 2 deaths ( 1 in each group ) . One hundred other infants ( 47 iron , 53 controls ) received transfusion(s ) . There was no significant difference in the primary outcome ranking ( P = .59 ) , in the number of transfusions per subject ( P = .64 ) , or in 36-week Hct ( iron mean ± SD , 29.2 % ± 4.0 % ; control , 28.3 % ± 4.5 % ; mean difference and 95 % confidence interval 0.9 [ −0.5 to 2.3 ] ; P = .21 ) or reticulocyte count among survivors . No short-term adverse effects of iron supplementation were observed . CONCLUSIONS : Among infants < 1500 g birth weight  , iron supplementation , in addition to routine iron intake , did not significantly increase the 36-week Hct or the decrease number of transfusions OBJECTIVE : Low birth weight ( LBW ) infants are at increased risk of cognitive and behavioral problems and at risk for iron deficiency , which is associated with impaired neurodevelopment . We hypothesized that iron supplementation of LBW infants would improve cognitive scores and reduce behavioral problems . METHODS : In a r and omized controlled trial , 285 marginally LBW ( 2000–2500 g ) infants received 0 , 1 , or 2 mg/kg/day of iron supplements from 6 weeks to 6 months of age . At 3.5 years of age , these infants and 95 normal birth weight controls were assessed with a psychometric test ( Wechsler Preschool and Primary Scale of Intelligence ) and a question naire of behavioral problems ( Child Behavior Checklist ; CBCL ) . RESULTS : There were no significant differences in IQ between the LBW groups or LBW infants versus controls  .  Mean ( SD ) full-scale IQ was 105.2 ( 14.5 ) , 104.2 ( 14.7 ) , and 104.5 ( 12.7 ) in the placebo , 1 mg , and 2 mg groups , respectively ( P = .924 ) . However , for behavioral problems , there was a significant effect of intervention . The prevalence of children with CBCL scores above the US sub clinical cutoff was 12.7 % , 2.9 % , and 2.7 % in the placebo , 1-mg , and 2-mg groups , respectively ( P = .027 ) , compared with 3.2 % in controls . Relative risk ( 95 % confidence interval ) for CBCL score above cutoff in placebo-treated children versus supplemented was 4.5 ( 1.4–14.2 ) . CONCLUSIONS : Early iron supplementation of marginally LBW infants does not affect cognitive functions at 3.5 years of age but significantly reduces the prevalence of behavioral problems . The study suggests a causal relation between infant iron deficiency and later behavioral problems Background Low-birth-weight infants ( LBW ) are at an increased risk of iron deficiency that has been associated with impaired neurodevelopment . We hypothesized that iron supplementation of LBW infants improves cognitive scores and reduces behavioral problems until school age . Methods We r and omized 285 marginally LBW ( 2,000–2,500 g ) infants to receive 0 , 1 , or 2 mg/kg/day of iron supplements from 6 weeks to 6 months of age . At 7 years of age , 205 participants were assessed regarding cognition using Wechsler Intelligence Scale for Children ( WISC-IV ) and behavior using the parental question naires Child Behavior Checklist ( CBCL ) and Five  to Fifteen  ( FTF ) . Results There were no significant differences between the intervention groups in WISC-IV or FTF . However , the CBCL scores for externalizing problems were significantly different , in favor of supplemented children ( P=0.045 ) . When combining the supplemented groups , they had significantly lower scores for externalizing behavior compared with placebo ( median ( interquartile range ) : 44 [ 34;51 ] vs. 48.5 [ 41;56 ] P=0.013 ) , and their risk ratio ( 95 % confidence interval ) for a total behavioral score above the cutoff for clinical problems was 0.31 ( 0.09–1.0 ) , P=0.054 . Conclusion Lower scores of externalizing behavior in supplemented children support our previous findings at 3 years , and suggest that iron supplementation may have long-lasting effects on behavioral functions Background / Objectives : Low serum ferritin concentrations at birth , which reflect neonatal iron stores , track through to early childhood and have been associated with poorer neurodevelopmental outcomes . We aim ed to identify maternal , antenatal and birth-associated factors that influence iron stores at birth in a prospect i ve maternal – infant birth cohort . Subjects/ Methods : In a population -based , longitudinal , birth cohort in Irel and , 413 maternal – infant dyads with prospect ively collected lifestyle and clinical data from 15 weeks ’ gestation had umbilical cord serum ferritin concentrations measured . Regression models were developed to identify independent factors associated with cord ferritin concentrations . Results : Median ( IQR ) cord ferritin concentrations were 185.7 ( 131.7 , 385.5 ) μg/l , and 8 % ( n=33 ) of infants had low iron stores ( ferritin < 76 μg/l ) at birth . Maternal obesity ( BMI ⩾30 kg/m2 ) at 15 weeks ’ gestation ( adj . estimate ( 95 % confidence interval ( CI ) ) : −66.4 ( −106.9 , −25.9 ) μg/l , P<0.0001 ) and delivery by caesarean section ( −38.8 ( −70.2 , −7.4 ) μg/l , P=0.016 ) were inversely associated with cord ferritin concentrations . In addition , maternal smoking at 15 weeks ’ gestation ( adj . odds ratio ( 95 % CI ) : 2.9 ( 1.2 , 7 ) , P=0.020 ) and being born small-for-gestational age ( 3.4 ( 1.3 , 8.9 ) , P=0.012 ) were associated with an increased risk of low iron stores ( ferritin < 76 μg/l ) at birth . Conclusions : We have identified a number of potentially modifiable lifestyle factors that influence iron stores at birth , with the important role of overall maternal health and lifestyle during pregnancy highlighted . Public health policies targeting women of child-bearing age to improve nutrition and health outcomes should be prioritised for the health of the next generation ABSTRACT : Erythrocyte superoxide dismutase ( ESOD ) activity reflects copper utilization and the risk of copper deficiency . To investigate the possible effects of inorganic iron on the metabolism of copper in low birth weight infants , we have measured ESOD activities in three groups of infants receiving different iron supplements . Fifty-five low birth weight infants were r and omly assigned to receive daily from 28 d either 13.8 mg ( HiFe ) , 7 mg ( MidFe ) , or no elemental iron ( NatFe ) as iron edetate . At 27 d , 8 , 12 , and 20 wk postnatal age , infants were weighed and measured and hematologic indices , plasma ferritin , zinc , and copper concentrations , and ESOD activities were assayed . Anthropometrical and hematologic indices and plasma copper and zinc concentrations did not differ among treatment groups at any time , but at 20 wk , plasma ferritin concentrations [ ( μg/L ) mean ; SD ] were lower in the NatFe group ( 17 ; 2.0 ) than in the HiFe group ( 32 ; 1.9 : 95 % confidence interval for mean difference 6.6 to 22.0 , p < 0.01 ) . ESOD activities ( U/g Hb ) were similar in HiFe ( 1447 ; 263 ) , MidFe ( 1552 ; 322 ) , and NatFe ( 1538 ; 382 ) groups at 27 d , but by 20 wk activities in the HiFe group ( 1537 ; 211 ) were lower than in the MidFe ( 1789 ; 403:95 % confidence interval 38 to 466 , p < 0.05 ) and NatFe ( 1858 ; 304 : 95 % confidence interval 150 to 492 , p < 0.01 ) groups . The lower ESOD activities found in the HiFe group at 20 wk may reflect altered copper metabolism induced by the iron supplement , but the clinical importance of this observation is unknown BACKGROUND . Iron deficiency in early childhood may impair neurodevelopment . In a masked , r and omized , controlled trial of early versus late enteral iron supplementation in preterm infants with birth weights of < 1301 g , early iron supplementation reduced the incidence of iron deficiency and the number of blood transfusions . OBJECTIVE . We sought to examine whether early enteral iron supplementation improves neurocognitive and motor development in these infants . METHODS . Children who participated in the above mentioned trial were evaluated by applying the Kaufmann Assessment Battery for Children and the Gross Motor Function Classification Scale at the age of school entry . RESULTS . Of the 204 infants initially r and omized , 10 died and 30 were lost to follow-up . A total of 164 ( 85 % of the survivors ) were evaluated at a median corrected age of 5.3 years . In this population ( n = 164 ) , the mean ( ±SD ) mental processing composite in the early iron group was 92 ( ±17 ) versus 89 ( ±16 ) in the late iron group . An abnormal neurologic examination was found in 17 of 90 versus 26 of 74 , and a Gross Motor Function Classification Scale score of > 1 was found in 2 of 90 versus 5 of 74 , respectively . Fifty-nine of 90 children in the early iron group were without disability , compared with 40 of 74 in the late iron group . Severe disability was found in 5 of 90 versus 6 of 74 children and 67 of 90 versus 49 of 74 qualified for regular schooling , respectively . CONCLUSIONS . Early enteral iron supplementation showed a trend toward a beneficial effect on long-term neurocognitive and psychomotor development and showed no evidence for any adverse effect . Because the initial study was not design ed to evaluate effects on neurocognitive development , the power was insufficient to detect small but potentially clinical ly relevant improvements . Additional studies are required to confirm the trend towards a better outcome observed in the early iron group Objective . Survival rates for preterm infants who weigh between 501 and 1500 g at birth have continued to improve over time . In response to this continuing decrease in birth weight of surviving preterm infants , Enfamil Human Milk Fortifier has recently been reformulated to meet the nutritional requirements of these smaller , more rapidly growing infants . It now provides an increased protein level of 1.1 g/58 kJ , a decreased carbohydrate level of 0.2 g/58 kJ , and a combined linoleic and α-linolenic fatty acid content of 157 mg/58 kJ. As these very small preterm infants have an increased requirement for dietary iron , the fortifier has been supplemented with 1.44 mg/58 kJ of iron , an amount of iron similar to that provided in a typical iron-fortified term infant formula . An iron-fortified product obviates the need for administration of an iron supplement , a hyperosmolar-inducing intervention . The purpose of this prospect i ve , double-blind , r and omized , controlled study was to evaluate growth , safety , and efficacy in a population of very low birth weight ( VLBW ) preterm infants who received human milk fortified with either the reformulated iron-fortified powdered human milk fortifier test product ( HMF-T ) or a powdered commercially available human milk fortifier control product ( HMF-C ) .  Methods . Infants who weighed ≤1500 g , had a gestational age ≤33 weeks postmenstrual age , and had an enteral intake of at least 100 mL/kg per day of unfortified human milk were stratified by gender and birth weight and r and omized to receive HMF-T or HMF-C product from study day 1 to study day 28 , hospital discharge , or the termination of human milk feedings , whichever came first . Unless medically indicated , investigators were not to administer iron supplements from study days 1 to 14 . Infants were assessed serially for growth ; enteral and parenteral intake ; serum chemistry and hematologic values ; clinical histories , including the administration of blood transfusions ; feeding tolerance ; respiratory outcomes ; and morbidities , including adverse events . Results . Of the 181 participating infants in this study , 96 received HMF-T and 85 received HMF-C. At r and omization , there were no significant differences in infant characteristics between the fortifier groups . The percentage of participants who remained in the study for 28 days was similar between fortifier groups ( 57 % HMF-T , 46 % HMF-C ) . For both fortifier groups , the most frequent reasons for discontinuing the study before study day 28 were unavailability of human milk and hospital discharge . Rate of weight gain was similar between the fortifier groups ( 17.5 ± 0.53 g/kg per day for HMF-T and 17.3 ± 0.59 g/kg per day for HMF-C  ) . Mean achieved weight , length , and head circumference were comparable between groups across the 28-day study period . Total protein intake from enteral and parenteral nutrition was significantly greater for the HMF-T fortifier group ; however , this difference did not result in any difference in growth between the 2 fortifier groups . An analysis of the growth and energy intake data of a subset of the intent-to-treat population who adhered more strictly to the study feeding protocol yielded results similar to those seen for the intent-to-treat population . There were no clinical ly significant differences in the results of laboratory studies between the groups at study days 0 , 14 , and 28 . Anemia of prematurity was prevalent in both study groups ; by study day 28 , median hematocrit levels were 27.0 % ( interquartile range [ IQR ] : 24.0%–29.6 % ) for the HMF-T group and 26.0 % ( IQR : 24.0%–31.0 % ) for the HMF-C group . Median ferritin levels were 77.0 ng/mL ( IQR : 37 - 155 ng/ml ) for HMF-T and 92.0 ng/mL ( IQR : 33 - 110 ng/mL ) for HMF-C. There were no significant differences between the study fortifier groups in regard to the receipt of medically indicated iron supplements on or before study day 14 or in the administration of blood transfusions before study day 0 or from study days 0 through 14 . However , from study day 15 to study day 28 , fewer HMF-T infants ( n = 12 ) required a blood transfusion than did HMF-C infants ( n = 20 ) . Although the higher levels of iron in the HMF-T fortifier ( 1.44 mg vs 0.35 mg for HMF-C per 4 packets of powdered fortifier ) did not prevent anemia per se , it did reduce the frequency of one of the most serious outcomes of anemia : the need for a blood transfusion . There was no statistically significant difference between fortifier groups in regard to feeding tolerance . Rates of suspected sepsis ( 26 % HMF-T vs 31 % HMF-C ) and confirmed sepsis ( 5 % HMF-T , 7 % HMF-C ) were low as were the rates of suspected necrotizing enterocolitis ( NEC ; 6 % HMF-T and 5 % HMF-C ) and confirmed Bell 's stage 2 or more NEC ( 1 % HMF-T and 1 % HMF-C ) . There were no statistically significant differences between the study fortifier groups in regard to the incidence of confirmed and suspected sepsis and NEC . Conclusion . Both human milk fortifiers studied are safe , are well tolerated , and facilitate comparable good growth ; however , using the iron-fortified product may reduce the need for blood transfusions in VLBW infants . The similar low rates of suspected and confirmed NEC and sepsis seen in both fortifier groups in this study refutes the premise that the inclusion of iron in fortifiers will increase the incidence of sepsis and NEC . Indeed , the incidence for NEC and sepsis for both groups in this study was lower than is reported for VLBW infants and similar to that seen for infants who are fed human milk Preterm infants with birth weights between 1,001 and 1,600 gm were r and omly assigned at one week of age to three groups and fed a st and ard milk-based formula , the same formula with iron , or a soy-based formula with iron .  Hematologic values and selenium status were then studied prospect ively for five weeks . Rates of decline in hematocrit and hemoglobin did not differ significantly among the three groups and did not correlate with red cell selenium values or glutathione peroxidase activity . Attainment of vitamin E sufficiency was variable among the infants , with no significant intergroup differences . Plasma selenium concentrations did not change significantly , but plasma glutathione peroxidase activity declined consistently in all three groups . Under the conditions of this study , iron at a concentration of 12 mg/L of infant formula did not accelerate hemolysis ; nor was there evidence of a direct association between selenium values and early anemia of prematurity OBJECTIVE To determine whether extremely low birth weight infants ( ELBW ) transfused at lower hemoglobin thresholds versus higher thresholds have different rates of survival or morbidity at discharge . STUDY DESIGN Infants weighing < 1000 g birth weight were r and omly assigned within 48 hours of birth to a transfusion algorithm of either low or high hemoglobin transfusion thresholds . The composite primary outcome was death before home discharge or survival with any of either severe retinopathy , bronchopulmonary dysplasia , or brain injury on cranial ultrasound . Morbidity outcomes were assessed , blinded to allocation . RESULTS Four hundred fifty-one infants were r and omly assigned to low ( n = 223 ) or high ( n = 228 ) hemoglobin thresholds . Groups were similar , with mean birth weight of 770 g and gestational age of 26 weeks . Fewer infants received one or more transfusions in the low threshold group ( 89 % low versus 95 % high , P = .037 ) . Rates of the primary outcome were 74.0 % in the low threshold group and 69.7 % in the high ( P = .25 ; risk difference , 2.7 % ; 95 % CI -3.7 % to 9.2 % ) . There were no statistically significant differences between groups in any secondary outcome . CONCLUSIONS In extremely low birth weight infants , maintaining a higher hemoglobin level results in more infants receiving transfusions but confers little evidence of benefit Objectives To evaluate whether preterm very low birth weight ( VLBW ) infants receiving early iron ( EI ) supplementation ( 2 mg/kg/day elemental iron ) at 2 weeks postnatal age have improved serum ferritin levels compared with late iron ( LI ) supplementation at 6 weeks postnatal age . Design Single-blinded parallel-group interventional r and omised controlled trial . Setting Tertiary care centre in southern India . Interventions R and omised at 2 weeks postnatal age to EI and LI groups and evaluated at 2 , 6 and 12 weeks postnatal age . Outcome The primary outcome was serum ferritin level at 12 weeks , and the secondary outcomes were the incidence of neonatal morbidities , haemoglobin level , anthropometric parameters and blood transfusion requirements . Results Of the 104 babies r and omised , outcomes were analysed in 46 and 47 babies in EI and LI groups , respectively . Serum ferritin level was significantly higher ( p<0.001 ) at 12 weeks ( 82±5 vs 63±3 ng/mL ) in the EI group . Haemoglobin ( 10.1±0.4 vs 9.2±0.4 g/dL ) and mean corpuscular haemoglobin concentration ( 31±0.5 vs 29.4±0.5 g/dL ) were also significantly ( p<0.001 ) higher at 12 weeks in the EI group . There was a significant decrease of ferritin in the LI group and significant increase in ferritin in the EI group at 6 weeks compared with 2 weeks . There were no significant differences in the incidences of neonatal morbidities ( necrotising enterocolitis , periventricular leukomalacia , retinopathy of prematurity ) , anthropometric parameters and blood transfusion requirements between the two groups . Conclusions EI supplementation in preterm VLBW infants  improves serum ferritin and haemoglobin levels . Trial registration : CTRI/2013/01/003277 OBJECTIVE : Low birth weight infants are at risk for iron deficiency ( ID ) . Most LBW infants have marginally low birth weight ( MLBW , 2000–2500 g ) and it is not known whether they benefit from iron supplements . The objective of this trial was to study the effects of iron supplementation in MLBW infants . METHOD : In a r and omized controlled trial , we assigned 285 healthy , MLBW infants to receive iron supplements at a dose of 0 ( placebo ) , 1 , or 2 mg/kg per day between 6 weeks and 6 months of age .  Hemoglobin levels , ferritin levels , transferrin saturation , mean cell volume , and transferrin receptor levels were analyzed at 6 months . Growth and morbidity were monitored . RESULTS : Iron supplementation result ed in significant dose-dependent effects on hemoglobin and all iron status indicators at 6 months . The prevalence of ID at 6 months was 36 % in the placebo group , 8.2 % in the 1 mg/kg per day group , and 3.8 % in the 2 mg/kg per day group ( P < .001 ) . The prevalence rates of ID anemia ( IDA ) were 9.9 % , 2.7 % , and 0 % , respectively ( P = .004 ) . Among infants who were exclusively breastfed at 6 weeks , the prevalence of IDA was 18 % in the placebo group . There were no significant differences between groups in growth or morbidity . CONCLUSIONS : MLBW infants have relatively high risks of ID and IDA , especially if they are breastfed . Iron supplementation at 2 mg/kg per day from 6 weeks to 6 months reduces this risk effectively , with no short-term adverse effects on morbidity or growth AIMS To prospect ively evaluate the iron nutritional status of preterm infants fed either a term ( 0.5 mg/dl iron ) or preterm ( 0.9 mg/dl ) formulas fortified with iron after hospital discharge . METHODS Healthy low birthweight preterm infants were r and omly assigned into three groups at the time of hospital discharge . Group A were fed an iron fortified preterm formula ( 0.9 mg/dl iron ) until 6 months corrected age ; group B , a fortified term formula ( 0.5 mg/l iron ) until 6 months corrected age group C , the preterm formula between hospital discharge and term , then the term formula until 6 months corrected age . RESULTS Seventy eight infants were followed up to 6 months corrected age . Iron intake from formula differed significantly between the groups ( A , 1.17 mg/kg/day ( SD 0.32 ) > C , 0.86 mg/kg/day ( SD 0.40 ) = B , 0.81 mg/kg/day ( SD 0.23 ) ; p < 0.0001 ) . Haemoglobin concentrations were similar to those of iron sufficient preterm infants of the same postnatal age , and term infants of the same postmenstrual age ( after 3 months of age ) . There were no significant differences in haemoglobin concentration ( p = 0.391 ) , plasma ferritin ( A vs B , p = 0.322 ) , or in the incidence of iron deficiency ( A vsB , p = 0.534 ) . CONCLUSIONS Iron fortified formulas containing between 0.5 and 0.9 mg/dl iron seem to meet the iron nutritional needs of preterm infants after hospital discharge OBJECTIVE To explore the hypothesis that excessive iron loads may increase the formation of free radicals and the development of retinopathy of prematurity  in preterm infants , we carried out a prospect i ve observational study of the association between transfusion volume , iron status , and retinopathy OBJECTIVES To test the utility of zinc protoporphyrin to heme ratio ( ZnPP/H ) as an indicator of iron status in premature infants and to evaluate the effect of oral iron supplements on oxidative injury . We hypothesized that iron sulfate supplementation would decrease the ZnPP/H in preterm infants . STUDY DESIGN Infants eligible for this prospect i ve study were : hospitalized , 24 to 32 weeks of gestation , 7 to 60 days old , feeding > or = 70 mL/kg/d , with a ZnPP/H > or = the mean for age .  Iron dose was determined by the ZnPP/H.  Iron status and oxidative injury were evaluated at study entry and completion . Concurrent control subjects met entry criteria but were not enrolled and were not treated with iron during the study interval . Statistical evaluation included repeated measures analysis of variance and Z-score conversions . RESULTS Entry ZnPP/H of iron-treated subjects ( n = 16 ) and control subjects ( n = 16 ) were not different . The ZnPP/H of iron-treated infants was lower at study end ( P < .05 ) but did not change in control infants . Iron treatment ( 3 to 12 mg/kg/day ) was not associated with changes in conventional measures of iron status nor in measures of oxidative injury . CONCLUSIONS Iron sulfate supplementation ( 3 - 12 mg/kg/d ) decreases ZnPP/H , is tolerated , and is not associated with increased oxidative injury BACKGROUND Blood transfusion has been recognised as a risk factor for the development of retinopathy of prematurity ( ROP ) or chronic lung disease ( CLD ) in preterm infants , but the precise mechanism involved is not understood . AIM To investigate the level of non-transferrin bound “ free ” iron , which has the potential to promote the generation of reactive oxygen species , and its redox status in the plasma of preterm infants immediately before and after blood transfusion . METHODS Twenty one preterm infants with a median gestational age and birth weight of 27 weeks and 1021 g respectively were prospect ively enrolled in the study . Sixteen of the 21 infants developed ROP and /or CLD . The infants were transfused with concentrated red blood cells at a median age of 32 days . The plasma concentration of total bleomycin detectable iron ( BDI ) was measured and also the ferrous iron ( Fe2 + ) activity by bleomycin-iron complex dependent degradation of DNA . RESULTS Even before blood transfusion , BDI was detectable in one third of the blood sample s , and all but one sample had ferrous iron activity . After transfusion , both BDI and ferrous iron activity were significantly increased , in contrast with the situation in full term infants . Plasma ascorbic acid ( AA ) concentration was significantly decreased after blood transfusion , whereas the level of its oxidation product , dehydroascorbic acid ( DHAA ) , and the DHAA/AA ratio were significantly increased compared with before the transfusion . The activity of plasma ferroxidase , which converts iron from the ferrous to the ferric state , was appreciably decreased in preterm infants , as expected from their very low plasma caeruloplasmin concentration . CONCLUSIONS Plasma non-transferrin bound iron was significantly increased in preterm infants after blood transfusion and existed partly in the ferrous form , because of the low ferroxidase activity and the reduction of ferric iron ( Fe3 + ) by ascorbic acid . This finding was specific to preterm infants and was not observed in full term infants after blood transfusion . Non-transferrin bound “ free ” iron may catalyse the generation of reactive oxygen species , which may be responsible for the clinical association of blood transfusion with ROP and CLD . Key messages Plasma non-transferrin bound iron was significantly increased in preterm infants after blood transfusion and existed partly in the ferrous pro-oxidant form The increase in plasma non-transferrin bound iron after blood transfusion was not observed in full term OBJECTIVE To evaluate whether our current practice of giving iron 18 mg daily to 6-week-old infants with very low birth weight ( VLBW ) was associated with increased oxidative stress markers or decreased antioxidant status . STUDY DESIGN The study was a prospect i ve observational study of 21 healthy VLBW infants ( born at gestational age < 32 weeks , birth weight < 1500 g ) . Blood and urine were sample d twice before starting iron supplementation at 6 weeks postnatal age and after 1 week of iron supplementation at age 7 weeks . Urine 8-isoprostane was analyzed by gas chromatography-mass spectrometry and plasma total hydroperoxides were measured . Antioxidant status was assessed by ascorbic acid ( vitamin C ) , alpha-tocopherol ( vitamin E ) , ferric-reducing ability of plasma , and plasma glutathione . RESULTS After 1 week of iron supplementation , no significant changes in urine 8-isoprostane or plasma total hydroperoxides were seen , and plasma antioxidants were largely unchanged . CONCLUSIONS Markers of oxidative stress in urine and plasma antioxidant status in healthy VLBW infants fed human milk remained unchanged after high-dose oral iron supplementation Objectives . To examine whether early enteral iron supplementation ( EI ) would improve serum ferritin as a measure of nutritional iron status at 2 months of age and would prevent definite iron deficiency ( ID ) in infants with a birth weight of < 1301 g. Methods . Infants were r and omly assigned to receive enteral iron supplementation of 2 to 6 mg/kg/day as soon as enteral feedings of > 100 mL/kg/day were tolerated ( EI ) or at 61 days of life ( late enteral iron supplementation [ LI ] ) . Nutritional iron status was assessed : 1 ) at birth , 2 ) at 61 days of life , 3 ) when the infants reached a weight of 1.6 times birth weight , and 4 ) before blood was transfused at a hematocrit of < .25 . ID was defined by any one of the following criteria : ferritin , < 12 μg/L ; transferrin saturation , < 17 % ; or increase of absolute reticulocyte counts by > 50 % one week after the onset of enteral iron supplementation . Restrictive red cell transfusion guidelines were followed and all transfusions were documented . Erythropoietin was not administered . The primary outcome variables were : 1 ) ferritin at 61 days and 2 ) the number of infants with ID . Results . Ferritin at 61 days was not different between the groups . Infants in the LI group were more often iron-deficient ( 26/65 vs 10/68 ) and received more blood transfusions after day 14 of life . No adverse effects of EI were noted . Conclusions . EI is feasible and probably safe in infants with birth weight < 1301 g. EI may reduce the incidence of ID and the number of late blood transfusions . ID may occur in very low birth weight infants despite early supplementation with iron and should be considered in the case of progressive anemia . preterm infant , iron supplementation , iron deficiency , blood transfusion Aims : To determine the haematological effects of iron supplementation in predominantly breast fed term low birth weight ( LBW ) infants . Methods : Seventy three healthy term LBW ( < 2500 g ) , predominantly breast fed infants aged 50–80 days were r and omised into two groups to receive either iron ( 3 mg/kg/day ) ( iron supplemented ( IS ) group ; n = 37 ) or placebo drops ( placebo ( P ) group ; n = 36 ) . Haematological parameters and anthropometry were measured at baseline and repeated after four and eight weeks . Results : A total of 62 subjects ( 32 in the IS group and 30 in the P group ) came for the first follow up and 26 ( 13 in the IS group and 13 in the P group ) reported for the second visit . There were no significant differences in serum ferritin and anthropometry . However , covariates ( infant age , haemoglobin , and ferritin , and maternal haemoglobin ) adjusted haemoglobin change was significantly higher in the IS group after four weeks ( 4.6 g/l ; 95 % CI 0.5 to 8.8 ) and eight weeks ( 8.6 g/l ; 95 % CI 1.8 to 15.4 ) . Conclusions : Iron supplementation in a therapeutic dose in term breast fed LBW infants results in a marginal increase in haemoglobin . The functional benefit of this haemoglobin rise requires further evaluation LBW infants are at risk of iron deficiency ( ID ) , which is associated with impaired nervous system development and may lead to prolonged auditory brainstem response ( ABR ) latencies . We hypothesized that iron supplementation shortens ABR latencies in marginally LBW ( MLBW , 2000 - 2500 g ) infants . In a r and omized , controlled trial , 285 healthy MLBW infants received 0 , 1 , or 2 mg iron/kg/d of iron supplements from 6 wk to 6 mo of age . ABR absolute wave V latencies and central conduction time ( CCT ) were measured at the endpoint . There were no significant differences between groups in ABR wave V latencies ( n = 218 ) . Furthermore , there were no significantly prolonged ABR latencies in infants with ID ( n = 32 ) . CCT was significantly higher in the 2 mg group than in the placebo group ( n = 126 ) . However , there were no significant correlations between CCT and iron intake or any iron status variable , suggesting that differences in CCT were not caused by iron . We conclude that iron supplements did not improve ABR latencies , and iron-deficient MLBW infants did not have impaired ABR latencies at 6 mo , suggesting that ABR is not a sensitive measure of impaired neurological development or that mild/moderate ID causes no such impairment in MLBW infants OBJECTIVES To investigate the effect of increased iron intakes on hematologic status and cognition in low birth weight infants . STUDY DESIGN We r and omly assigned 58 infants to receive formula with 13.4 mg iron/L ( normal iron ) or 20.7 mg iron/L ( high iron ) . At baseline , discharge , and at 3 , 6 , 9 , and 12 months ' corrected age , we assessed anthropometry ; infections ; red blood cell hemoglobin , catalase , glutathione peroxidase , red blood cell fragility ( hydrogen peroxide test ) , and superoxide dismutase values ; plasma malondialdehyde , ferritin , iron , transferrin , zinc and copper levels ; and  diet intake . Griffiths ' Development Assessment was done at 3 , 6 , 9 , and 12 months only . RESULTS No statistical differences ( P < .05 ) were noted for weight , catalase or malondialdehyde levels , red blood cell fragility , or Griffith 's Development Assessment . Iron intakes were greater in the high iron group except at 12 months . Hemoglobin ( high iron , 123 + /- 9 ; normal iron , 118 + /- 8) was not different at 3 months ( P = .07 ) . Plasma zinc levels ( high iron , 70 + /- 14 ; normal iron , 89 + /- 27 ) and copper levels ( high iron , 115 + /- 26 ; normal iron , 132 + /- 27 ; P = .06 ) at 12 months suggested inhibition of absorption by high iron formula . Glutathione peroxidase levels were higher in the high iron group . The total number of respiratory tract infections was greater in the high iron group ( 3.3 + /- 0.9 ) than in the normal iron group ( 2.5 + /- 0.9 ) . CONCLUSION In terms of cognitive outcome , there is no advantage associated with elevated iron intake for low birth weight infants OBJECTIVE A r and omized , double-blind study was conducted comparing high-iron content ( 15 mg/L ) with low-iron content ( 3 mg/L ) premature formula given during initial hospitalization to infants with birth weights less than 1800 g to determine the influence of these differing intakes on the iron nutritional status during the first 4 months of life . A third group of similar infants received human milk mixed with an equal volume of liquid fortifier result ing in an iron content of approximately 1.7 mg/L. PATIENTS AND METHODS Mean birth weight , gestational age , age at study entry , volume of blood removed for studies , and volume of red cells transfused were not different among the three groups . After hospitalization both formula-fed groups were given a cow milk formula with an iron content of 12 mg/L , and breast-fed infants were given an iron-containing multivitamin with a result ing iron intake of 10 mg/d . Infants were observed to 8 weeks after discharge . RESULTS There were no differences in serum iron , ferritin , transferrin , transferrin saturation , hemoglobin , hematocrit , or reticulocyte count among the three groups at study entry , although mean corpuscular hemoglobin and mean corpuscular volume were lower in infants in the low-iron formula group . Mean plasma ferritin was significantly lower in infants receiving low-iron content premature formula at the time of hospital discharge compared with the other two groups . The incidence of anemia ( hemoglobin < 9.0 g/dL ) and low transferrin saturation ( < 24 % ) was also greater in the low-iron content formula group . Eight weeks after discharge , the incidence of low plasma ferritin ( < 19 ng/mL ) remained greater in infants receiving low-iron content formula than in the other two groups . No adverse effects of iron intake were observed . Growth was not different among the three groups . CONCLUSIONS These data indicate that preterm infants with < 1800 g birth weight receiving premature infant formula benefit from formula given during initial hospitalization containing 15 mg/L iron compared with that containing 3 Objective : The objective of this study was to determine the effect of incrementally higher doses of iron on the zinc protoporphyrin to heme ratio ( ZnPP/H ) and serum ferritin , and developmental outcomes in premature infants at risk for iron deficiency . Study Design : Infants eligible for this prospect i ve , r and omized blinded trial were between 27 and 30 completed weeks of gestation , older than 1 week of age and tolerating 100 ml kg−1 per day of enteral feedings . The control group was treated with 2.2 mg kg−1 per day of ferrous sulfate and the treatment group was treated with 3 to 12 mg kg−1 per day based on the ZnPP/H. Infants had follow-up with Bayley exams at 6 and 24 months corrected age . Statistical evaluation included Student ’s t-tests and Fisher ’s exact test . Result : Eighty-one infants were enrolled ( 40 control , 41 treatment ) . The average total iron dose for the control group was 2.2 mg kg−1 per day and for the treatment group was 10.4 mg kg−1 per day ( P<0.05 ) . The ZnPP/H was not different between the two groups . The ferritin at the end of the study was decreased in the control group but remained stable in the treatment group ( control initial 202±109 ng ml−1 , final 168±141 ng ml−1 ( P<0.05 ) ; treatment initial 187±131 ng ml−1 , final 176±118 ng ml−1 ) . At 24 months , infants with psychomotor development index < 85 occurred in 25 % of the subjects in the control group and in 7 % of subjects in the treatment group in a post hoc analysis ( odds ratio , 4.2 ; 95 % confidence interval , 0.7 to 43 , P=0.07 ) . Conclusion : The ZnPP/H may not be a reliable marker of iron status when used in a short period of time during iron supplementation . Infants treated with a lower dose of ferrous sulfate had a decreasing serum ferritin and a trend toward increased motor delays at 24 months Objectives : Low-birth-weight ( LBW ) infants ( < 2500 g ) have an increased risk of iron deficiency ( ID ) during their first 6 months of life . The optimal dose and duration of iron supplementation to LBW infants are , however , unknown . The objective of the present study was to investigate the long-term effect on iron status and growth in marginally LBW ( 2000–2500 g ) infants , of iron supplements given until 6 months of life . Methods : In a r and omized controlled trial , 285 healthy marginally LBW infants received  0 , 1 , or 2 mg · kg−1 · day−1 of iron supplements from 6 weeks to 6 months of age . At 12 months and 3.5 years of life we measured length , weight , head circumference , and indicators of iron status ( hemoglobin , ferritin , mean corpuscular volume , and transferrin saturation ) and assessed the prevalence of iron depletion , functional ID , and ID anemia . Results : At 12 months of age , there was a significant difference in ferritin between the groups ( P = 0.006 ) . Furthermore , there was a significant difference in the prevalence of iron depletion ( 23.7 % , 10.6 % , and 6.8 % , respectively , in the placebo , 1-mg , and 2-mg groups , P = 0.009 ) and similar nonsignificant trends for functional ID and ID anemia . At 3.5 years of life there were no significant differences in iron status and the mean prevalence of iron depletion was 3.2 % . Anthropometric data were not affected by the intervention . Conclusions : Iron supplements with 2 mg · kg−1 · day−1 until 6 months of life effectively reduces the risk of ID during the first 12 months of life and is an effective intervention for preventing early ID in marginally LBW infants
CONTEXT Enteral iron supplementation in preterm infants is recommended to supply sufficient iron for growth and development without increasing the risk of iron overload .
However , the current recommendations date from 2010 and are based on limited evidence .
OBJECTIVE This systematic review aim ed to investigate the effects of enteral iron supplementation on iron status , growth , neurological development , and adverse clinical outcomes in preterm ( < 37 weeks ' gestation ) and low-birth-weight ( LBW , < 2500 g ) infants .