Vitamin E status in preterm infants fed human milk or infant formula. Iron nutritional status in preterm infants fed formulas fortified with iron. The effect of cobalt and iron salts on the anaemia of prematurity. Feeding iron-fortified premature formula during initial hospitalization to infants less than 1800 grams birth weight. Prospective randomized trial of early versus late enteral iron supplementation in infants with a birth weight of less than 1301 grams. Medicinal iron to low birth weight infants. At what age does iron supplementation become necessary in low-birth-weight infants? Vitamin E-dependent anemia in the premature infant. I. Effects of large doses of medicinal iron. Effect of a cobalt-iron mixture on the anemia of prematurity. Hematologic and selenium status of low-birth-weight infants fed formulas with and without iron. Vitamin E levels during early iron supplementation in preterm infants. Do all pre-term infants need iron supplements? IRON METABOLISM IN PREMATURE INFANTS. II. PREVENTION OF IRON DEFICIENCY. Early iron supplementation in very low birth weight infants--a randomized controlled trial. 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. Iron supplements reduce the risk of iron deficiency anemia in marginally low birth weight infants. Growth, efficacy, and safety of feeding an iron-fortified human milk fortifier. Anemia of the premature infant; a two-year study of the response to iron medication. Haematological effect of iron supplementation in breast fed term low birth weight infants. The effect of cobalt-iron therapy on the blood picture in premature infants. [On the use of iron in the treatment of premature infants].
Vitamin E status was assessed in 36 infants with birth weights less than 1500 gm who were assigned randomly to receive one of three sources of nutrition: milk obtained from mothers of preterm infants (preterm milk), mature human milk, or infant formula. Infants in each dietary group were further assigned randomly to receive iron supplementation (2 mg/kg/day) beginning at 2 weeks or to receive no iron supplementation. All infants received a standard multivitamin, providing 4.1 mg alpha-tocopherol daily. Serum vitamin E concentrations at 6 weeks were significantly related both to type of milk (P less than 0.0001) and to iron supplementation (P less than 0.05). Infants fed preterm milk had significantly higher serum vitamin E levels than did infants fed mature human milk, and both groups had significantly higher levels than did those fed formula. Ratios of serum vitamin E/total lipid were also significantly greater for infants fed human milks than for those fed formula. The addition of iron to all three diets resulted in significantly lower serum vitamin E levels at 6 weeks (P less than 0.05); however, only in the group fed formula was there evidence of vitamin E deficiency. Preterm milk with routine multivitamin supplementation uniformly resulted in vitamin E sufficiency in VLBW infants whether or not iron was administered. To prospectively 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.
                Healthy low birthweight preterm infants were randomly 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.
                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 vs B, p = 0.534).
                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. nan A randomized, 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 resulting in an iron content of approximately 1.7 mg/L.
                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 resulting iron intake of 10 mg/d. Infants were observed to 8 weeks after discharge.
                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.
                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 mg/L. 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.
                Infants were randomly 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 microg/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.
                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.
                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. Serum ferritin concentrations were measured during the first 6 months of life in 28 low birth weight infants (mean birth weight 1820 g range 900-2460; mean gestational age 34 weeks range 29-37) fed a standard formula fortified with ferrous sulphate. Fifteen of the infants received supplementary medicinal iron (ferrous succinate) from 3 weeks of age, and 13 only from 2 months of age. All were given vitamin E from 10 days of age. The serum ferritin values did not differ between the groups at 1-2 days, 8-10 weeks or at 6 months. Furthermore, there were no signs of hyperhaemolysis at 8-10 weeks in the group receiving medicinal iron early. The data indicate that the iron content in the formula is sufficient until 2 months of age, but also that thereis no disadvantage in starting medicinal iron at 3 weeks of age, if the diet is sufficient in vitamin E. Prevention of iron deficiency in low-birth-weight infants requires iron supplementation before neonatal iron stores are exhausted. In order to accurately determine when this depletion occurs, we measured the hemoglobin, mean corpuscular volume, serum iron/iron-binding capacity, and serum ferritin in 117 low-birth-weight infants (1,000 to 2,000 gm) from 0.5 until 6 months of age. All infants received banked breast milk in the hospital and breast milk or cow milk formula later; those with odd birth dates received 2 mg iron as ferrous sulfate/kg/day starting at 0.5 months; those with even birth dates received no additional iron unless they developed anemia. The results indicate that low-birth-weight infants who receive no supplemental iron may develop iron deficiency by three months of age and that a dose of iron of 2 mg/kg/day started at two weeks of age prevents iron deficiency without providing excess. nan nan Preterm infants with birth weights between 1,001 and 1,600 gm were randomly assigned at one week of age to three groups and fed a standard milk-based formula, the same formula with iron, or a soy-based formula with iron. Hematologic values and selenium status were then studied prospectively 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. On the basis of preliminary data, this larger bi-institutional continuation trial evaluating the efficacy and safety of early iron supplementation in preterm infants calls attention to the levels of vitamin E, a marker of antioxidant activity, during iron treatment. A total of 116 preterm infants were randomly assigned to receive at 2 or 4 weeks of age ( N = 62, N = 54, respectively) 5 mg/kg/d of nonionic iron polymaltose complex concomitantly with a daily dose of 25 IU vitamin E (as dl-alpha-tocopherol acetate) from 2 weeks of age. Vitamin E (alpha-tocopherol) levels, iron, ferritin, hemoglobin concentration, and reticulocyte count were recorded from 2 to 8 weeks of age. The morbidities of prematurity associated with free radicals formation were also documented. A gradual increase of alpha-tocopherol levels within physiological range (0.8 to 3.5 mg/dL) was found in the 2-week and 4-week groups during the study period with no difference among the groups ( P > 0.05 for all comparisons). At 8 weeks of age, iron and ferritin levels, hemoglobin concentration, and reticulocyte count were higher in the 2-week group. No correlation was observed between timing of both iron and vitamin E supplement and hemolysis or morbidities associated with prematurity. Thus, treatment of iron with vitamin E supplement at 2 weeks of age is, in our experience, an efficacious and safe treatment for improving anemia in preterm infants. nan nan To evaluate if supplementing iron at 2 weeks of age improves serum ferritin and/or haematological parameters at 2 months of life in very low birth weight (VLBW) infants.
                Preterm VLBW infants who received at least 100 mL/kg/day of oral feeds by day 14 of life were randomized to either 'early iron' (3-4 mg/kg/day orally from 2 weeks) or 'control' (no iron until 60 days) groups. Infants were followed up fortnightly and all morbidities were prospectively recorded. Serum ferritin was measured at 60 days by enzyme immunoassay method.
                Forty-six infants were included in the study; primary outcome was available for 42 infants.There was no difference in either serum ferritin (mean: 50.8 vs. 45.3 microg/L; adjusted difference in means: 5.8, 95% CI: -3.0, 14.6; p = 0.19) or haematocrit (32.5 +/- 5.3 vs. 30.8 +/- 6.3%; p = 0.35)at 60 days between the early iron and control groups. The magnitude of fall in serum ferritin from baseline to the end of study period was also not different between the groups (4.9 vs. 13.8 microg/L; difference in means: 8.8; 95% CI: -0.3, 17.9; p = 0.06). The requirement of blood transfusions (9.5 vs. 13%; p = 0.63) and a composite outcome of common neonatal morbidities (19% vs. 21.7%; p = 0.55) were also not different between the two groups.
                Supplementing iron at 2 weeks of age in preterm VLBW infants did not improve either serum ferritin or the haematological parameters at 2 months when compared to the standard practice of starting iron from 8 weeks of age. 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 randomly 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 [(micrograms/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 less than 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 less than 0.05) and NatFe (1858; 304: 95% confidence interval 150 to 492, p less than 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. Iron deficiency in early childhood may impair neurodevelopment. In a masked, randomized, 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.
                We sought to examine whether early enteral iron supplementation improves neurocognitive and motor development in these infants.
                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.
                Of the 204 infants initially randomized, 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.
                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 designed to evaluate effects on neurocognitive development, the power was insufficient to detect small but potentially clinically relevant improvements. Additional studies are required to confirm the trend towards a better outcome observed in the early iron group. 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.
                In a randomized 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.
                Iron supplementation resulted 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.
                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. 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 alpha-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 prospective, double-blind, randomized, 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).
                Infants who weighed < or =1500 g, had a gestational age < or =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 randomized 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.
                Of the 181 participating infants in this study, 96 received HMF-T and 85 received HMF-C. At randomization, 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 clinically 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.
                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. nan To determine the haematological effects of iron supplementation in predominantly breast fed term low birth weight (LBW) infants.
                Seventy three healthy term LBW (<2500 g), predominantly breast fed infants aged 50-80 days were randomised 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.
                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).
                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. nan nan
The available data suggest that infants who receive iron supplementation have a slightly higher haemoglobin level, improved iron stores and a lower risk of developing iron deficiency anaemia when compared with those who are unsupplemented. However, it is unclear whether iron supplementation in preterm and low birth weight infants has long term benefits in terms of neurodevelopmental outcome and growth. The optimum timing and duration of iron supplementation remains unclear.