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Early versus late enteral prophylactic iron supplementation in preterm very

low birth weight infants: A randomised controlled trial

Article  in  Archives of Disease in Childhood - Fetal and Neonatal Edition · December 2013

DOI: 10.1136/archdischild-2013-304650 · Source: PubMed


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6 authors, including:

Sriram Krishnamurthy Bethou Adhisivam

Jawaharlal Institute of Postgraduate Medical Education & Research Jawaharlal Institute of Postgraduate Medical Education & Research


Medha Rajappa Ananthanarayanan P H

Jawaharlal Institute of Postgraduate Medical Education & Research Jawaharlal Institute of Postgraduate Medical Education & Research


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

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

F2 Joy R, et al. Arch Dis Child Fetal Neonatal Ed 2013;0:F1–F5. doi:10.1136/archdischild-2013-304650

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

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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
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

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Funding JIPMER, Pondicherry (intramural research grant).

Box 1 Transfusion guidelines Competing interests None.
Patient consent Obtained.
Do not transfuse for blood alone Ethics approval Institute Ethical Committee for Human Studies, JIPMER,
Do not transfuse for low haematocrit (Hct) alone Pondicherry, India.
Transfuse at Hct ≤35% for infants who are Provenance and peer review Not commissioned; externally peer reviewed.
▸ receiving >35% oxygen
▸ on CPAP or mechanical ventilation with mean airway
pressure of 6–8 cm H2O REFERENCES
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Joy R, et al. Arch Dis Child Fetal Neonatal Ed 2013;0:F1–F5. doi:10.1136/archdischild-2013-304650 F5

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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

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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.

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To order reprints go to:

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