Published online August 31, 2007
PEDIATRICS Vol. 120 No. 3 September 2007, pp. 538-546 (doi:10.1542/peds.2007-0495)
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow P3Rs: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when P3Rs are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Steinmacher, J.
Right arrow Articles by Franz, A. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Steinmacher, J.
Right arrow Articles by Franz, A. R.
Related Collections
Right arrow Blood

ARTICLE

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

Jochen Steinmacher, MDa,b, Frank Pohlandt, MD, MSa, Harald Bode, MDb, Silvia Sander, MSc, Martina Kron, PhDc and Axel R. Franz, MDa,d

a Divisions of Neonatology and Pediatric Critical Care
b Pediatric Neurology, Department of Pediatrics
c Institute of Biometrics, University of Ulm, Ulm, Germany
d Department of Neonatology, Center for Pediatrics, University of Bonn, Bonn, Germany


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
BACKGROUND. 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.

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 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.

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 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.

Key Words: neurocognitive outcome • preterm infant • very low birth weight • iron deficiency • iron supplementation

Abbreviations: GMFCS—Gross Motor Function Classification Scale • LOS-KF 18—Lincoln-Oseretzky Scale (Short Form) 18 • MPC—Mental Processing Composite • KABC—Kaufmann Assessment Battery for Children • OR—odds ratio • CI—confidence interval

Iron deficiency in infancy is associated with short-term1,2 and long-term3–8 neurodevelopmental deficits, delayed maturation of the auditory brainstem response,9,10 and abnormalities of memory11 and behavior,6,12 despite adequate correction of the initial iron deficit. The long-lasting neural and behavioral effects of iron deficiency in infancy have recently been reviewed.13

Iron supplementation of term infants at risk of iron deficiency is associated with improved neurodevelopmental outcome at 12 and 24 months of age.14–17 Because small preterm infants are susceptible to iron deficiency because of their small iron store at birth,18,19 their high growth velocity, and the iron losses caused by frequent blood sampling, we hypothesized that iron supplementation of preterm infants may also be associated with improved neurodevelopmental outcomes.

We previously showed in a randomized trial that early enteral iron supplementation in infants with a birth weight <1301 g is feasible and safe, and may reduce the incidence of iron deficiency and the number of late blood transfusions.20 However, the effect of early enteral iron supplementation on neurodevelopment is unknown in these very preterm infants. Because preterm infants may be particularly vulnerable to oxygen radical injury,21,22 iron supplementation may theoretically even be harmful for the premature brain.

The aim of this study, therefore, was to examine whether early enteral iron supplementation improves long-term neurocognitive and motor development in very preterm infants with a birth weight of <1301 g.

The initial randomized trial was designed to evaluate the effects of early enteral iron supplementation on iron status and iron deficiency and not on long-term neurocognitive development. This follow-up study was, therefore, not sufficiently powered to detect small, but potentially clinically relevant, differences between the treatment groups.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
The initial randomized trial and our follow-up study were both approved by the institutional review board of the University of Ulm, and written parental consent was obtained for both studies.

Study Subjects
Eligible were all inborn infants with a birth weight of <1301 g admitted to the University of Ulm level 3 NICU between June 1996 and June 1999. Exclusion criteria were major anomalies, hemolytic disease, twin-to-twin transfusion syndrome, and missing parental consent. For the trial profile and details of the trial interventions and statistical analyses please refer to Franz et al.20 In the initial randomized trial, of 380 eligible infants with a birth weight of <1301 g, 108 were excluded because parents refused consent, 68 were excluded on the basis of predefined exclusion criteria, 105 were randomly assigned to receive early enteral iron supplementation, and 99 were randomly assigned to receive late enteral iron supplementation.20

Randomization
Infants were assigned to 1 of 2 strata according to the need for blood transfusion within the first 7 days of life (stratum 1: no transfusion; stratum 2: ≥1 transfusion within the first 7 days of life). At day 7 of life, the infants were randomly allocated in blocks of 10 within each stratum to early or late enteral iron supplementation by using computer-generated randomization lists.

Treatment Groups
Early enteral iron supplementation was started at a dose of 2 mg/kg per day of ferrous sulfate as soon as 100 mL/kg per day of enteral feedings were reached.23 In 39 of 105 infants randomly assigned to early iron supplementation, the dose was increased to 4 mg/kg per day when the hematocrit fell below 0.30. Late enteral iron supplementation was started at 61 days of life at a dose of 2 mg/kg per day.24 If iron deficiency was diagnosed at any time throughout the study, iron was started at 4 mg/kg per day.

Enteral iron supplementation was started at a median age of 14 days (range: 7–61 days) in the early-iron group versus 61 days (range: 12–74 days) in the late-iron group.20 In both groups, iron was administered with the milk feeds,25 erythropoietin was not administered, and restrictive red cell transfusion guidelines were followed.26 Of a total of 306 red cell transfusions, only 10 (6 in the early-iron group and 4 in the late-iron group) were not in agreement with the transfusion guidelines.

Primary End Points, Sample Size, and Blinding of the Initial Randomized Trial
Primary outcome variables were (1) ferritin level at 61 days of life and (2) the number of infants who fulfilled the criteria of iron deficiency at any time throughout the study.

A sample-size calculation revealed that 63 patients were required per group.20 Because of death, early discharge, or referral to affiliated hospitals, 204 patients had to be randomly assigned to evaluate 133 infants who completed the initial protocol.

The study was performed as a masked study: the laboratory personnel who handled the blood samples were unaware of treatment-group assignment, and the primary outcome variables were objective, predefined laboratory criteria. Double-blinding for enteral iron supplementation was impossible because of the effect on stool color.

Follow-up
All surviving infants were followed. At 5 years of age, the infants were contacted by mail (twice) and telephone (if necessary) to arrange for a follow-up examination.

Of the initially randomly assigned 204 infants, 6 died during their initial hospitalization, and 4 died after discharge from the hospital. Of the surviving 194 infants, 164 (85%) were evaluated. Thirty infants were not evaluated because 5 (3%) refused participation, and 12 (6%) were unable to attend because the family had moved, had no means of transportation, or did not come to several (at least 3) appointments for various reasons, and 13 (7%) were lost to follow-up.

Standardized Follow-up Assessment
The neurologic examination and all neurophysiological testing was performed by an experienced pediatric neurologist (Dr Steinmacher) who was blinded to the infants' treatment-group assignment.

The neurologic examination was rated as normal, mildly abnormal (in the presence of minor neurologic signs, such as broad gait, dysdiadochokinesis, or dysmetria) and severely abnormal (in the presence of any paresis with or without spasticity, any cerebral nerve palsy, or any ataxia).

For evaluation of mobility, that is, the motor functioning, the Gross Motor Functioning Classification Scale (GMFCS)27 was performed. A score of 0 represents normal mobility, 1 represents mild abnormality (ie, walking, running, jumping are possible but somewhat reduced in precision and velocity). A score of 2, 3, or 4 represent obviously and severely impaired mobility and the lack of individual mobility, respectively.

To assess motor coordination, the Lincoln-Oseretzky Scale (Short Form) 18 (LOS-KF 18)28 was applied. The test consists of 18 tasks including walking backward, standing on 1 foot, touching one's nose, jumping, throwing, catching, clapping, balancing tiptoe, and so on. Different reference values are available for this test for children with a mental processing composite (MPC) of <71, 71 to 85, and >85. Abnormal motor coordination was defined as an LOS-KF 18 score in the ≤3rd percentile.

For evaluation of the cognitive function the Kaufmann Assessment Battery for Children (KABC) was performed. The KABC comprises 2 summative scales: (1) the MPC, a global measure of cognitive ability in 2 subscales, sequential processing, and simultaneous processing, and (2) the achievement scale, an assessment of knowledge of facts, language concepts, and school-related skills. The range of possible scores for both scales is 40 to 150. The test was last standardized in 1992 to a mean of 100 and an SD of 15 in a German reference population.29 The MPC can be interpreted similarly to an IQ test. Children whose severe cognitive impairment or disability precluded the use of this assessment tool were assigned a score of 30 if minimal speech and the ability for minimal communication with the parents were present, and a score of 20 if no speech was present but at least minimal sensory or motor achievements were elicited.

Assessment of visual impairment was based on ophthalmologic records, and visual acuity was evaluated by standard visual acuity charts. Severe visual impairment was defined as a refractory error in ≥1 eye of more than ±10 diopter or any amblyopia defined as a best-corrected visual acuity of <20/40. A visual acuity after best-possible correction for ametropia <20/200 was defined as blindness.

Visual perception was assessed in children who achieved a MPC on KABC of >85 by applying the scales of visual perception of the Tübinger Lurija Christensen neurophysiological examination for children.30 This test includes evaluation of eye-motor coordination, spatial orientation (position in space and spatial relationship), and pattern recognition. Raw scores are obtained and then converted to age-adjusted percentiles. Visual perception was defined as impaired if the child scored in the <15th percentile of a previously published cohort of normal children31 in all subscales.

To assess developmental abnormalities in childhood behavior, the parents were asked to complete the Child Behavior Check List for 4- to 18-year-old children in its German adaptation of 1994.32 Parents completed a questionnaire regarding their child's performance in games, activities, chores, and the quality of relationships with friends and family. A total of 113 items related to behavior had to be scored on a 3-point scale ranging from not true (0), somewhat true (1), to often true (2). A total problem score was obtained by summing all items. Raw scores were converted to age-standardized scores (t scores [mean: 50; SD: 10]). Higher scores indicate more behavioral problems: t scores of >70 and >63 defined abnormal behavior in each subscale and in the summary scales of total problems and internalizing and externalizing behavior, respectively.

Composite Outcome Criteria
Severe disability was defined as any of the following: an abnormal neurologic examination resulting in severely impaired mobility (GMFCS: >1), severe cognitive impairment (MPC: <51), hearing loss requiring amplification, or blindness. Provided that none of the previously mentioned criteria for classification as severe disability were met, moderate disability was defined as any of the following: any abnormal neurologic examination associated with a detectable impairment of mobility (GMFCS: 1), cognitive impairment (MPC: 51–70), or any severe impairment of vision. Provided that none of the above mentioned criteria for classification as severe or moderate disability were met, mild disability was defined as any abnormal neurologic examination result with normal mobility (GMFCS: 0) and/or an MPC of 71 to 85.

The absence of significant impairment (without disability) was defined as normal neurologic examination, normal mobility (GMFCS: 0), and normal cognitive development (MPC: >85), and the absence of severe hearing and visual impairment.

Recommendations for school assignment were based on the previously described evaluations and the ability to compensate impairments; that is, everyday functioning of the children. In general, an MPC of >85 and absence of any severe impairment were required. If impairments were present, these had to be compensated.

Statistical Analyses
For qualitative data, counts and percentages were calculated; for quantitative data, the mean, SD, median, minimum, and maximum were calculated.

Categorical variables were compared between the patient group with early and the patient group with late iron supplementation with {chi}2 test, or in case of small numbers with Fisher's exact test, continuous variables were compared with the Wilcoxon test.

Associations between risk factors and poor neurodevelopmental outcome were described by odds ratios (ORs) adjusted for treatment-group assignment with a 95% confidence interval (CI) and a P value of the {chi}2 test from a logistic regression. The following risk factors were evaluated: gestational age, gender, multiple birth, severe intraventricular or periventricular hemorrhage (≥3°), periventricular leukomalacia, severe retinopathy of prematurity (≥3°), need for mechanical ventilation, intrauterine growth retardation, language, and maternal education.

Multiple logistic regression with forward selection (selection level: 5%) was performed to identify important risk factors with simultaneous value for prediction among the previously mentioned risk factors for poor neurodevelopmental outcome adjusted for assignment to late versus early iron supplementation. ORs with 95% CIs and P values were calculated. The value for prediction of outcome of the important risk factors identified was assessed by the area under the receiver operating characteristic curve.

All analyses were performed with SAS 9.0 (SAS Institute, Cary, NC).


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
A total of 164 (85%) of 194 surviving initially randomly assigned children completed the follow-up assessment at a median corrected age of 5.3 years (range: 4.7–6.6 years). The demographic data and neonatal morbidities of these 164 infants and of the 30 infants who were lost to follow-up are summarized according to treatment-group assignment in Table 1. Infants lost to follow-up were similar to infants with complete follow-up. In the infants with complete follow-up, there were no differences in any prenatal or perinatal variable between the 2 treatment groups.


View this table:
[in this window]
[in a new window]

  		TABLE 1 Demographic and Neonatal Morbidity Data

 
In the late-iron group, 8 infants with complete follow-up received the first dose of enteral iron "early" (ie, at days of life 12, 32, 40, 41, 41, 42, 43, and 46) according to the study protocol on the basis of predefined criteria of iron deficiency.20 In the early-iron group, 11 infants with complete follow-up received the first dose of enteral iron >1 week too late (ie, at the days of life 16, 18, 21, 21, 26, 27, 28, 31, 37, 51, and 61). In these infants, iron was started late because the staff forgot to initiate supplementation as soon as enteral nutrition of >100 mL/kg per day was reached.

Table 2 summarizes the main outcome data. First, there were more infants with an abnormal result on standardized neurologic examination in the group receiving late enteral iron supplementation. This difference was mainly because of an increased number of infants with mild neurologic abnormalities (19 of 74 in the late-iron and 11 of 90 in the early-iron group; P = .04). Second, there were suggestive trends toward improved cognitive development with early iron supplementation in the overall MPC, the subscale of simultaneous processing, and the achievement scale of the KABC.


View this table:
[in this window]
[in a new window]

  		TABLE 2 Outcome Data

 
There was no difference in the proportion of children with impaired motor coordination; the incidence of an LOS-KF 18 score in the ≤3rd percentile was 25 (28%) in the early-iron group and 20 (27%) in the late-iron group (P = .93). The number of infants with abnormal behavior according to the Child Behavior Checklist was also similar in both groups: 17 (20%) of 87 vs 13 (19%) of 67 (P = .98).

In children with normal MPC (>85; n = 115), the incidence of impaired visual perception was 7 (11%) of 66 in the early-iron group versus 5 (10%) of 49 in the late-iron group (P = .97).

A total of 133 infants completed the initial randomized trial per protocol. One of these infants died after completion of the trial, 115 (87% of the survivors) were reevaluated with similar results as in the intention-to-treat population described earlier (data available on request).

Table 3 presents the crude OR of late versus early iron supplementation as a risk factor for moderate or severe disability and for cognitive impairment along with the adjusted ORs for several prenatal and perinatal risk factors for poor neurodevelopmental outcome.


View this table:
[in this window]
[in a new window]

  		TABLE 3 ORs of Risk Factors for Mildly or Severely Abnormal Neurologic Examination, for Moderate or Severe Disability, and for Cognitive Impairment (MPC < 71) Adjusted for Assignment to Late Versus Early Iron Supplementation

 
The results of multiple logistic regression analyses evaluating the effect of early versus late enteral iron supplementation with variable selection of the risk factors listed in Table 3 are summarized in Table 4. In the final model, late versus early iron supplementation was not an important risk factor with additional value for prediction for impaired outcome. The areas under the receiver operating characteristic curve for the logistic models of mildly or severely abnormal neurologic examination, of moderate or severe disability, and of cognitive impairment (MPC: <71) were 0.739, 0.861, and 0.869, respectively.


View this table:
[in this window]
[in a new window]

  		TABLE 4 Results of Multiple Logistic Regression With Forward Selection of Risk Factors for Mildly or Severely Abnormal Neurologic Examination, for Moderate or Severe Disability, and for Cognitive Impairment (MPC <71) Adjusted for Assignment to Late Versus Early Iron Supplementation

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
Preterm infants are at risk of impaired neurodevelopmental outcome,34–36 and additional efforts to identify effective interventions to improve outcome in these vulnerable children are required, although it is unlikely that a single therapeutic approach will improve long-term outcome to a major degree.

Thus far, iron supplementation of preterm infants has only been shown to be an effective component to prevent and/or treat anemia of prematurity.20,23 We hypothesized that iron supplementation administered early to prevent iron deficiency may also be a successful strategy to improve long-term neurodevelopmental outcome in preterm infants on the basis of the following observations.

Iron deficiency is common in unsupplemented preterm infants as outlined previously, and iron deficiency is associated with impaired neurodevelopmental outcome. The negative effects of iron deficiency during infancy and childhood on neurodevelopment may at least in part be long-lasting or even irreversible despite adequate treatment of iron deficiency.3–12 Similarly, iron deficiency during intrauterine development seems to have long-lasting negative effects on neurodevelopment (reviewed by Lozoff and Georgieff37), because decreased umbilical cord serum ferritin levels were associated with poorer neurobehavioral status at 37 weeks' postmenstrual age38 and impaired mental and psychomotor development at 5 years of age.39 Furthermore, infants of diabetic mothers who have decreased iron stores, defined as umbilical cord serum ferritin levels of <35 µg/L, had abnormal auditory recognition memory and a lower physical developmental index at 1 year of age.11,40 Finally, low levels of neonatal hemoglobin, serum iron, and or ferritin in cord blood were associated with higher levels of negative emotionality, and lower levels of alertness and soothability.41

Our hypothesis, that early iron supplementation of preterm infants may improve neurodevelopmental outcome, was further supported by the fact that iron supplementation of term infants at risk of iron deficiency improves neurodevelopmental outcome at 12 and 24 months of age.14–17

In our study, early enteral iron supplementation was associated with fewer long-term neurologic abnormalities on standardized physical examination and trends toward improved outcomes on formal assessment of mental processing (Table 2). These findings may reflect long-term consequences of perinatal iron deficiency previously observed by others38–41 and may be related to negative effects of perinatal iron deficiency on myelination, brain iron content, striatal and hippocampal organization, and neurotransmitter metabolism observed in rodent models of perinatal iron deficiency (recently reviewed in37). However, taking into account that multiple comparisons were made, the findings of our study have to be interpreted with caution.

The lack of more obvious beneficial results of early iron supplementation may have several explanations. First, there may be no benefit (and the previously mentioned results are chance findings). Second, our initial randomized trial was designed to examine effects of early iron supplementation on iron stores, the incidence of iron deficiency, and the need for blood transfusions and not to evaluate long-term neurodevelopmental outcome. The study was, therefore, underpowered to detect small but clinically important differences in long-term outcome data between groups. To have 80% power to demonstrate at a 2-sided significance level of 5% in a confirmatory trial that early iron supplementation does indeed improve neurodevelopment assuming a degree suggested in the present sample (eg, effect size for the MPC = 0.2 [ie, difference of the means divided by SD]) a sample size of n = 394 infants per treatment group would be required. One may argue that an effect size of 0.2 is negligible and not worth pursuing. On the other hand, it is unlikely that any single intervention in neonatal care will result in a higher standardized mean difference in the MPC, because the population and the associated problems are so heterogeneous.

Third, an oral dose of 4 to 6 mg/kg per day may have been insufficient to meet the iron needs of all growing preterm infants. In fact, despite increasing iron supplementation up to 4 mg/kg per day (in formula-fed infants up to 6 mg/kg per day) as soon as the hematocrit fell below 0.30, iron deficiency occurred in ~15% of infants in the early-iron group during the initial randomized trial.20 This is not surprising, considering that (1) only ~25% (range: 10%–50%) of enterally administered iron is absorbed,25,42 (2) the daily needs of growing preterm infants are thought to be ~0.5 to 1 mg/kg per day,43 and (3) that every milliliter of blood loss represents a loss of 0.35 to 0.5 mg of iron (assuming hemoglobin concentrations of 10–15 g/dL). Consequently, higher doses of enteral iron supplementation may be required to meet the needs of at least some preterm infants and to optimize neurodevelopmental outcome in this vulnerable population.

One of the concerns with iron supplementation is that free ferrous iron is thought to increase the production of free radicals (known as Fenton reaction) and thereby to increase oxidative stress especially in the premature infant who has a limited capacity to assimilate free iron and to degrade free radicals.21,22,44 Early iron supplementation of premature infants may therefore theoretically cause oxidative injury to the developing brain and consequently may result in impaired long-term neurodevelopment. However, there was no evidence of such an adverse effect after early enteral iron supplementation in our sample. This is in agreement with the fact that, to our knowledge, enteral iron supplementation has not yet been shown to increase surrogate markers of oxidative injury in preterm infants.45,46 However, the sample size of our study was insufficient to detect infrequent adverse effects of early enteral iron supplementation.

The main limitations of this study were the insufficient sample size as mentioned earlier and the fact that the evaluation of the effects on neurodevelopmental outcome was not considered when the initial randomized trial was designed. The results of this study, therefore, do not confirm but may support the hypothesis that early enteral iron supplementation improves neurocognitive and motor development in very preterm infants.

Furthermore, because the study was conducted at a single institution, the results may not have general validity and require verification by a larger multicenter trial.

On the basis of the results reported and discussed earlier, such a multicenter trial of iron supplementation in preterm infants should aim to evaluate measures of myelination (eg, latency in brainstem-evoked response audiometry9,10), hippocampal function, that is, memory (eg, auditory recognition memory in response to mother's voice11), frontal lobe function, that is, emotionality and behavior (as described in detail in12,17,47,48) in addition to standardized neurologic examination, and global evaluation of motor and neurocognitive development.

On the basis of the results of our study, the incidence of an abnormal result on standardized neurologic examination should be chosen as primary outcome variable. Assuming an OR of 1.8 (Table 4), a 2-sided significance level of .05, a power of 80%, and an incidence of abnormal neurologic examination of 19% in the early-iron group (Table 2), a sample-size calculation revealed that 252 infants would be required per group for such a trial.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
This long-term follow-up study after a randomized trial of early versus late enteral iron supplementation in very preterm infants with a birth weight <1301 g showed trends toward improved neurodevelopmental outcome in the early-iron group. These trends and the reduction of late blood transfusion observed during the initial trial20 suggest that early enteral iron supplementation may do more good than harm. However, additional sufficiently powered trials on the long-term effects of early enteral iron supplementation in very preterm infants are required to test this hypothesis.


   ACKNOWLEDGMENTS
 
This study was supported by the Else-Kröner-Fresenius Foundation (Bad Homburg, Germany) and the Rudolf and Clothilde Eberhardt Foundation (Ulm, Germany).


   FOOTNOTES
 
Accepted Apr 25, 2007.

Address correspondence to Axel R. Franz, MD, Department of Neonatology, Center for Pediatrics, University Women's Hospital, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany. E-mail: axel.franz{at}ukb.uni-bonn.de

The authors have indicated they have no financial relationships relevant to this article to disclose.

This trial has been registered at www.clinicaltrials.gov (identifier NCT00457990).


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

  1. Lozoff B, Brittenham GM, Wolf AW, et al. Iron deficiency anemia and iron therapy effects on infant developmental test performance [published correction appears in Pediatrics. 1988;81:683]. Pediatrics. 1987;79 :981 –995[Abstract/Free Full Text]
  2. Walter T, De Andraca I, Chadud P, Perales CG. Iron deficiency anemia: adverse effects on infant psychomotor development. Pediatrics. 1989;84 :7 –17[Abstract/Free Full Text]
  3. Palti H, Meijer A, Adler B. Learning achievement and behavior at school of anemic and non-anemic infants. Early Hum Dev. 1985;10 :217 –223[CrossRef][ISI][Medline]
  4. Lozoff B, Jimenez E, Wolf AW. Long-term developmental outcome of infants with iron deficiency. N Engl J Med. 1991;325 :687 –694[Abstract]
  5. Hurtado EK, Claussen AH, Scott KG. Early childhood anemia and mild or moderate mental retardation. Am J Clin Nutr. 1999;69 :115 –119[Abstract/Free Full Text]
  6. Lozoff B, Jimenez E, Hagen J, Mollen E, Wolf AW. Poorer behavioral and developmental outcome more than 10 years after treatment for iron deficiency in infancy. Pediatrics. 2000;105 (4). Available at: www.pediatrics.org/cgi/content/full/105/4/e51
  7. Lozoff B, Jimenez E, Smith JB. Double burden of iron deficiency in infancy and low socioeconomic status: a longitudinal analysis of cognitive test scores to age 19 years. Arch Pediatr Adolesc Med. 2006;160 :1108 –1113[Abstract/Free Full Text]
  8. Shafir T, Angulo-Barroso R, Calatroni A, Jimenez E, Lozoff B. Effects of iron deficiency in infancy on patterns of motor development over time. Hum Mov Sci. 2006;25 :821 –838[CrossRef][ISI][Medline]
  9. Roncagliolo M, Garrido M, Walter T, Peirano P, Lozoff B. Evidence of altered central nervous system development in infants with iron deficiency anemia at 6 mo: delayed maturation of auditory brainstem responses. Am J Clin Nutr. 1998;68 :683 –690[Abstract]
  10. Algarin C, Peirano P, Garrido M, Pizarro F, Lozoff B. Iron deficiency anemia in infancy: long-lasting effects on auditory and visual system functioning. Pediatr Res. 2003;53 :217 –223[CrossRef][ISI][Medline]
  11. Siddappa AM, Georgieff MK, Wewerka S, Worwa C, Nelson CA, Deregnier RA. Iron deficiency alters auditory recognition memory in newborn infants of diabetic mothers. Pediatr Res. 2004;55 :1034 –1041[CrossRef][ISI][Medline]
  12. Corapci F, Radan AE, Lozoff B. Iron deficiency in infancy and mother–child interaction at 5 years. J Dev Behav Pediatr. 2006;27 :371 –378[CrossRef][ISI][Medline]
  13. Lozoff B, Beard J, Connor J, Barbara F, Georgieff M, Schallert T. Long-lasting neural and behavioral effects of iron deficiency in infancy. Nutr Rev. 2006;64 :S34 –S43[CrossRef][ISI][Medline]
  14. Moffatt ME, Longstaffe S, Besant J, Dureski C. Prevention of iron deficiency and psychomotor decline in high-risk infants through use of iron-fortified infant formula: a randomized clinical trial. J Pediatr. 1994;125 :527 –534[CrossRef][ISI][Medline]
  15. Williams J, Wolff A, Daly A, MacDonald A, Aukett A, Booth IW. Iron supplemented formula milk related to reduction in psychomotor decline in infants from inner city areas: randomised study [published correction appears in BMJ. 2000;321:23]. BMJ. 1999;318 :693 –697[Abstract/Free Full Text]
  16. Friel JK, Aziz K, Andrews WL, Harding SV, Courage ML, Adams RJ. A double-masked, randomized control trial of iron supplementation in early infancy in healthy term breast-fed infants. J Pediatr. 2003;143 :582 –586[CrossRef][ISI][Medline]
  17. Lozoff B, De Andraca I, Castillo M, Smith JB, Walter T, Pino P. Behavioral and developmental effects of preventing iron-deficiency anemia in healthy full-term infants [published correction appears in Pediatrics. 2004;113:1853]. Pediatrics. 2003;112 :846 –854[Abstract/Free Full Text]
  18. Widdowson EM, Spray CM. Chemical development in utero. Arch Dis Child. 1951;26 :205 –215[ISI][Medline]
  19. Hågå P. Plasma ferritin concentrations in preterm infants in cord blood and during the early anaemia of prematurity. Acta Paediatr Scand. 1980;69 :637 –641[ISI][Medline]
  20. Franz AR, Mihatsch WA, Sander S, Kron M, Pohlandt F. Prospective randomized trial of early versus late enteral iron supplementation in infants with a birth weight of less than 1301 grams. Pediatrics. 2000;106 :700 –706[Abstract/Free Full Text]
  21. Lackmann GM, Schnieder C, Bohner J. Gestational age-dependent reference values for iron and selected proteins of iron metabolism in serum of premature human neonates. Biol Neonate. 1998;74 :208 –213[CrossRef][ISI][Medline]
  22. Sullivan JL Iron, plasma antioxidants, and the "oxygen radical disease of prematurity. " Am J Dis Child. 1988;142 :1341 –1344[Medline]
  23. Lundström U, Siimes MA, Dallman PR. At what age does iron supplementation become necessary in low-birth-weight infants? J Pediatr. 1977;91 :878 –883[ISI][Medline]
  24. American Academy of Pediatrics, Committee on Nutrition. Nutritional needs of low-birth-weight infants. Pediatrics. 1985;75 :976 –986[Abstract/Free Full Text]
  25. McDonald MC, Abrams SA, Schanler RJ. Iron absorption and red blood cell incorporation in premature infants fed an iron-fortified infant formula. Pediatr Res. 1998;44 :507 –511[ISI][Medline]
  26. Franz AR, Pohlandt F. Red blood cell transfusions in very and extremely low birthweight infants under restrictive transfusion guidelines: is exogenous erythropoietin necessary. Arch Dis Child Fetal Neonatal Ed. 2001;84 :F96 –F100[Abstract/Free Full Text]
  27. Palisano R, Rosenbaum P, Walter S, Russell D, Wood E, Galuppi B. Development and reliability of a system to classify gross motor function in children with cerebral palsy. Dev Med Child Neurol. 1997;39 :214 –223[ISI][Medline]
  28. Luer G, Cohen R, Eggert D. Determination of motor ability in handicapped children by use of a Hamburg version of the Lincoln-Oseretzky motor development scale [in French]. Prax Kinderpsychol Kinderpsychiatr. 1970;19 :18 –25[ISI][Medline]
  29. Melchers P, Preuss U. Adaptation of the Kaufman Assessment Battery for Children for German- speaking areas. Part 1: Introduction of the battery [in German]. Z Kinder Jugendpsychiatr. 1992;20 :85 –93[ISI][Medline]
  30. Deegener B. Neuropsychological Diagnostics in Children and Adolescents [in German]. Weinheim, Germany: Beltz; 1992
  31. Steinmacher J, Storck M, Fingerle J, Gräβle A, Kupferschmid C, Bode H. Diagnosis of partial cognitive deficits in 5-year-old children [in German]. Kinder Jugendarzt. 2002;33 :638 –642
  32. Dopfner M, Schmeck K, Berner W, Lehmkuhl G, Poustka F. Reliability and factorial validity of the Child Behavior Checklist: an analysis of a clinical and field sample [in German]. Z Kinder Jugendpsychiatr. 1994;22 :189 –205[ISI][Medline]
  33. International Neonatal Network. The CRIB (Clinical Risk Index for Babies) score: a tool for assessing initial neonatal risk and comparing performance of neonatal intensive care units. Lancet. 1993;342 :193 –198[CrossRef][ISI][Medline]
  34. Hack M, Taylor HG, Klein N, Eiben R, Schatschneider C, Mercuri Minich N. School-age outcomes in children with birth weights under 750 g. N Engl J Med. 1994;331 :753 –759[Abstract/Free Full Text]
  35. Vohr BR, Allan WC, Westerveld M, et al. School-age outcomes of very low birth weight infants in the indomethacin intraventricular hemorrhage prevention trial. Pediatrics. 2003;111 (4). Available at: www.pediatrics.org/cgi/content/full/111/4/e340
  36. Marlow N, Wolke D, Bracewell MA, Samara M. Neurologic and developmental disability at six years of age after extremely preterm birth. N Engl J Med. 2005;352 :9 –19[Abstract/Free Full Text]
  37. Lozoff B, Georgieff MK. Iron deficiency and brain development. Semin Pediatr Neurol. 2006;13 :158 –165[CrossRef][Medline]
  38. Armony-Sivan R, Eidelman AI, Lanir A, Sredni D, Yehuda S. Iron status and neurobehavioral development of premature infants. J Perinatol. 2004;24 :757 –762[CrossRef][Medline]
  39. Tamura T, Goldenberg RL, Hou J, et al. Cord serum ferritin concentrations and mental and psychomotor development of children at five years of age. J Pediatr. 2002;140 :165 –170[CrossRef][ISI][Medline]
  40. Nelson CA, Wewerka SS, Borscheid AJ, Deregnier RA, Georgieff MK. Electrophysiologic evidence of impaired cross-modal recognition memory in 8-month-old infants of diabetic mothers. J Pediatr. 2003;142 :575 –582[CrossRef][ISI][Medline]
  41. Wachs TD, Pollitt E, Cueto S, Jacoby E, Creed-Kanashiro H. Relation of neonatal iron status to individual variability in neonatal temperament. Dev Psychobiol. 2005;46 :141 –153[CrossRef][ISI][Medline]
  42. Widness JA, Serfass RE, Haiden N, Nelson SE, Lombard KA, Pollak. A Erythrocyte iron incorporation but not absorption is increased by intravenous iron administration in erythropoietin-treated premature infants. J Nutr. 2006;136 :1868 –1873[Abstract/Free Full Text]
  43. Friel JK, Andrews WL, Hall MS, et al. Intravenous iron administration to very-low-birth-weight newborns receiving total and partial parenteral nutrition. JPEN J Parenter Enteral Nutr. 1995;19 :114 –118[Abstract]
  44. Inder TE, Clemett RS, Austin NC, Graham P, Darlow BA. High iron status in very low birth weight infants is associated with an increased risk of retinopathy of prematurity. J Pediatr. 1997;131 :541 –544[CrossRef][ISI][Medline]
  45. van Zoeren Grobben D, Moison RMW, Haasnoot AA. Iron containing feeding formula and oxidative stress in preterm babies. Pediatr Res. 1998;43 :270A
  46. Friel JK, Aziz K, Andrews WL, Serfass RE. Iron absorption and oxidant stress during erythropoietin therapy in very low birth weight premature infants: a cohort study. BMC Pediatr. 2005;5 :29[CrossRef][Medline]
  47. Perez EM, Hendricks MK, Beard JL, et al. Mother-infant interactions and infant development are altered by maternal iron deficiency anemia. J Nutr. 2005;135 :850 –855[Abstract/Free Full Text]
  48. Lozoff B, Corapci F, Burden MJ, et al. Preschool-aged children with iron deficiency anemia show altered affect and behavior. J Nutr. 2007;137 :683 –689[Abstract/Free Full Text]
PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow P3Rs: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when P3Rs are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Steinmacher, J.
Right arrow Articles by Franz, A. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Steinmacher, J.
Right arrow Articles by Franz, A. R.
Related Collections
Right arrow Blood