Iron supplementation in enterally fed preterm infants

(Protocol)

Mills RJ, Davies MW, McGuire W

This is a reprint of a Cochrane protocol, prepared and maintained by The Cochrane Collaboration and published in The Cochrane
Library 2007, Issue 4

http://www.thecochranelibrary.com

1

Iron supplementation in enterally fed preterm infants (Protocol)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd

T A B L E O F C O N T E N T S

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ABSTRACT

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BACKGROUND

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OBJECTIVES

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CRITERIA FOR CONSIDERING STUDIES FOR THIS REVIEW

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SEARCH METHODS FOR IDENTIFICATION OF STUDIES

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METHODS OF THE REVIEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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POTENTIAL CONFLICT OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . .

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SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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COVER SHEET

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i

Iron supplementation in enterally fed preterm infants (Protocol)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd

Iron supplementation in enterally fed preterm infants
(Protocol)

Mills RJ, Davies MW, McGuire W

This record should be cited as:
Mills RJ, Davies MW, McGuire W. Iron supplementation in enterally fed preterm infants. (Protocol) Cochrane Database of Systematic
Reviews 2005, Issue 1. Art. No.: CD005095. DOI: 10.1002/14651858.CD005095.

This version first published online: 24 January 2005 in Issue 1, 2005.
Date of most recent substantive amendment: 15 November 2004

A B S T R A C T

This is the protocol for a review and there is no abstract. The objectives are as follows:
The primary objective of this systematic review is to determine whether enteral iron supplementation improves the growth and
neurodevelopmental outcome of premature and low birth weight infants.
The secondary objectives are:
(a) To determine whether iron supplementation results in improved haematological parameters and body iron stores in premature and
low birth weight infants
(b) To assess whether enteral iron supplementation to these infants prevents other causes of morbidity and mortality
(c) To determine the optimum dosage and timing of enteral iron supplementation
A subgroup analysis will separately compare trials involving exclusively formula-fed infants, and those involving exclusively or partially
breast-fed infants.
Data permitting, further sub-group analyses are planned to determine whether outcomes differ by:
i. Postnatal age of commencement of iron supplementation
ii. Total duration of iron supplementation
iii. Daily dose of supplemental iron administered
iv. Gestational age at birth of subjects
vi. Birth weight of subjects

B A C K G R O U N D

Most of the healthy term newborn’s iron stores have been laid down
during the third trimester. Therefore, this important acquisition
of iron stores is reduced in preterm infants. The preterm infant has
a higher requirement for iron due to proportionally more rapid
postnatal growth than that of the term infant. This exacerbates
the total body iron deficit of the preterm infant, as iron stores
decrease over the first three months of postnatal life. While non-
iron supplemented term infants have not been shown to develop
biochemical or haematological iron deficiency before six months
of age, there is a high rate of iron deficiency anaemia in preterm
infants fed only breast milk (Doyle 1992).

Human milk contains only 0.5 mg/L of elemental iron, while iron

fortified formulas contain at least 10 times that amount of iron per
volume. Despite their limited erythropoiesis, breast fed preterm
infants are in negative iron balance for at least the first 30 days
of life, due to obligatory intestinal and insensible skin loss of iron
(Shaw 1982).

Several studies have demonstrated improved haemoglobin and fer-
ritin levels in low or very low birth weight infants who were sup-
plemented with enteral iron, when compared with breast milk or
unfortified cow milk formula (Lundstrom 1977; Friel 2001; Grif-
fin 1999; Hall 1993; Franz 2000; Melnick 1988). In particular,
this improvement is observed after several months of life, during
the “late” anaemia of prematurity, rather than at the time of the
“early” anaemia of prematurity, in which the red cell mass has its
nadir at around six weeks’ postnatal age.

1

Iron supplementation in enterally fed preterm infants (Protocol)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd

However, the evidence is unclear as to whether this improvement
in biochemical and haematological parameters is associated with
a clinically detectable degree of difference in neurodevelopmental
outcome in preterm and low birth weight infants. Studies in term
infants have demonstrated a correlation between iron deficiency
anaemia and reduced performance in developmental testing (Lo-
zoff 1987, Walter 1989). A benefit of iron supplementation on low
birth weight infants’ weight gain was suggested by Reedy 1952,
but has not been consistently demonstrated (for example, Hall
1993).

The potential risks of iron supplementation need to be considered.
While studies to date do not suggest an association between iron
supplementation of preterm or low birth weight infants and in-
creased mortality or hospital readmission rates, putative risks have
been suggested related to iron’s ability to cause oxidative injury.
Iron overload can occur in the setting of multiple transfusions
(Ng 2001). High transfusion requirements early in life have been
shown to be associated with a greater risk of retinopathy of pre-
maturity (Dani 2001; Inder 1997; Hesse 1997). Increased body
iron load has also been hypothesized to increase the risk of chronic
lung disease (Cooke 1997). In addition to the direct oxidative
property of iron, large iron doses decrease the absorption of the
anti-oxidant Vitamin E, thus exacerbating anaemia in Vitamin E
deficient neonates (Doyle 1992). Another possible adverse effect
of enteral iron supplementation is impairment of zinc and copper
absorption (Friel 2001).

Iron fortification of formulas has been suspected, but not proven,
to cause a range of gastrointestinal symptoms in infants (Hyams
1995). While necrotizing enterocolitis (NEC) has not been explic-
itly linked to enteral iron supplementation, it is recognized that
human milk is protective against NEC (McGuire 2003).

If enteral iron supplementation is accepted as being a beneficial
intervention, the optimum time of initiation and cessation remains
to be defined. For example, Franz et al found that early initiation of
iron supplementation, as soon as enteral feeding was established,
resulted in superior haematological outcomes than when treatment
was begun at 61 days of age (Franz 2000). It is suggested that
premature infants should receive iron supplementation for at least
the first year of life (Gorten 1964). Similarly, the optimal dose of
iron requires clarification.

O B J E C T I V E S

The primary objective of this systematic review is to determine
whether enteral iron supplementation improves the growth and
neurodevelopmental outcome of premature and low birth weight
infants.

The secondary objectives are:

(a) To determine whether iron supplementation results in im-
proved haematological parameters and body iron stores in prema-
ture and low birth weight infants
(b) To assess whether enteral iron supplementation to these infants
prevents other causes of morbidity and mortality
(c) To determine the optimum dosage and timing of enteral iron
supplementation

A subgroup analysis will separately compare trials involving ex-
clusively formula-fed infants, and those involving exclusively or
partially breast-fed infants.

Data permitting, further sub-group analyses are planned to deter-
mine whether outcomes differ by:

i. Postnatal age of commencement of iron supplementation
ii. Total duration of iron supplementation
iii. Daily dose of supplemental iron administered
iv. Gestational age at birth of subjects
vi. Birth weight of subjects

C R I T E R I A F O R C O N S I D E R I N G
S T U D I E S F O R T H I S R E V I E W

Types of studies

All randomised controlled trials, in which individual infants were
either:
i. Allocated to enteral iron supplementation, and compared with
a control group; or
ii. Allocated to different regimens of iron supplementation (in
regard to dosage, duration and timing of initiation)

Cross-over studies will be excluded.

Types of participants

Infants born preterm (before 37 weeks’ completed gestation), or
of low birth weight (<2500g).

Types of intervention

i. Provision of an enteral iron supplement of at least 1mg/kg/day of
iron in breast feeding babies, compared to unsupplemented breast
milk
ii. Feeding with iron fortified formula (providing at least the equiv-
alent of 1mg/kg/day of iron), compared with low iron formula
(less than 1mg/kg/day of iron)
iii. Comparison of two or more different regimens of iron sup-
plementation, in regard to the dosage, duration, and timing of
initiation of iron supplementation

Types of outcome measures

Primary outcomes:
i. Standardised measures of neurodevelopmental outcome (e.g.
Bayley MDI and PDI), at 12 months or less, 2 years or less, and
5 years or less

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Iron supplementation in enterally fed preterm infants (Protocol)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd

ii. Length, weight and head circumference at 12 months or less, 2
years or less, and 5 years or less

Secondary outcomes:
i. Blood haemoglobin concentration and mean corpuscular vol-
ume (MCV), at 6-8 weeks, 3-4 months, 6-9 months, and 12
months
ii. Serum ferritin concentration, transferrin saturation, and to-
tal iron binding capacity (TIBC), at 6-8 weeks, 3-4 months, 6-9
months, and 12 months
iii. Significant anaemia (haemoglobin level <8g/dl or haematocrit
<0.25) with evidence of oxidative stress (e.g. Heinz bodies)
iv. Mortality
v. Chronic lung disease (persisting oxygen requirement at 36 weeks
post-conceptional age)
vi. Retinopathy of prematurity
vii. Necrotising enterocolitis
viii. Septicaemia (blood culture proven)
ix. Enteral feed intolerance
x. Total duration of primary hospitalisation
xi. Requirement for readmission to hospital in the first year of life

S E A R C H M E T H O D S F O R
I D E N T I F I C A T I O N O F S T U D I E S

See: methods used in reviews.

Searches will be made of MEDLINE from 1951, CINAHL from
1982, the Oxford Database of Perinatal Trials, and the current
Cochrane Central Register of Controlled Trials (CENTRAL, The
Cochrane Library, Issue 1, 2004) using the following strategy:

MeSH search terms ’Iron/tu [Therapeutic use]’, ’Iron/ad
[Administration and dosage]’, ’Iron, Dietary’, ’Ferrous
compounds/tu [Therapeutic use]’, or text words ’ferrous
sulphate’, ’ferrous sulfate’, ’ferrous gluconate’
AND
MeSH search term ’infant’, or text words ’preterm’, ’premature’,
’low birth weight’

We will also search previous reviews (including cross references),
abstracts, and conference and symposia proceedings published
in Pediatric Research. Searches will not be restricted by language
of publication. Lead investigators of included studies will
be contacted to identify unpublished studies which fulfil the
inclusion criteria.

M E T H O D S O F T H E R E V I E W

To assess the methodological quality of the trials, the standard
criteria and methods of the Cochrane Collaboration (Clarke 2002)
and its Neonatal Review Group will be used. The reviewers
will work independently to search for trials for inclusion and

to assess methodological quality. Studies will be assessed using
the following key criteria: blinding of randomization, blinding
of intervention, completeness of follow up and blinding of
outcome measurement. Data will be extracted independently by
the reviewers. Differences will be resolved by discussion and
consensus of the reviewers. If necessary, investigators will be
contacted for additional information or data.

For individual trials, where possible, mean differences (and 95%
confidence intervals) will be reported for continuous variables.
For categorical outcomes, the relative risk and risk difference (and
95% confidence intervals) will be reported.

For the meta-analysis, where possible, weighted mean differences
(and 95% confidence intervals) will be reported for continuous
variables, and the relative risk and risk difference (and 95%
confidence intervals) for categorical outcomes. A fixed effects
model will be used. Number needed to treat will be calculated
where appropriate.

Given sufficient numbers of included studies we will test for
heterogeneity where appropriate before deciding to pool the
results.

Results of studies involving formula-fed babies and breast-fed
babies will be pooled for the primary analysis, and then examined
separately as a subgroup analysis.

The details of the planned subgroup analyses are as follows:
(a) Separately compare trials involving exclusively formula-fed
infants, and those involving exclusively or partially breast-fed
infants

(b) Where data permits, further sub-group analyses are planned
to determine whether outcomes differ by:
i. Postnatal age of commencement of iron supplementation (less
than one month vs. one month or more)
ii. Total duration of iron supplementation (less than nine months
vs. nine months or more)
iii. Daily dose of supplemental iron administered (less than 1.5
mg/kg/day vs. 1.5 mg/kg/day ore more)
iv. Gestational age at birth of subjects (less than or equal to 33
completed weeks vs. more than 33 completed weeks)
vi. Birth weight of subjects (less than 1500g vs. 1500g or more)

Where data permits, sensitivity analysis will be performed on the
basis of study quality.

P O T E N T I A L C O N F L I C T O F
I N T E R E S T

None

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Iron supplementation in enterally fed preterm infants (Protocol)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd

S O U R C E S O F S U P P O R T

External sources of support

• No sources of support supplied

Internal sources of support

• Grantley Stable Neonatal Unit, Royal Women’s Hospital, Bris-

bane AUSTRALIA

• Dept of Paediatrics and Child Health, University of Queens-

land, Brisbane AUSTRALIA

• Dept of Paediatrics, Logan Hospital AUSTRALIA

R E F E R E N C E S

Additional references

Cooke 1997

Cooke RW, Drury JA, Yoxall CW, James C. Blood transfusion and
chronic lung disease in preterm infants. European Journal of Pediatrics
1997;156:47–50.

Curran 2000

Curran JS, Barness LA. The Feeding of Infants and Children. In:
BehrmanRE, KliegmanRM, JensonHB editor(s). Nelson Textbook of
Pediatrics. 16. Sydney: WB Saunders Company, 2000:149–168.

Dani 2001

Dani C, Reali MF, Bertini G, Martelli E, Pezzati M, Rubaltelli FF.
The role of blood transfusions and iron intake on retinopathy of
prematurity. Early Human Development 2001;62:57–63.

Doyle 1992

Doyle JJ, Zipursky A. Neonatal blood disorders. In: SinclairJC,
BrackenMB editor(s). Effective Care of the Newborn Infant. Oxford:
Oxford University Press, 1992:Oxford University Press; 1992. p. 425-
253.

Franz 2000

Franz AR, Mihatsch WA, Sander S, Kron M, Pohlandt F. Prospective
randomized trial of early versus late enteral iron supplementation in
infants with a birth weight of less than 1301grams. Pediatrics 2000;
106:700–6.

Friel 1990

Friel JK, Andrews WL, Matthew JD, Long DR, Cornel AM, Cox
M, et al. Iron status of very-low-birth-weight infants during the first
15 months of infancy. CMAJ 1990;143:733–7.

Friel 2001

Friel JK, Andrews WL, Aziz K, Kwa PG, Lepage G, L’Abbe MR. A
randomized trial of two levels of iron supplementation and devel-
opmental outcome in low birth weight infants. Journal of Pediatrics
2001;139:254–60.

Gorten 1964

Gorten MK, Cross ER. Iron metabolism in premature infants: II.
Prevention of iron deficiency. Journal of Pediatrics 1964;64:509–20.

Griffin 1999

Griffin IJ, Cooke RJ, Reid MM, McCormick KP, Smith JS. Iron
nutritional status in preterm infants fed formulas fortified with iron.

Archives of Disease in Childhood Fetal & Neonatal Edition 1999;81:
F45–9.

Gross 1974

Gross S, Melhorn DK. Vitamin E-dependent anemia in the prema-
ture infant. Journal of Pediatrics 1974;85:753–9.

Gross 1985

Gross SJ, Gabriel E. Vitamin E status in preterm infants fed human
milk or infant formula. Journal of Pediatrics 1985;106:635–9.

Hall 1993

Hall RT, Wheeler RE, Benson J, Harris G, Rippetoe L. Feeding iron-
fortified premature formula during initial hospitalization to infants
less than 1800 grams birth weight. Pediatrics 1993;92:409–14.

Hammond 1960

Hammond D, Murphy A. The influence of exogenous iron of for-
mation of hemoglobin in the premature infant. Pediatrics 1960;25:
362–74.

Hesse 1997

Hesse L, Eberl W, Schlaud M, Poets CF. Blood transfusion. Iron load
and retinopathy of prematurity. European Journal of Pediatrics 1997;
156:465–70.

Hyams 1995

Hyams JS, Treem WR, Etienne NL Weinerman H, MacGilpin D,
Hine P, Choy K, Burke G. Effect of infant formula on stool charac-
teristics of young infants. Pediatrics 1995;95:50–4.

Inder 1997

Inder TE, Clemett RS, Austin NC, Graham P, Darlow BA. High iron
status in very low birth weight infants is associated with an increased
risk of retinopathy of prematurity. Journal of Pediatrics 1997;131:
541–4.

James 1960

James JA, Combes M. Iron deficiency in the premature infant: Signif-
icance, and prevention by the intramuscular administration of iron-
dextran. Pediatrics 1960;26:368–74.

Lozoff 1987

Lozoff B, Brittenham GM, Wolf AW, McClish DK, Kuhnert PM,
Jimenez E, et al. Iron deficiency anaemia and iron therapy effects on
infant developmental test performance. Pediatrics 1987;79:981–95.

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Iron supplementation in enterally fed preterm infants (Protocol)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd

Lundstrom 1977

Lundstrom U, Siimes MA, Dallman PR. At what age does iron sup-
plementation become necessary in low-birth-weight infants?. Journal
of Pediatrics 1977;91:878–83.

McGuire 2003

McGuire W, Anthony MY. Donor human milk versus formula for
preventing necrotising enterocolitis in preterm infants: systematic
review. Archives of Disease in Childhood Fetal & Neonatal Edition
2003;88:F11–14.

Melhorn 1971

Melhorn DK, Gross S. Vitamin E-dependent anemia in the prema-
ture infant. I. Effects of large doses of medicinal iron. Journal of Pe-
diatrics 1971;79:569–80.

Melnick 1988

Melnick G, Crouch JB, Caksackkas HL, Churella HR. Iron status
of low-birth-weight infants fed formulas containing high or low iron
content. Pediatric Research 1988;23:488A.

Moffatt 1994

Moffatt ME, Longstaffe S, Besant J, Dureski C. Prevention of iron
deficiency and psychomotor decline in high-risk infants through use
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Ng 2001

Ng PC, Lam CW, Lee CH, To KF, Fok TF, Chan IH, et al. Hepatic
iron storage in very low birthweight infants after multiple blood
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Olivares M, Llaguno S, Marin V, Hertrampf E, Mena P, Milad M.
Iron status in low-birth-weight infants, small and appropriate for
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Rao R, Georgieff RR. Perinatal aspects of iron metabolism. Acta
Paediatrica Suppl 2002;91:124–9.

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Reedy ME, Schwartz SO, Plattner EB. Anemia of the premature
infant: A two-year study of the response to iron medication. Journal
of Pediatrics 1952;41:25–39.

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Rudolph N, Preis O, Bitzos E, Reale MM, Wong SL. Hematologic
and selenium status of low-birth-weight infants fed formulas with
and without iron. Journal of Pediatrics 1981;99:57–62.

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Shaw JC. Iron absorption by the premature infant. The effect of
transfusion and iron supplements on the serum ferritin levels. Acta
Paediatrica Scandinavica Suppl 1982;299:83–9.

Sitarz 1960

Sitarz AL, Wolff JA, Von Hofe FH. Comparison of oral and intra-
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C O V E R S H E E T

Title

Iron supplementation in enterally fed preterm infants

Authors

Mills RJ, Davies MW, McGuire W

Contribution of author(s)

Information not supplied by author

Issue protocol first published

2005/1

Date of most recent amendment

22 November 2004

Date of most recent
SUBSTANTIVE amendment

15 November 2004

What’s New

Information not supplied by author

Contact address

Dr Ryan John Mills
Senior Paediatric Registrar
Department of Paediatrics
Logan Hospital
Meadowbrook
Queensland
AUSTRALIA
E-mail: [e-mail]

DOI

10.1002/14651858.CD005095

Cochrane Library number

CD005095

5

Iron supplementation in enterally fed preterm infants (Protocol)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd

Editorial group

Cochrane Neonatal Group

Editorial group code

HM-NEONATAL

6

Iron supplementation in enterally fed preterm infants (Protocol)
Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd