Downloaded from fn.bmj.com on December 31, 2013 - Published by group.bmj.

com
ADC-FNN Online First, published on December 3, 2013 as 10.1136/archdischild-2013-304650
Original article

Early versus late enteral prophylactic iron

supplementation in preterm very low birth weight
infants: a randomised controlled trial
Rojo Joy, Sriram Krishnamurthy, Adhisivam Bethou, Medha Rajappa,
P H Ananthanarayanan, B Vishnu Bhat

Departments of Pediatrics and ABSTRACT

Biochemistry, Jawaharlal
Institute of Postgraduate
Medical Education and
Research ( JIPMER),
Pondicherry, India
Correspondence to
Dr B Vishnu Bhat,
Department of Pediatrics,
Jawaharlal Institute of
Postgraduate Medical
Education and Research
( JIPMER), Pondicherry 605
006, India;
drvishnubhat@yahoo.com
Received 12 June 2013
Revised 7 August 2013
Accepted 2 November 2013
To cite: Joy R,
Krishnamurthy S, Bethou A,
et al. Arch Dis Child Fetal
Neonatal Ed Published
Online First: [ please include
Day Month Year]
doi:10.1136/archdischild-
2013-304650
Objectives To evaluate whether preterm very low birth
weight (VLBW) infants receiving early iron (EI)
supplementation (2 mg/kg/day elemental iron) at
2 weeks postnatal age have improved serum ferritin
levels compared with late iron (LI) supplementation at
6 weeks postnatal age.
Design Single-blinded parallel-group interventional
randomised controlled trial.
Setting Tertiary care centre in southern India.
Interventions Randomised at 2 weeks postnatal age
to EI and LI groups and evaluated at 2, 6 and 12 weeks
postnatal age.
Outcome The primary outcome was serum ferritin level
at 12 weeks, and the secondary outcomes were the
incidence of neonatal morbidities, haemoglobin level,
anthropometric parameters and blood transfusion
requirements.
Results Of the 104 babies randomised, outcomes were
analysed in 46 and 47 babies in EI and LI groups,
respectively. Serum ferritin level was significantly higher
( p<0.001) at 12 weeks (82±5 vs 63±3 ng/mL) in the EI
group. Haemoglobin (10.1±0.4 vs 9.2±0.4 g/dL) and
mean corpuscular haemoglobin concentration (31±0.5
vs 29.4±0.5 g/dL) were also significantly ( p<0.001)
higher at 12 weeks in the EI group. There was a
significant decrease of ferritin in the LI group and
significant increase in ferritin in the EI group at 6 weeks
compared with 2 weeks. There were no significant
differences in the incidences of neonatal morbidities
(necrotising enterocolitis, periventricular leukomalacia,
retinopathy of prematurity), anthropometric parameters
and blood transfusion requirements between the two
groups.
Conclusions EI supplementation in preterm VLBW
infants improves serum ferritin and haemoglobin levels.
Trial registration: CTRI/2013/01/003277.
INTRODUCTION
Iron deficiency in infancy is associated with neuro-
developmental deficits, delayed maturation of the
auditory brainstem response and abnormalities of
memory and behaviour. Since iron stores are laid
down primarily during the third trimester of preg-
nancy, they are reduced in preterm infants.
Depletion of iron stores is the first step in the con-
tinuum of changes that occur in iron deficiency.
Early iron (EI) supplementation could potentially
improve iron stores and prevent their depletion.1–5
One of the concerns with iron supplementation is
that free ferrous iron is believed to increase produc-
tion of free radicals, thereby increasing oxidative
What is already known on this topic
▸ Iron deficiency in infancy is associated with
neurodevelopmental deficits, delayed
maturation of the auditory brainstem response
and abnormalities of memory and behaviour.
▸ Preterm babies are especially prone to iron
deficiency due to decreased intrauterine
accretion of iron.
▸ Most international bodies recommend delayed
initiation of prophylactic enteral iron
supplementation considering the potentially
increased risk of free radical mediated
morbidities in preterm neonates.
What this study adds
Early iron supplementation at 2 weeks postnatal
age improves serum ferritin and haemoglobin
levels in preterm very low birth weight infants
(1000–1500 g).
stress, especially in premature infants who have
limited capacity to assimilate free iron and degrade
free radicals, potentially leading to oxidative injury
to the developing brain and retina.6 7 However, in
earlier studies, there was no evidence of adverse
effects after early enteral iron supplementation.8–10
The timing of prophylactic enteral iron supplemen-
tation in preterm very low birth weight (VLBW)
infants has been a matter of great controversy.
Various international bodies have recommended
different timings of initiation of enteral prophylac-
tic iron supplementation in these babies. While the
American Academy of Paediatrics (AAP) and the
Nutrition Committee of Canadian Pediatric Society
have recommended delayed iron supplementation
in preterm VLBW infants at 4 weeks and 6–8 weeks
postnatal age, respectively11 12 the European
Society of Pediatric Gastroenterology, Hepatology
and Nutrition (ESPGHAN) recommends initiation
over a wide range of 2–6 weeks of age.13 The issue
of optimal timing of initiation of iron supplementa-
tion therefore remains unsettled. Moreover, little is
known about the optimal time for iron supplemen-
tation in VLBW infants, especially in the develop-
ing country scenario. Therefore, we conducted the

Copyright Article
Joy R, et al. author
Arch Dis Child (or their
Fetal Neonatal employer)
Ed 2013;0:F1–F5. 2013. Produced by BMJ Publishing Group Ltd (& RCPCH) under licence.
doi:10.1136/archdischild-2013-304650 F1
 Downloaded from fn.bmj.com on December 31, 2013 - Published by group.bmj.com
Original article
present study with the objective of determining whether EI sup-
plementation at 2 weeks of age would improve the iron stores
(as measured by serum ferritin) compared with late iron (LI)
supplementation at 6 weeks of age, with the objective that EI
supplementation of iron would improve nutritional iron status
of preterm VLBW infants.
MATERIALS AND METHODS
This single-blinded parallel-group randomised controlled trial
was conducted during April 2012 to March 2013 at a tertiary
care centre in southern India. The trial was approved by the
institutional ethical committee. Written informed consent was
obtained from the parents prior to the enrolment of subjects in
the study.
Intramural preterm (<37 weeks gestational age) VLBW
infants (birth weight 1000–1500 g) who reached full enteral
feeds of 180 mL/kg/day by 2 weeks postnatal age were included
in the study. Babies with major congenital anomalies, multiple
gestation and Rh or ABO haemolytic disease were excluded.
Babies satisfying the inclusion criteria were randomised to the
EI and LI groups using computer-generated random numbers,
which were kept in sequentially numbered, opaque-sealed envel-
opes (for allocation concealment), that were opened by a person
not involved in the trial to enrol the participants and then
assigned to interventions. Blood samples were sent for analysis
in bottles with only numbers identifying each patient, and
patient details and treatment details, respectively, were not pro-
vided to the biochemist and statisticians for the purpose of
blinding them to the study.
Based on a study by Franz et al,14 the sample size was calcu-
lated as 86 subjects using an ά error of 0.05 and 80% power, an
expected difference of natural logarithm ferritin at 12 weeks of
0.5 and an estimated SD of natural logarithm ferritin of 0.95
and a one-tailed test. Accounting for 20% attrition, the total
sample size required was 104 subjects (52 per group).
The intervention used was colloidal ferric hydroxide
(Tonoferon drops; East India Pharmaceuticals Limited, Kolkata,
India) at a dose of 2 mg/kg/day of elemental iron PO once daily
mixed with expressed breast milk. Babies were breastfed from
their respective mothers. Iron supplementation was started at
2 weeks postnatal age for babies in the EI group and at 6 weeks
postnatal age for babies in the LI group. Restrictive transfusion
guidelines were followed, and microsampling techniques were
used to minimise phlebotomy losses. The subjects were evalu-
ated clinically, biochemically and radiologically (using cranial
ultrasound) at 2, 6 and 12 weeks postnatal age. Blood samples
(3 mL) were taken at 2, 6, 12 weeks postnatal age for ferritin
and high-sensitivity C-reactive protein (hs-CRP) estimation in
both groups. Serum ferritin levels were estimated by two-site
sandwich immunoassay using direct chemiluminometric technol-
ogy in Advia Centaur CP Immunoassay system (Siemens AG,
Health Care Sector, Erlangen, Germany), with a sensitivity of
1 ng/mL. Serum hs-CRP was estimated using commercially avail-
able ELISA kit (Diagnostics Biochem Canada Inc, Ontario,
Canada), with a sensitivity of 0.010 mg/L. Haemoglobin was
estimated by taking 1 mL venous sample at 2 and 12 weeks in
an EDTA vial using Coulter LH 500 haematology analyzer
(Beckman Coulter Inc, Brea, California, USA).
Outcome measures and follow-up
The proposed and measured primary outcome variable was the
serum ferritin level at 12 weeks postnatal age in both groups.
The secondary outcome variables were the incidences of neo-
natal morbidities such as retinopathy of prematurity (ROP),
F2 Joy R, et al. Arch Dis Child Fetal Neonatal Ed 2013;0:F1–F5. doi:10.1136/archdischild-2013-304650
necrotising enterocolitis (NEC) and periventricular leukomalacia
(PVL); and anthropometric parameters at 2, 6 and 12 weeks of
postnatal age, neurological assessment, haemoglobin levels at 2
and 12 weeks and incidence of blood transfusion till 12 weeks
postnatal age. ROP screening was done at 4 weeks postnatal age
by indirect ophthalmoscopy, and further follow-up was done
based on standard protocols. NEC was diagnosed based on
modified Bell’s staging.15 Screening for PVL was done using
ultrasonography and classified based on de Vries classification.16
Sepsis was defined as clinical signs of infection and either a posi-
tive blood culture result or hs-CRP level >10 mg/L.
Neurological assessment was done by Hammer Smith neuro-
logical examination at 12 weeks by a person not involved in the
trial. All outcome analysers were unaware of patient assignment.
Statistical analysis
The categorical data were presented as frequencies and percen-
tages, and normally distributed continuous data were presented
as mean±SD. χ2 test or Fisher exact test was used to compare
the categorical data between the two groups. Unpaired t test
was used to compare the means of the primary and secondary
outcome variables between the two groups. Paired t test was
used to analyse the serum ferritin levels at 2 weeks versus
6 weeks within each group. To analyse the risk of developing
neurological deficit at 12 weeks, relative risk with 95% CI was
calculated.
RESULTS
The Consolidated Standards of Reporting Trials (CONSORT)
diagram for the study is depicted in figure 1. The demographic
characteristics of the two groups were similar with respect to
gestational age, anthropometric parameters, antenatal complica-
tions, transfusion requirements till day 14, baseline ferritin,
haemoglobin levels and hs-CRP (table 1).
Serum ferritin, haemoglobin levels and mean corpuscular
haemoglobin concentration were significantly higher at
12 weeks in the EI group compared with the LI group (table 2).
There was a significant decrease ( p<0.001) in ferritin in the
LI group at 6 weeks (111±5 ng/mL) compared with 2 weeks
(113±6 ng/mL), and there was a significant increase (p<0.001)
in ferritin in the EI group at 6 weeks (130±4 ng/mL) compared
with 2 weeks (112±5 ng/mL). Serum ferritin at 6 weeks was sig-
nificantly higher in the EI group than in the LI group. There
was lesser requirement for blood transfusion in the EI group,
but this was not statistically significant (table 2). One patient
died before and after 6 weeks in the EI group, while two
patients died in the LI group before 6 weeks. All deaths were
due to late-onset sepsis.
Neonatal morbidities such as NEC, ROP and PVL were
similar in incidence when both groups were compared. The
growth parameters were also similar between the two groups on
follow-up (table 2).
DISCUSSION
Preterm babies are at negative iron balance due to the absence
of third trimester iron transfer, associated intrauterine growth
restriction, rapid postnatal growth velocity and accelerated
erythropoiesis associated with anaemia of prematurity. There are
various ways of replenishing iron such as fortification of human
milk, iron-fortified formulae, enteral medicinal iron supplemen-
tation and parenteral iron supplementation.2 17–19 In our study,
we used oral colloidal iron at a dose of 2 mg/kg/day based on
the AAP and ESPGHAN recommendations.11 13 The two time
periods chosen for the two groups (2 weeks and 6 weeks,
 Downloaded from fn.bmj.com on December 31, 2013 - Published by group.bmj.com

Original article

Figure 1 Consolidated Standards of Reporting Trials (CONSORT) flowchart of the study design and enrolment of subjects in the study.

respectively) were based on the ESPGHAN recommendations
for iron supplementation initiation and on the evidence that
supplemental iron gets well incorporated into red blood cells
when administered after the onset of erythropoiesis, that is, at 6
weeks.13 20 We used colloidal ferric hydroxide because of the
presence of high elemental iron (52.26%) and its easy availabil-
ity in the form of appropriate drop formulation. When com-
pared with ferrous sulfate, ferric hydroxide has better
absorption with minimal gastric irritation, as it can be easily
converted to soluble form by the action of gastric acid and
reduced to ferrous form by the mucoproteins present in the
secretions of the stomach and the small intestine. Though newer
iron compounds such as carbonyl iron and polymaltose
complex are supposed to have lesser gastrointestinal intolerance
and faster increase in iron stores, these have not been proven
scientifically and are costlier than conventional forms.21 We
used serum ferritin as an indicator of iron stores, and each
ferritin value was correlated with the hs-CRP value to detect the
effect of inflammation. In our study, we used non-invasive
methods of clinical monitoring and microsampling techniques
to reduce phlebotomy losses, and restrictive transfusion guide-
lines were followed (box 1).22
There was no statistically significant difference in the baseline
ferritin, haemoglobin values, gestational age and anthropometric
parameters between the two groups, reflecting that both groups
were similar in baseline characteristics. We found significantly
higher serum ferritin and haemoglobin values on follow-up in
the EI group than in the LI group, which implies that EI supple-
mentation increases serum ferritin. These findings are similar to
the findings of Arnon et al,10 who randomised babies less than
32 weeks gestational age to EI (at 2 weeks) and LI (4 weeks) of
age to receive enteral iron polymaltose complex and found that
the EI group (n=32) had a better iron status than the LI group
(n=36) at 4 weeks and at 8 weeks postnatal age. Our results are
also in agreement with Franz et al,14 who randomised 133
infants with birth weight less than 1301 g to EI (at the

Joy R, et al. Arch Dis Child Fetal Neonatal Ed 2013;0:F1–F5. doi:10.1136/archdischild-2013-304650 F3

 Downloaded from fn.bmj.com on December 31, 2013 - Published by group.bmj.com

Original article

by day 14 postnatal age were randomised to the EI (2 weeks) or

Table 1 Baseline maternal and neonatal characteristics of the two
LI (60 days) groups.23 There was no difference in serum ferritin
groups
or haematocrit at 60 days, or in the requirement of blood trans-
Group 1 (EI) Group 2 (LI) fusions between the EI and LI groups. It must be however noted
Parameter (N=52) (N=52) that the sample size in their study was much smaller than the
Birth weight (kg) 1.35±0.15 1.33±0.14
sample size of our study. Similarly, Miller et al24, in their study
Gestational age (weeks) 32.4±1.7 32.4±1.6
on iron supplementation at a dose of 3–12 mg/kg/day in 7- to
Sex (male/female) 27/23 24/26
60-day-old preterm babies of 24–32 weeks gestation, could not
Small for gestational age*† 20 (38) 21 (40)
find any changes in conventional measures of iron status. The
Antenatal complications*
differences in the results of the aforementioned studies could
Pregnancy-induced 11 (22) 9 (18)
also be related to heterogeneity of study populations, with inclu-
hypertension sion of different gestational ages, birth weights and timing of
Premature rupture of 9 (18) 11 (22) iron initiation.
membranes We also found that a delay in initiation of iron supplementa-
Abruption 5 (10) 4 (8) tion led to a decrease in serum ferritin. Similarly, early initiation
Mode of delivery* of iron supplementation led to an increase in iron stores within
Vaginal delivery 38 37 the margin of safety (25–200 ng/mL), thereby justifying early
Caesarean section 12 13 initiation of iron supplementation in preterm VLBW babies.
Transfusion till day 14* 1 (2) 2 (4) We did not find any difference in weight, length and head cir-
Serum ferritin at 2 weeks (ng/mL) 112±5 113±6 cumference between the EI and LI groups. This was in concord-
hs-CRP at 2 weeks (mg/L) 6.2±3.4 6.4±2.5 ance with the findings of some earlier studies.8 25 26 Similar to
Haemoglobin at 2 weeks (g/dL 12.9±0.8 13.1±0.6 other studies, we also did not document any significant increase
Weight at 2 weeks (kg) 1.27±0.16 1.29±0.15 in immediate neonatal morbidities, such as ROP, PVL and NEC,
Length at 2 weeks (cm) 39.3±1.9 39.7±1.7 due to EI supplementation.10 27 We documented clinically signifi-
Head circumference at 2 weeks (cm) 28.4±1.3 28.9±1.4 cant short-term neurological improvement at 12 weeks of life in
*Values represented in number (percentages) and all other values represented in the EI group, though not statistically significant. Steinmacher
mean±SD. et al28 demonstrated more mild neurological abnormalities and
†Defined according to Kandraju et al.29
EI, early iron; hs-CRP, high sensitivity C-reactive protein; LI, late iron.
poorer cognitive performance at 5 years of age in the LI group
(iron supplementation at 2 months) than in the EI group (iron
supplementation at 2 weeks). It is probable that due to a smaller
sample size (as compared with this study) and a lack of long-term
attainment of full enteral feeds) and LI at 61 days postnatal age follow-up we could not document statistical significance.
and found that the LI group was more often iron-deficient and We found decreased serum ferritin levels in both groups at
received more blood transfusions after day 14. They did not 12 weeks compared with 6 weeks. This may be due to acceler-
detect any significant differences in serum ferritin levels, pre- ated erythropoiesis due to anaemia of prematurity, and this is in
sumably due to the greater blood transfusion requirements in accordance with the evidence found in literature that even with
the LI group. In a study from northern India, 46 preterm EI supplementation anaemia of prematurity could not be
VLBW infants who received at least 100 mL/kg/day of oral feeds prevented.1 2

Table 2 Effect of iron supplementation on the primary and secondary outcome variables
Parameter Group 1 (EI) (n=46) Group 2 (LI) (n=47) p Value RR (CI)

Serum ferritin at 12 weeks (ng/mL) 82±5 63±3 <0.001

Haemoglobin at 12 weeks (g/dL) 10.1±0.4 9.2±0.4 <0.001
MCHC at 12 weeks (g/dL) 31.0±0.5 29.4±0.5 <0.001
hs-CRP at 12 weeks (mg/L) 5.5±3.0 5.7±2.8 0.69
Weight at 12 weeks (kg) 2.57±0.25 2.54±0.21 0.67
Head circumference at 12 weeks (cm) 33.5±0.8 33.4±0.7 0.46
Length at 12 weeks (cm) 46.1±1.8 46.1±1.2 0.76
Transfusion till 12 weeks* 2 (4.3) 7 (14.8) 0.15 0.29 (0.06 to 1.33)
ROP* 3 (6.5) 4 (8.5) 1.0 0.78 (0.18 to 3.30)
PVL* 1 (2.1) 2 (4.2) 1.0 0.51 (0.04 to 5.44)
Neurological deficits at 12 weeks* 1 (2.1) 4 (8.5) 0.36 0.25 (0.02 to 2.2)
NEC* (from 2 to 12 weeks postnatal age) 3 (6.5) 4 (8.5) 1.0 0.76 (0.18 to 3.23)
Sepsis* (from 2 to 12 weeks postnatal age) 3 (6.5) 4 (8.5) 1.0 0.76 (0.18 to 3.23)
Serum ferritin at 6 weeks (ng/mL)† 130±4 111±5 <0.001
Weight at 6 weeks (kg) 1.77±0.40 1.71±0.47 0.54
Head circumference at 6 weeks (cm) 31.2±1 31.1±1 0.49
Length at 6 weeks (cm) 41.5±8.7 40.7±10.5 0.18
*Values represented in number (percentages) and all other values represented in mean±SD.
†Assessed for 49 subjects in each group.
EI, early iron; hs-CRP, high-sensitivity C-reactive protein; LI, late iron MCHC, mean corpuscular haemoglobin concentration; NEC, necrotising enterocolitis; PVL, periventricular
leukomalacia; ROP, retinopathy of prematurity.

F4 Joy R, et al. Arch Dis Child Fetal Neonatal Ed 2013;0:F1–F5. doi:10.1136/archdischild-2013-304650

 Downloaded from fn.bmj.com on December 31, 2013 - Published by group.bmj.com
Box 1 Transfusion guidelines
Do not transfuse for blood alone
Do not transfuse for low haematocrit (Hct) alone
Transfuse at Hct ≤35% for infants who are
▸ receiving >35% oxygen
▸ on CPAP or mechanical ventilation with mean airway
pressure of 6–8 cm H2O
Transfuse at Hct ≤30% for infants who are
▸ receiving any supplemental oxygen
▸ on CPAP or mechanical ventilation with mean airway
pressure <6 cm H2O
▸ having significant apnoea and bradycardia (>9 episodes in
12 h or 2 episodes in 24 h requiring bagging) while on
therapeutic doses of methylxanthines
▸ experiencing heart rates >180 beats/min or RR >80 breaths/
min for 24 h
▸ experiencing weight gain <10 g/day over at least 4 days
while receiving 100 kcal/kg/day
▸ undergoing surgery
Transfuse at Hct ≤20% for infants who are
▸ asymptomatic with reticulocytes <100 000/μL
The merits of our study include a robust study design. We were
able to assess a high percentage of patients in both groups at
12 weeks. The study also had an adequate statistical power to
examine the primary outcome variable, that is, serum ferritin
levels. Also, there is paucity of medical literature regarding the
issue of EI versus LI supplementation in preterm VLBW neonates
in the developing countries. Earlier studies were mostly con-
ducted in developed countries,10 14 which limits the generalis-
ability of data. Our study therefore adds to medical literature
regarding this subject and has implications for policy and practice
parameters regarding the management of preterm VLBW babies.
Our study does have limitations. First, the caregivers were not
blinded to the interventions due to the effect of iron on stool
colour. Second, although the incidences of ROP, NEC and PVL
were not significantly different between the two groups, our
study was not powerful enough to examine these variables since
the sample size was calculated according to the primary
outcome variable. Therefore, further studies are needed to
examine these parameters.
In conclusion, we showed that early enteral supplementation
of iron at 2 weeks of age improves the nutritional iron status of
preterm VLBW (1000–1500 g) infants (as evidenced by serum
ferritin levels) compared with late supplementation at 6 weeks
postnatal age. Based on the findings of our study, it seems
prudent to include EI supplementation at 2 weeks postnatal age
in the routine care of preterm VLBW (1000–1500 g) infants.
Acknowledgements Intramural research grant was provided by the authors’
institution for estimation of serum ferritin and C-reactive protein, which is gratefully
acknowledged. We also thank Dr Bahubali (MBBS, MD, PhD scholar), JIPMER, for
helping in statistical analysis, and Anjana (PhD student, department of biochemistry)
and Durga Devi (biochemist), JIPMER, for assisting in laboratory work.
Contributors RJ collected data, reviewed literature, performed statistical analysis,
participated in protocol preparations and drafted the manuscript. SK conceptualised
the study, reviewed the literature, participated in protocol preparations and critically
reviewed the manuscript. AB participated in protocol preparations and management
of patients. MR and PHA supervised the laboratory tests. BVB participated in
protocol preparations, review of literature, management of patients and critically
revised the manuscript. All authors were involved in drafting of the manuscript and
approved the final version of the manuscript.
Joy R, et al. Arch Dis Child Fetal Neonatal Ed 2013;0:F1–F5. doi:10.1136/archdischild-2013-304650
Original article
Funding JIPMER, Pondicherry (intramural research grant).
Competing interests None.
Patient consent Obtained.
Ethics approval Institute Ethical Committee for Human Studies, JIPMER,
Pondicherry, India.
Provenance and peer review Not commissioned; externally peer reviewed.
REFERENCES
1 Rao R, Georgieff MK. Neonatal iron nutrition. Semin Neonatol 2001;6:425–35.
2 Rao R, Georgieff MK. Iron therapy for preterm infants. Clin Perinatol
2009;36:27–42.
3 Barclay SM, Lloyd DJ, Duffty P, et al. Iron supplements for preterm or low birth
weight infants. Arch Dis Child 1989;64:1621–2.
4 Halliday HL, Lappin TR, McClure G. Iron status of the preterm infant during the first
year of life. Biol Neonate 1984;45:228.
5 Olivares M, Llaguno S, Marin V, et al. Iron status in low-birth-weight infants, small
and appropriate for gestational age. A follow-up study. Acta Paediatr
1992;81:824–8.
6 Braekke K, Bechensteen AG, Halvorsen BL, et al. Oxidative stress markers and
antioxidant status after oral iron supplementation to very low birth weight infants.
J Pediatr 2007;151:23–8.
7 Thibeault DW. The precarious antioxidant defenses of the preterm infant. Am J
Perinatol 2000;17:167–81.
8 Friel JK, Andrews WL, Aziz K, et al. A randomized trial of two levels of iron
supplementation and developmental outcome in low birth weight infants. J Pediatr
2001;139:254–60.
9 Lundström U, Siimes MA, Dallman PR. At what age does iron supplementation
become necessary in low-birth-weight infants? J Pediatr 1977;91:878–83.
10 Arnon S, Shiff Y, Litmanovitz I, et al. The efficacy and safety of early
supplementation of iron polymaltose complex in preterm infants. Am J Perinatol
2007;24:95–100.
11 American Academy of Pediatrics, Committee on Nutrition. Nutritional needs of the
preterm infant. In: Kleinman RE, ed. Pediatric nutrition handbook. 5th edn. Chapel
Hill, NC: American Academy of Pediatrics, 2004:23–54.
12 Nutrition Committee, Canadian Pediatric Society. Nutrition needs and feeding of
premature infants. Can Med Assoc J 1995;152:1765–85.
13 Agostoni C, Buonocore G, Carnielli VP, et al. Enteral nutrient supply for preterm infants:
commentary from the European Society for Paediatric Gastroenterology, Hepatology and
nutrition committee on Nutrition. J Paediatr Gastroenterol Nutr 2010;50:1–9.
14 Franz AR, Mihatsch WA, Sander S, et al. Prospective randomized trial of early versus
late enteral iron supplementation in infants with a birth weight of less than 1301
grams. Pediatrics 2000;106:700–6.
15 Walsh MC, Kliegman RM. Necrotizing enterocolitis: treatment based on staging
criteria. Pediatr Clin North Am 1986;33:179–201.
16 De Vries LS, Van Haastert IL, Rademaker KJ, et al. Ultrasound abnormalities
preceding cerebral palsy in high-risk preterm infants. J Pediatr 2004;144:815–20.
17 Iannotti LL, Tielsch JM, Black MM, et al. Iron supplementation in early childhood:
health benefits and risks. Am J Clin Nutr 2006;84:1261–76.
18 Brozovic B, Burland WL, Simpson K, et al. Iron status of preterm low birthweight
infants and their response to oral iron. Arch Dis Child 1974;49:386–9.
19 Hall RT, Wheeler RE, Benson J, et al. Feeding iron-fortified premature formula
during initial hospitalization to infants less than 1800 grams birth weight. Pediatrics
1993;92:409–14.
20 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;44:507–11.
21 Sunita SP, Chitra CK, Sunil KP. Conventional and newer oral iron preparations.
Int J Med Pharm Sci 2012;2:16–22.
22 Shannon KM, Keith JF III, Mentzer WC, et al. Recombinant human erythropoietin
stimulates erythropoiesis and reduces erythrocyte transfusions in very low birth
weight preterm infants. Pediatrics 1995;95:1–8.
23 Sankar MJ, Saxena R, Mani K, et al. Early iron supplementation in very low
birth weight infants–a randomized controlled trial. Acta Paediatr 2009;98:953–8.
24 Miller SM, McPherson RJ, Juul SE. Iron sulfate supplementation decreases zinc
protoporphyrin to heme ratio in premature infants. J Pediatr 2006;148:44–8.
25 Berglund S, Westrup B, Domellof M. Iron supplements reduce the risk of iron deficiency
anemia in marginally low birth weight infants. Pediatrics 2010;126:874–83.
26 Aggarwal D, Sachdev HP, Nagpal J, et al. Haematological effect of iron supplementation
in breast fed term low birth weight infants. Arch Dis Child 2005;90:26–9.
27 Long H, Yi JM, Hu PL, et al. Benefits of Iron supplementation for low birth weight
infants: a systematic review. BMC Pediatr 2012;12:99.
28 Steinmacher J, Pohlandt F, Bode H, et al. Randomized trial of early versus late enteral
iron supplementation in infants with a birth weight of less than 1301grams:
neurocognitive development at 5.3 years’ corrected age. Pediatrics 2007;120:538–46.
29 Kandraju H, Agrawal S, Geetha K, et al. Gestational age-specific centile charts for
anthropometry at birth for South Indian infants. Indian Pediatr 2012;49:199–202.
F5
 Downloaded from fn.bmj.com on December 31, 2013 - Published by group.bmj.com

Early versus late enteral prophylactic iron

supplementation in preterm very low birth
weight infants: a randomised controlled trial
Rojo Joy, Sriram Krishnamurthy, Adhisivam Bethou, et al.

Arch Dis Child Fetal Neonatal Ed published online December 3, 2013

doi: 10.1136/archdischild-2013-304650

Updated information and services can be found at:

http://fn.bmj.com/content/early/2013/12/03/archdischild-2013-304650.full.html

These include:
References This article cites 28 articles, 9 of which can be accessed free at:
http://fn.bmj.com/content/early/2013/12/03/archdischild-2013-304650.full.html#ref-list-1

P<P Published online December 3, 2013 in advance of the print journal.

Email alerting Receive free email alerts when new articles cite this article. Sign up in
service the box at the top right corner of the online article.

Topic Articles on similar topics can be found in the following collections

Collections
Clinical trials (epidemiology) (202 articles)
Epidemiologic studies (683 articles)
Eye Diseases (67 articles)
Ophthalmology (96 articles)

Advance online articles have been peer reviewed, accepted for publication, edited and
typeset, but have not not yet appeared in the paper journal. Advance online articles are
citable and establish publication priority; they are indexed by PubMed from initial
publication. Citations to Advance online articles must include the digital object identifier
(DOIs) and date of initial publication.

To request permissions go to:

http://group.bmj.com/group/rights-licensing/permissions

To order reprints go to:

http://journals.bmj.com/cgi/reprintform

To subscribe to BMJ go to:

http://group.bmj.com/subscribe/
 Downloaded from fn.bmj.com on December 31, 2013 - Published by group.bmj.com

Notes

Advance online articles have been peer reviewed, accepted for publication, edited and
typeset, but have not not yet appeared in the paper journal. Advance online articles are
citable and establish publication priority; they are indexed by PubMed from initial
publication. Citations to Advance online articles must include the digital object identifier
(DOIs) and date of initial publication.

To request permissions go to:

http://group.bmj.com/group/rights-licensing/permissions

To order reprints go to:

http://journals.bmj.com/cgi/reprintform

To subscribe to BMJ go to:

http://group.bmj.com/subscribe/