Summary
In this single blinded parallel-group randomized
controlled trial (RCT), preterm very-low-birth-weight (VLBW) infants
received early iron (EI) supplementation (starting at 2 weeks postnatal
age), or late iron (LI) supplementation (starting at 6 weeks postnatal
age) [1]. The primary outcome was serum ferritin level at 12 weeks, and
the secondary outcomes were the incidence of neonatal morbidities,
hemoglobin level, anthropometric parameters and blood transfusion
requirements. Outcomes were analyzed in 46 and 47 babies in EI and LI
groups, respectively. Serum ferritin level was significantly higher (P<0.001)
at 12 weeks in the EI group. Hemoglobin and mean corpuscular hemoglobin
concentration (MCHC) were also significantly (P<0.001) higher at
12 weeks in the EI group. There were no significant differences in the
incidences of neonatal morbidities [necrotizing enterocolitis (NEC),
periventricular leukomalacia, retinopathy of prematurity (ROP)],
anthropometric parameters and blood transfusion requirements between the
two groups. The authors concluded that EI supplementation in preterm
VLBW infants improves serum ferritin and hemoglobin levels.
Commentaries
Evidence - based - medicine Viewpoint
This RCT on early versus late enteral iron
supplementation in preterm VLBW babies is timely, generalizable and well
conceived. The authors concluded that EI supplementation in preterm VLBW
infants improves serum ferritin, hemoglobin and MCHC at 12 weeks of
postnatal age without any concomitant difference in inflammation to
account for the difference in ferritin levels. The study is justified
because there is still substantial uncertainty about the optimal age at
which enteral iron supplementation should commence in such infants. The
method of randomization and allocation concealment in the study is
appropriate. Measurement bias was restricted by masking the outcome
analyzers. One of the potential dangers of EI supplementation is
increase in free radical mediated diseases, such as NEC and ROP. The
authors rightly concluded that although their trial was not able to
detect a significant difference in these diseases, the study was
underpowered to do so. The study confirms the efficacy of early iron
supplementation but it is inconclusive regarding the safety of the
intervention. Only a large study or a meta-analysis of existing trials
may be able to shed light on the equally important issue of safety.
On the downside, the authors seem to have randomized
to force equal numbers in the two arms (this was an unblocked trial!).
This can create a selection bias towards the end of an unblinded study.
They did not administer a placebo from 2-5 weeks in the standard
treatment arm using the plea that stool color would have anyways
unmasked the group of allocation; but I believe there are simple and
imaginative ways to get around this problem. They mention in passing
that "restrictive transfusion guidelines were followed" but it is not
clear how assiduously these were enforced. There is no data on the type
of milk feeds. Not blinding the caregivers could potentially result in
performance bias and consequent differences in blood transfusions, type
of milk feeds and frequency of blood sampling between the two groups –
all of which can affect the ferritin levels. The authors did not perform
an intention to treat analysis. They calculated the sample size based on
a one-tailed alpha error – which is methodologically suspect.
The authors noted a substantial decline in the
ferritin levels from 6 weeks to 12 weeks in both the arms. They
explained this as being due to ‘accelerated erythropoesis due to anemia
of prematurity’ which does not appear a convincing explanation because
anemia of prematurity has suppressed erythropoesis. It accelerates only
when erythropoetin is supplemented, which was not the case in this
study.
This study, with a low to moderate risk of bias,
suggests that EI improves iron stores. More data are required to
demonstrate that EI does not increase the risk of free radical mediated
diseases in preterms.
Sourabh Datta
Department of Pediatrics,
PGIMER, Chandigarh, India.
Email:
[email protected]
Hematologist’s Viewpoint
Joy, et al. [1] have demonstrated that early
iron supplementation (at 2 weeks of age) improves iron status of preterm
VLBW infants (as evidenced by serum ferritin levels) compared with late
supplementation at 6 weeks of postnatal age – in a typical Indian milieu
[1]. It is unclear if children in either group received formula milk in
addition to breast milk. Formula milk is iron fortified; information
would have helped to understand the feeding profile of the cohort.
The findings are consistent with recent systematic
reviews: data suggest that iron supplementation increases the levels of
hematologic indicators of iron status in low birth weight/premature
infants. However, it is unclear whether iron supplementation in preterm
and low birth weight infants has long term benefits in terms of
neurodevelopmental outcome and growth, or the occurrence of adverse
effects [2,3].
A serum ferritin less than 12 µg/L is typically
described as the cut-off for defining iron deficiency. It is not stated
if any infant had a serum ferritin <12 µg/L at any time period. It would
be noteworthy, as the increment in hemoglobin was higher in early
supplementation group, despite plausibly none/or few infants fulfilling
definition of iron deficiency. It makes one contemplate, if the ‘adult’
reference for serum ferritin of 12 µg/L is a suboptimal cut-off for
defining iron deficiency in this patient profile [4].
Early iron supplementation appears alluring for
preterm VLBW infants, though robust long term neuro-developmental data
is lacking.
Deepak Bansal
Pediatric Hematology-Oncology Unit
PGIMER, Chandigarh, India.
Email:
[email protected]
Neonatologist’s Viewpoint
This study suggests that early iron supplementation
in VLBW infants – at 2 weeks rather than at 6 weeks – improved
hematological indices without any difference in major neonatal
morbidities. ‘How it will influence the practice of neonatologists and
pediatricians in private sector in India’ is a fascinating research
question. Neonatal care in private health sector in India is highly
heterogeneous and is delivered in private nursing homes, smaller
community hospitals, corporate hospitals, and National Neonatology Forum
(NNF) accredited level II and level III neonatal units. These units are
in variable stages of development in terms of available resources,
infrastructure and nursing and medical workforce. Thus, outcomes of VLBW
infants in private sector not only depend on actual clinical policies
and practices, but also in the context in which the individual neonate
receives the care.
A brief literature review of bibliographic databases
Google scholar and PubMed using search terms ‘iron supplementation’,
‘neonates’, ‘preterm’, ‘India’ did not reveal any study about
neonatologists’/pediatricians’ practices on the issue of iron
supplementation in VLBW neonates. In the absence of any such information
and high heterogeneity in the current practices, it is improbable that
these will be influenced with this research study. I suggest researching
the practices and knowledge of private health care providers on iron
supplementation in preterm neonates.
Pankaj Garg
Discipline of Pediatrics and Child
Health
Central Clinical School,
University of Sydney, Australia.
Email:
[email protected]
1. Joy R, Krishnamurthy S, Bethou A, Rajappa M,
Ananthanarayanan PH, Bhat BV. Early versus late enteral prophylactic
iron supplementation in preterm very low birth weight infants: a
randomised controlled trial. Arch Dis Child Fetal Neonatal Ed. 2014;
99:F105-9.
2. Long H, Yi JM, Hu PL, Li ZB, Qiu WY, Wang F, et
al. Benefits of iron supplementation for low birth weight infants: a
systematic review. BMC Pediatr. 2012;12:99.
3. Mills RJ, Davies MW. Enteral iron supplementation
in preterm and low birth weight infants. Cochrane Database Syst Rev.
2012;3:CD005095.
4. Siddappa AM, Rao R, Long JD, Widness JA, Georgieff
MK. The assessment of newborn iron stores at birth: a review of the
literature and standards for ferritin concentrations. Neonatology.
2007;92:73-82.