Long et al.

BMC Pediatrics 2012, 12:99

http://www.biomedcentral.com/1471-2431/12/99

NEONATOLOGY Open Access

Benefits of Iron supplementation for low birth

weight infants: A systematic review
Hui Long, Jing-Mei Yi*, Pei-Li Hu, Zhi-Bin Li, Wei-Ya Qiu, Fang Wang and Sing Zhu

Abstract
Background: A number of studies have reported on the effects of iron supplementation in low birth weight
infants; however, no systematic review of the available evidence has been conducted to date. Hence, we
performed a systematic review of the literature to examine the effects of iron supplementation on hematologic iron
status, growth, neurodevelopment, and adverse effects in low birth weight/premature infants.
Methods: We searched the Cochrane Library, Medline, and PubMed for articles reporting on the effects of iron
supplementation in low weight infants. The following search terms were used: “preterm born infant(s)/children”;
“preterm infants”; “prematurely born children” “weight less than 1500 g at birth”; “born prematurely”; “low birth
weight infant(s)”; “infants born preterm”; “prematurity”; “small-for-gestational age”; “very small gestational age
infants”; “iron supplementation”; “iron intake”; “iron supplements”; “ferric and/or ferrous compounds”; and “ferrous
sulphate/fumarate/sulfate”.
Results: A total of 15 studies were identified and included in the systematic review. Supplemental iron was given
orally or as an iron-fortified formula in 14/15 studies. The duration of treatment ranged from 1 week to 18 months.
Iron supplementation significantly increased hematologic measures of iron status (including hemoglobin,
hematocrit, serum ferritin) relative to placebo or over time in most studies. All controlled studies that examined
iron-deficiency anemia (IDA)/ID reported a decreased prevalence of IDA/ID with iron supplementation. Dose
dependent decreases in the prevalence of IDA/ID were reported in several studies. Of the 5 studies reporting on
growth, none found any significant effect on growth-related parameters (length, height, weight, and head
circumference). Only 2 studies reported on neurodevelopment; no marked effects were reported. There were no
consistently reported adverse effects, including oxidative stress, inhibited nutrient absorption, morbidity, or the
requirement for blood transfusion.
Conclusion: The available data suggest that iron supplementation increases the levels of hematologic indicators of
iron status and reduces the prevalence of IDA/ID in low birth weight/premature infants. There is insufficient
evidence to make a definitive statement regarding the effects of iron supplementation on growth,
neurodevelopment, or the occurrence of adverse effects in low birth weight/premature infants.
Keywords: Anemia, Infant, Iron deficiency, Iron supplementation, Low birth weight

Background especially susceptible to developing iron deficiency anemia

Iron is an essential micronutrient that plays a critical (IDA) because these infants have smaller iron stores at birth
role in many cellular functions and processes, including and a greater iron requirement concurrent with a rapid in-
growth and development. As such, having an adequate crease in the red cell mass than term infants [2-5].
supply of iron, along with other micronutrients, is Increased hemolysis, shortened red blood cell lifespan, low
thought to be particularly important for infants [1]. Low circulating erythropoietin levels, blood sampling, and blood
birth weight infants, including premature infants, are loss associated with medical and surgical procedures may
all contribute to anemia in low birth weight and premature
infants.
* Correspondence: YIYijingmei1201@126.com
Department of Pediatrics, General Hospital of Chinese People’s Liberation
Army, #28 Fuxing Road, Haidian District, Beijing 100853, China

© 2012 LONG et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
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The potential consequences of IDA during infancy in- The search and inclusion and exclusion criteria were
clude impaired development [6-11] and altered longer term developed by an investigative team, including experts in
neurodevelopment [12-14]. Due to the high risk of IDA, the field of pediatric development and nutrient research.
iron supplementation is recommended for low birth weight Our team included a biostatistician who was instrumen-
infants [15]. Whether or not such supplementation is of tal in defining the criteria.
any benefit to low birth weight infants is unclear. Interes-
tingly, the findings from several systematic reviews / meta- Study Selection
analyses examining the effects of iron supplementation The first step in study selection was the exclusion of
in children suggest that supplementation improves duplicates (ie, reports of the same study). The title and
hematologic markers of iron status [16,17], but does not abstract of the trials retrieved in the search were
markedly improve growth, or mental or motor develop- scanned and studies that were obviously irrelevant were
ment [18-20]. Although a number of studies have reported excluded. The full text of each remaining study was
on the effects of iron supplementation in low birth weight reviewed to establish eligibility and all relevant informa-
infants, no systematic review of the available evidence has tion and data were extracted.
been conducted to date. Hence, we performed a systematic
review of the literature, focusing on the effects of iron sup- Data Extraction and Quality Assessment
plementation in low birth weight / premature infants on Data were extracted by 3 independent reviewers. Each
hematologic iron status, growth, and neurodevelopment. reviewer used a standardized data collection form to in-
We also examined potential adverse effects of iron crease uniformity and reduce bias. In the case of dis-
supplementation. crepancy, the reviewers made a consensus decision. The
following information / data were extracted from each
eligible study: first author; year of publication; journal;
Methods
eligibility criteria; definition of premature or low-birth
Search Strategy
weight; number of cases and control; population demo-
The Cochrane Library, Medline, and PubMed databases
graphics; hematological data (hemoglobin, hematocrit,
were searched from inception to June 2011. We limited
serum iron) before iron supplementation; iron supple-
the searches to include only articles written in English
ment dose; duration of iron supplementation; hema-
using the following terms: “preterm born infant(s) /
tological data after iron supplementation; growth status
children”; “preterm infants”; “prematurely born children”
after iron supplementation; and adverse effects of iron
“weight less than 1500 g at birth”; “born prematurely”;
supplementation.
“low birth weight infant(s)”; “infants born preterm”; “pre-
The quality of each study identified for inclusion was
maturity”; “small-for-gestational age”; “very small gesta-
assessed using the Delphi list for quality assessment of
tional age infants”; “iron supplementation”; “iron intake”;
randomized clinical trials [21].
“iron supplements”; “ferric and/or ferrous compounds”;
and “ferrous sulphate / fumarate / sulfate”. Boolean opera-
Results
tors (not, and, or) were also used in succession to narrow
Literature Search
and widen the search. To locate unpublished materials
A total of 2065 articles were identified by searching the 3
and avoid systemic bias, we manually searched the refe-
databases and a further 3 articles were identified by biblio-
rences lists of original and review articles for symposia
graphic searches (Figure 1). Of these articles, 3 duplicates
proceedings, poster presentations, and abstract from
were subsequently excluded. Abstracts and titles for the
major pediatric association meetings.
remaining 2065 articles were reviewed and 1962 were sub-
sequently excluded, typically because outcomes of interest
Eligibility Criteria were not presented or maternal supplements were given.
Studies were eligible for inclusion if they involved infants Full text review led to exclusion of a further 88 articles.
who were of low birth weight (< 2500 g) or premature Hence, a total of 15 articles [2,22-35] were included in the
(gestational age < 35 weeks) and received iron supple- systematic review.
mentation through the enteral (formula or iron drops)
or parenteral routes. Studies involving supplementation Study Characteristics
of other micronutrients were also eligible for inclusion if The studies included in this systematic review were pub-
the only difference between the treatment and the con- lished between 1960 and 2010 and included low birth
trol groups was iron supplementation. weight infants aged from birth to 80 days (Table 1).
Studies were excluded if there was no definite length The number of low birth weight infants in the iron
of treatment available, or if supplementation was com- supplementation treatment group ranged from 16 to 90,
bined erythropoietin treatment. with most studies having 20 to 40 infants per iron
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Figure 1 Study flow diagram.

supplementation treatment group. Iron was most com- Effect of Iron Supplementation on Hematologic
monly given orally [2,23,27,29-35] or as an iron-fortified Parameters
formula [2,24-26,28]. In 1 study, iron was given by intra- All but 1 study reported on the effects of iron supplementa-
muscular injection [22]. The duration of iron supple- tion on hematologic measures of iron status (Table 3). The
mentation varied considerably, ranging from 1 week up majority of studies reported that iron supplementation sig-
to 18 months. nificantly increased hematologic measures of iron status
The quality of studies included in the systematic re- relative to control. Specifically, Hammond et al. reported
view was generally acceptable for most items of quality that premature infants treated for 2–4 days with intra-
assessment. The majority of studies employed a method muscular iron-dextran (100 mg) had significantly higher
of randomization (10/15; 66.7%), had similar between hemoglobin concentrations and hematocrit values from
group characteristics at baseline (9/15; 60%), specified 3 months of age onwards and significantly higher erythro-
eligibility criteria (13/15; 86.7%), provided point esti- cyte counts from 5 months of age onwards compared with
mates and measures of variability for the primary premature infants in the control group [22]. In another
outcome measures (13/15; 86.7%), and included an study, Lundstrom et al. found that low birth weight infants
intention-to-treat analysis (12/15; 80.0%). Only 6/15 treated for approximately 6 months with an oral iron
(40%) studies provided any definitive information about supplement (2 mg/kg/day) had significantly higher
blinding (outcome assessor, care provider, or patient) hemoglobin, serum ferritin, mean corpuscular volume
(Table 2). (MCV), and transferrin saturation levels at 3 months com-
Meta-analyses of the extracted data were not per- pared with low birth weight infants in the control group
formed because mean values were not available or doses [2]. Iwai et al. similarly reported that low birth weight
were not adjusted by body weight in the majority of the infants fed an iron-fortified formula (8 mg/L) for 6 months
studies identified. There was significant heterogeneity had significantly higher hemoglobin, serum ferritin, and
(data not shown) among the 3 studies in which mean MCV concentrations than control infants fed human milk
values were available and dose was adjusted for body only [24]. Aggarwal et al. also reported that low birth
weight [31,34,35]. weight infants fed oral iron in a drop formulation (3 mg/
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Table 1 Characteristics of the studies examining the effects of iron supplementation in low birth weight infants
Study Agea Sample Eligibility Iron Dose, Duration of Treatment / Measurements
Sizeb Follow-up
Hammond et al. 2-3 wks T: 26 Premature birth T: 100 mg intramuscular iron-dextran; Hematologic: Hb, HCT, PCV, RBC
1960[22] C: 22 C: No ironTreatment: 1 mo; Follow-up:
12 mo
Brozovic et al. 5 wks 47 GA: 29–37 wks 36.3 mg/d oral ironTreatment and Hematologic: Hb, SI, TIBC
1974[23] BW: 920–1870 g follow-up: 9 mo
Lundstrom et al. 2 wks T: 40 BW: 1050–2000 g T: 2 mg/kg/d oral iron; C: No Hematologic: Hb, MCV, reticulocyte
1977[2] C: 50 ironTreatment and follow-up: 6 mo count, SI, SF, TRNSAT, TIBC
Iwai et al. 3 mo Formula: 30 GA: 30–40 wks Formula: 8 mg/L oral ironTreatment: Hematologic: Hb, RBC, SF, iron, TIBC,
1986[24] Human BW: 1000–2499 g 3 mo; Follow-up: 6 mo MCV
milk:15
Hall et al. 8-10 d High iron: 20 GA: < 35 wks High: 1.3 mg/kg/d oral iron; Low: Hematologic: Hb, MCV, TRNSAT, SF,
1993[25] Low iron: 23 BW: < 1800 g 0.3 mg/kg/d oral iron; Milk: 0.3 mg/kg/d HCT, RBC, PLFEDevelopment: weight,
Human ironTreatment: 25–34 d; Follow-up: ~11-13 length, head circumference
milk: 13 wks
Griffin et al. 3d A: 29 GA: ≥ 32 wks A: 0.9 mg/dL iron formula (1.17 mg/kg/d); Hematologic: Hb, plasma ferritin
1999[26] B: 34 BW: < 1750 g B: 0.5 mg/dL iron formula (0.81 mg/kg/d);
C: 15 C: 0.9 mg/dL iron formula until term and
then 0.5 mg/dL iron formula (0.86 mg/kg/d)
Treatment: 6 mo; Follow-up: 12 mo
Franz et al. 14/61 d T: 68 BW: < 1301 g T: 2–4 mg/kg/d oral iron once enteral Hematologic: SF, TRNAST, HCT, MCV,
2000[27] C: 65 feeding was tolerated; C: No ironTreatment MCH, RBC, ID
and follow-up: Until 61 days of age
Friel et al. Birth High: 29 BW: < 2500 g High: 20.7 mg/L iron formula (0.6-5.9 mg/ Hematologic: Hb, HCT, SF, TRN,
2001[28] Normal: 29 kg/d); Normal: 13.4 mg/L iron formula (0.6- TRNSAT, MCV, PLFE
3.0 mg/kg/d)Treatment and follow-up: Development: WTZ, GDA, HTZ
12 mo Oxidative stress: MDA, PLZN, PLCU,
FRAG, CAT, SOD, GHSPx
Adverse effects: frequency of
infection
Aggarwal et al. 50-80 d T: 37 GA: ≥ 37 wks T: 3 mg/kg/d oral iron; C: No ironTreatment Hematologic: Hb, SF, microcytic
2005[29] C: 36 BW: < 2500 g and follow-up: 8 wks hypochromic, NCHC, NCNC
Development: weight, length, head
circumference
Miller et al. 7-60 d T: 16 GA: 24–32 wks T: 3–12 mg/kg/d oral iron; Hematologic: RBC, SI, SF, TIBC, ZnPP/
2006[30] C: 16 C: No ironTreatment and follow-up: H, sTfRAdverse effects: blood and
2–3 wks urine isoprostanes
Arnon et al. 2 or 4 2 wks: 32 GA: < 32 wks 5 mg/kg/d oral ironTreatment and Hematologic: SI, SF, sTfR, reticulocyte,
2007[31] wks 4 wks: 36 follow-up: 4–6 wks HbAdverse effects: morbidity
Steinmacher 14/61 d Early: 90 BW: < 1301 g Early (14 d): 2–4 mg/kg/d oral iron; Neurologic examination,
et al. Late: 74 Late (61 d): 2 mg/kg/d oral ironTreatment: neurophysiological testing (Gross
2007[32] until BW = 1.6x birth BW; Motor Functioning Classification
Follow up: 5.3 yrs Scale,
Lincoln-Oseretzky Scale, Kaufmann
Assessment Battery for Children,
visual impairment, and
Child Behavior Check List)
Braekke et al. 5 wks 21 GA: < 32 wksBW: 9.4 mg/kg/d oral ironTreatment and Hematologic: Hb, reticulocytes, iron,
2007[33] < 1500 g follow-up: 1 wk SF, TRNSAT
Oxidative stress: urine isoprostane,
urine 2,3 dinor, plasma total
hydroperoxides
Plasma antioxidants: AA, TAA, DHAA,
alpha tocopherol, FRAP, GGT, total
glutathione
Sankar et al. 2 wks T: 22, BW: < 1500 g T: 3–4 mg/kg/d oral iron; Hematologic: SF, HbAdverse effects:
2009[34] C: 24 C: No ironTreatment and follow-up: morbidity
60 d
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Table 1 Characteristics of the studies examining the effects of iron supplementation in low birth weight infants
(Continued)
Berglund et al. 6 wks T1: 78 BW: 2000–2500 g T1: 1 mg/kg/d oral iron; Hematologic: Hb, SF, MCV, PLFE, TRN,
2010[35] T2: 82 T2: 2 mg/kg/d oral iron; TRNSAT, sTfR, ID, IDA
C: 83 C: No ironTreatment: 6 wks to 6 mo of age; Development: weight, weight SD
Follow-up: up to 6 mo score, length, length SD score, head
circumference, head circumference
SD
score, knee-heel lengthAdverse
effects:
morbidity
AA, ascorbic acid; BW, birth weight; C, control; CAT, catalase; CGA, corrected gestational age; d, days; DHAA, dehydroascorbic acid; FRAG, red blood cell fragility;
GA, gestational age; GDA, Griffiths’ Development Assessment; GHSPx, glutathione peroxidase; GGT, Gamma-glutamyl transferase; Hb, Hemoglobin; HCT,
hematocrit; HTZ, height for age z score; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; ID, iron deficiency; IDA, iron
deficiency anemia; MCV, mean corpuscular volume; MDA, malondialdehyde; mo, month; NA, not available; NCHC, normocytic hypochromic; NCNC, normocytic
normochromic; PCV, packed cell volume; PLFE, plasma iron; PLCU, plasma copper; PLZN, plasma zinc; RBC, red blood cell; ROP, retinopathy of prematurity; SF,
serum ferritin; SI, serum iron; SOD, superoxide dismutase; sTfR, soluble transferrin receptor; T, iron supplementation group; TAA, total ascorbic acid; TIBC, total iron
binding capacity; TRN, transferrin; TRNSAT, transferrin saturation; wks, weeks; WTZ, weight for age z score; ZnPP/H, zinc protoporphyrin to heme ratio.
a
Age at the start of supplementation.
b
Data analysis sample size.

kg/day) for 8 weeks had significantly higher adjusted reported that early iron supplementation (2 to 4 mg/kg/
(for age, hemoglobin, ferritin, and maternal hemoglobin) day once enteral feeding was tolerated) had no signifi-
hemoglobin concentrations from 4 weeks onwards com- cant impact on indicators of iron status in infants with a
pared with control infants [29]. Finally, Berglund et al. birth weight <1301 g [27].
found that marginally low birth weight infants fed an oral
iron supplement (1 or 2 mg/kg/day) between 6 weeks and Effect of Iron Supplementation on the Prevalence of Iron
6 months of age had significantly higher hemoglobin, MCV, Deficiency and Iron-Deficiency Anemia
ferritin, transferrin, iron, transferrin saturation, and trans- Most studies reported on the prevalence of iron deficiency
ferrin receptor levels compared with control infants [35]. (ID) and/or IDA (Table 3). All controlled studies that exam-
In a non-placebo controlled study, Arnon et al. found ined the prevalence of ID and/or IDA found that the preva-
that premature infants fed enteral iron (5 mg/kg/day) lence of ID and/or IDA was lower in infants who received
from 2 weeks of age to 8 weeks of age had significantly iron supplementation compared with infants who did not
higher hemoglobin, reticulocyte, iron, and ferritin con- receive iron supplementation [2,22,24,25,35]. Several stud-
centrations compared with premature infants fed enteral ies also reported dose-dependent effects of iron supplemen-
iron (5 mg/kg/day) from 4 weeks of age to 8 weeks of tation on the prevalence of ID and/or IDA, with higher
age [31]. In another non-placebo controlled study, iron doses being associated with decreased prevalence
Braekke et al. reported that very low birth weight infants [25,26,35]. In contrast, Friel et al. found no obvious effect
given oral iron supplementation (9.4 mg/kg/day) from of dose, with 4/29 (13.8%) infants in the high iron supple-
6 weeks of age had significantly higher iron and transfer- mentation group and 2/29 (6.9%) infants in the normal iron
rin saturation levels at 7 weeks of age [33]. supplementation group having ID after 12 months of treat-
A small number of studies included in the systematic ment [28]. Franz et al. also found that iron supplementation
review found that iron supplementation had no signifi- was associated with a decreased prevalence of ID [27].
cant effect on hematologic measures of iron status rela- Only 1 study found no obvious benefit of iron supple-
tive to control. These include studies by: Friel et al., in mentation on the prevalence of ID and/or IDA. Brozovic
which low birth weight infants were fed either a normal et al. reported that oral iron (36.3 mg/day) from 5 weeks to
(0.6-3.0 mg/kg/day) or high (0.6-5.9 mg/kg/day) iron for- 9 months of age did not prevent ID in premature low birth
mula from birth for 12 months [28]; Miller et al., in weight infants [23].
which 7 to 60 day-old premature infants were given oral
iron (3 to 12 mg/kg/day) or control (no iron) for 3 weeks Effect of Iron Supplementation on Growth and
[30]; Sankar et al., in which very low birth weight infants Neurodevelopment
were fed oral iron (3 to 4 mg/kg/day) or control (no Five studies included in the systematic review examined
iron) from 2 weeks of age until 60 days of age [34]. the effect of iron supplementation on growth, whereas
A study by Griffin et al. compared the effects of for- only 2 studies examined the effect of iron supplementa-
mulations containing either 0.9 mg/dL iron or 0.5 mg/ tion on neurodevelopment (Table 4). None of the studies
dL iron in premature infants and found that there were that examined growth-related variables, including
no dose-dependent differences in hematological indica- growth rate, length, height, head circumference, and
tors of iron status [26]. In another study, Franz et al. weight, found any effect of iron supplementation
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Long et al. BMC Pediatrics 2012, 12:99
Table 2 Quality assessment of studies examining the effects of iron supplementation in low birth weight infants
Item Was a method of Were the groups similar at Were the Was the Was Was the Were point estimates Did the analysis
randomization baseline regarding the eligibility outcome the care patient and measures of variability include an
used? most important criteria assessor provider blinded? presented for the primary intention-to-treat
prognostic indicators? specified? blinded? blinded? outcome measures? analysis?
Hammond et al. Y Y NA NA NA NA Y Y
1960[22]
Brozovic et al. NA NA Y NA NA NA Y N
1974[23]
Lundstrom et al. N NA Y NA NA NA Y Y
1977[2]
Iwai et al. 1986[24] NA NA N NA N N Y Y
Hall et al. 1993[25] Y Y Y NA NA Y Y Y
Griffin et al. Y N Y NA NA Y N Y
1999[26]
Franz et al. Y Y Y NA NA NA Y N
2000[27]
Friel et al. Y Y Y NA NA NA Y Y
2001[28]
Aggarwal et al. Y Y Y NA NA Y Y Y
2005[29]
Miller et al. N N Y NA NA NA N Y
2006[30]
Arnon et al. Y Y Y NA NA NA Y N
2007[31]
Steinmacher et al. Y Y Y NA NA NA Y Y
2007[32]
Braekke et al. N NA Y NA NA NA Y Y
2007[33]
Sankar et al. Y Y Y Y N Y Y Y
2009[34]
Berglund et al. Y Y Y NA Y Y Y Y
2010[35]
N, no; NA, information not available or not applicable; Y, yes.

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Table 3 Effects of iron supplementation on hematologic parameters in low birth weight infants
Study Effect No Effect % of ID Conclusion Comments
and/or IDA
Hammond Hb, HCT significantly Blood volume, 27.3 vs 7.7 % Early iron suppl. accelerates 27 % loss to follow up; other
et al. higher in T group by 3 circulating Hb IDA (C vs T) recovery from early IDA vitamins were administrated; BW
1960[22] mo; erythrocyte count mass and hematologic measurements
significantly higher in T slightly higher in C vs T group
group by 5 mo
Brozovic et al At 3 mo of age, most NA > 50 % IDA Iron suppl. was insufficient to No control group; all infants
1974[23] infants had low serum prevent IDA in most infants received vitamin K; some infants
iron concentrations, received other vitamins
which remained low
(6–9 mo)
Lundstrom SF, Hb, MCV, TRNSAT Reticulocyte 67 vs 0 % ID LBW infants who do not receive 23 % loss to follow up; after 3
et al. significantly higher in T count (C vs T) iron suppl. may develop ID by 3 mo of age, an increasing number
1977[2] group by 3 mo mo of age; 2 mg/kg/d iron is of C group infants were
adequate for the prevention of excluded; SF was higher than
IDA normal in C group; iron suppl.
given in 2 different forms
Iwai et al. Hb, SF, MCV significantly RBC, SI, TIBC 86 vs 33 % ID Breast-fed infants have a high Infants in formula group had
1986[24] higher in the formula (human milk risk of ID slightly higher BW than those in
group by 4 mo vs formula) human milk group; iron status of
LBW infants was not evaluated
Hall et al. Hospitalization: plasma Hb, HCT, 27, 69, 76 % Preterm infants receive more 44 and 25 % of infants in high
1993[25] ferritin lowest in low iron reticulocyte, TRN, IDA (high, low, benefit from receiving preterm and low dose groups dropped
groupDischarge: plasma TRNSAT human milk) infant formula containing out because of prematurity
ferritin significantly lower 1.3 mg/kg/d iron vs 0.3 mg/kg/d related diseases; 13 % of infants
in both formula groups 8 in the human milk group
wks after discharge; MCV, completed the study
MCH significantly lower in
low iron group
Griffin et al. NA Hb 18 vs 27 % ID 0.81-1.17 mg/kg/d iron seems to In group C, BW was slightly
1999[26] (A vs B) meet the iron nutritional needs lower, fewer transfusions were
of preterm infants received, and Hb was
significantly lower vs A and B; no
ferritin data for Group C
Franz et al. NA All markers of iron 14.7 vs 40.0 % Fewer infants in group T 34 % loss to follow up; group C
2000[27] nutrition ID (T vs C) received blood transfusion vs tended to have > chronic lung
group C; early iron suppl. is disease and ROP
feasible and safe in LBW infants
Friel et al. NA No difference in 6.9 vs 13.8 % In terms of cognitive outcome, No control group
2001[28] any hematologic ID (normal vs LBW infants did not benefit from
parameters high) high dose iron
Aggarwal et al. Adjusted Hb higher in T SF NA Iron suppl. marginally increases 42 % loss to follow up
2005[29] group Hb in LBW infants
Miller et al. NA SI, SF, TIBC, sTfR NA Corrected reticulocyte count Iron suppl. was adjusted by
2006[30] higher in the T group suggesting individual iron status; CGA,
improved erythropoiesis weight, age at enrollment > in T
group
Arnon et al. Hb, reticulocytes, iron, Reticulocytes, iron, NA Iron suppl. to preterm infants as All infants given 25 mg/d oral
2007[31] ferritin significantly ferritin at 4 wks of early as 2 weeks of age was vitamin E; 35 % loss to follow up
higher in the 2 wk age more beneficial for iron status,
group at 8 wks than at 4 weeks of age
Braekke et al. Iron, TRANSAT Ferritin NA Oral iron did not change markers No control group; all infants
2007[33] significantly increased of oxidative stress in LBW infants received other vitamins,
including vitamin E; 15 % loss to
follow up; short length of iron
administration
Sankar et al. NA SF, HCT, Hb NA Iron suppl. at 2 weeks of age did Iron suppl. group received folic
2009[34] not improve hematological acid and vitamin B12;
parameters at 2 mo of age in uncommon iron formulation
preterm very LBW infants used
NA NA
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Table 3 Effects of iron supplementation on hematologic parameters in low birth weight infants (Continued)
Berglund et al. All indicators of iron 2.7, 0, 9.9 % Marginally LBW infants had
2010[35] status differed IDA (T1, T2, C) higher risk of ID and IDA,
significantly between 9.5, 3.8, 35.8 % especially those exclusively
groups in a ID (T1, T2, C) breastfed; 2 mg/kg/d oral iron
dose-dependent manner significantly improved iron status
and reduced IDA risk
BW, birth weight; C, control; CGA, corrected gestational age; Hb, Hemoglobin; HCT, hematocrit; ID, iron deficiency; IDA, iron deficiency anemia; LBW, low birth
weight; MCV, mean corpuscular volume; mo, month; ROP, retinopathy of prematurity; RBC, red blood cell; SF, serum ferritin; SI, serum iron; sTfR, soluble transferrin
receptor; suppl., supplementation; T, iron supplementation group; TIBC, total iron binding capacity; TRN, transferrin; TRNSAT, transferrin saturation; wks, weeks; NA,
not available.

[25,28,29,34,35]. With regards to neurodevelopment, found that there was a tendency for there to be a higher
Friel et al. found that iron supplementation did not im- prevalence of respiratory tract infection in the iron supple-
prove cognitive development as measured using Grif- mentation group compared with the control group [29] or
fiths’ Development Assessment [28]. In the other study, the high compared with the normal iron supplementation
which focused on examining the effects of iron supple- group [28]. Two out of 3 studies examining the need for
mentation on neurocognitive development in premature blood transfusion found no effect of iron supplementation,
infants weighing < 1301 g, Steinmacher et al. found that [30,34] whereas Arnon et al. reported that significantly
early supplementation (< 61 days of age) tended to im- more infants who started iron supplementation at 4 weeks
prove neurocognitive and psychomotor development of age required blood transfusions than infants who started
compared with late supplementation (≥ 61 days of age), iron supplementation at 2 weeks of age [31]. Another ad-
as indicated by neurologic examination findings and verse effect reported by Aggarwal et al. included mild
Gross Motor Function Classification Scores [32]. vomiting (2/32 infants in the treatment group vs 0/30
infants in the control group) [29].
Adverse Effects of Iron Supplementation
Several studies included in the systematic review examined Discussion
potential adverse effects of iron supplementation, including This is the first systematic review to focus on the effects of
oxidative stress, inhibition of nutrient absorption, neonatal iron supplementation in low birth weight / premature
morbidity, the requirement for blood transfusion, and other infants. Only a relatively small number (N = 15) of studies
adverse effects (Table 5). None of the studies found any evi- were identified for review. Several consistent findings were
dence that iron supplementation increased oxidative stress apparent with iron supplementation, including increased
in low birth weight infants [28,30,33]. The study conducted concentrations of hematologic indicators of iron status,
by Friel et al. was the only study to examine absorption of decreased prevalence of ID / IDA, and a lack of an effect
other nutrients with iron supplementation and found that on growth parameters. Few studies that met the criteria for
both plasma zinc and copper concentrations were signifi- inclusion in our review reported on the effects of iron
cantly higher for the group of infants who received high vs supplementation on neurodevelopment or the occurrence
normal iron supplementation [28]. Three of the 5 studies of adverse effects.
that reported on neonatal morbidity found no differences Our observation that iron supplementation generally
between the control and treatment groups or dose- increased concentrations of hematologic indicators of
dependent effects of iron supplementation on the overall iron status (notably hemoglobin, hematocrit, and serum
incidence of morbidity [31,34,35]. The other 2 studies ferritin) in low birth weight / premature infants is

Table 4 Effects of iron supplementation on growth and neurodevelopment in low birth weight infants
Study Anthropometric Data Neurodevelopmental Outcome
Hall et al. 1993[25] No differences in growth rate, length, head circumference NA
Friel et al. 2001[28] No differences in WTZ, HTZ at 12 months of age No difference in GDA; no infant had abnormal development
Steinmacher et al. NA More infants in the late iron suppl. group had abnormal
2007[32] neurologic examination; no differences in cognitive
development, mobility, hearing, vision, growth; late vs early
iron suppl. was not an risk factor for abnormal neurologic
examination, disability, or cognitive impairment
Aggarwal et al. 2005[29] No differences in weight, length, head circumference NA
Sankar et al. 2009[34] No difference in weight NA
Berglund et al. 2010[35] No differences in weight, length, head circumference NA
GDA, Griffiths’ Development Assessment; HTZ, height for age z score; suppl., supplement; WTZ, weight for age z score; NA, not available.
Long et al. BMC Pediatrics 2012, 12:99 Page 9 of 11
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Table 5 Adverse effects of iron supplementation in low birth weight infants

Study Oxidative stress Inhibition of Other Neonatal Morbidity Blood Transfusion Other Adverse
Nutrient Absorption Effects
Hall et al. 1993[25] NA NA NA NA No adverse effects
in infants who
received higher
iron intake
Franz et al. 2000[27] NA NA NA NA No adverse effects
once enteral
feeding (100 mL/
kg/d) tolerated
Friel et al. 2001[28] No differences in MDA, PLCU and PLZN Prevalence of respiratory NA NA
SOD, CAT between the significantly lower in infection greater in the
high and normal groups; high group high group
GHSPx slightly higher in
the high group
Miller et al. 2006[30] No differences in blood NA NA No difference NA
or urine isoprostanes
Arnon et al. 2007[31] NA NA No difference More transfusions in NA
the 4 wk group vs
the 2 wk group (10/
36 vs 1/32)
Braekke et al. 2007[33] No significant changes in NA NA NA NA
urine isoprostane,
2,3-dinor, total
hydroperoxides; plasma
antioxidants were largely
unchanged
Aggarwal et al. 2005[29] NA NA Prevalence of respiratory NA 2 infants in the T
infection or bronchiolitis group reported
slightly higher in T vs C mild vomiting
group (10/32 vs 3/30)
Sankar et al. 2009[34] NA NA No difference (19 vs 22 % No difference (10 vs NA
for T and C groups) 13 for T and C
groups)
Berglund et al. 2010[35] NA NA No difference NA NA
C, control; CAT, catalase; GHSPx, glutathione peroxidase; MDA, malondialdehyde; PLCU, plasma copper; PLZN, plasma zinc; T, iron supplementation group; SOD,
superoxide dismutase; NA, not available.

consistent with the findings of other systematic reviews / consider the possibility of iron overload with iron supple-
meta-analyses which examined the effects of iron supple- mentation and identify any potential adverse effects of iron
mentation on hematologic indicators of iron status in chil- supplementation. Adverse effects of iron supplementation
dren [16] and young children [17]. Unsurprisingly, given have been suggested, including oxidative stress [36] and an
the improvements in iron status, there were correspond- increased risk infection [17]. None of the studies included
ing decreases in the prevalence of ID/IDA among infants in our review described any evidence of increased oxidative
who received iron supplementation. Similar to our review, stress with iron supplementation; however, two studies
the findings of several systematic reviews / meta-analyses reported an increased incidence of respiratory tract infec-
indicate that iron supplementation does not increase tion with iron supplementation. Given that iron (and other
growth in children [18,19]. We must emphasize, however, nutrients) can promote bacterial colonization, an increased
that both the studies included in our review and the previ- risk of respiratory infection is a plausible potential adverse
ous systematic reviews / meta-analyses typically focused effect of iron supplementation. Further evidence is needed
on assessing growth within the first 12 months of supple- to confirm or deny this possibility. Overall, there were no
mentation and did not assess longer term growth after consistent adverse effects of iron supplementation; however,
iron supplementation. The longer term effect of iron sup- not all studies monitored for adverse effects of iron supple-
plementation on growth in low birth weight / premature mentation and there was considerable between study vari-
infants remains to be determined. ability in the types of adverse effects monitored / reported.
As low birth weight / premature infants are particularly Clearly, further studies are on needed on the potential ad-
vulnerable, and given the fact that humans have no physio- verse effects of iron supplementation in low birth weight /
logic mechanism for excreting iron, it is important to premature infants.
Long et al. BMC Pediatrics 2012, 12:99 Page 10 of 11
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This systematic review has a number of limitations important intellectual content. All authors read and approved the final
that must be acknowledged. Perhaps the most important published manuscript.

limitation is was the lack homogeneity between studies

Acknowledgements
in terms of treatment dose, length of treatment, timing Medical writing assistance was provided by MedCom Asia (Taipei, Taiwan).
of treatment, age of the infants, length of follow-up, and
variables assessed. These differences clearly make be- Received: 16 January 2012 Accepted: 2 July 2012
Published: 16 July 2012
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doi:10.1186/1471-2431-12-99
Cite this article as: Long et al.: Benefits of Iron supplementation for low
birth weight infants: A systematic review. BMC Pediatrics 2012 12:99.

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