CV-young2012-Nutrient-Enriched Formula Versus Standard Term Formula For Preterms

Nutrient-enriched formula versus standard term formula for
preterm infants following hospital discharge (Review)
Young L, Morgan J, McCormick FM, McGuire W
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2012, Issue 3
http://www.thecochranelibrary.com
Nutrient-enriched formula versus standard term formula for preterm infants following hospital discharge (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Figure 6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Figure 7. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
Analysis 1.1. Comparison 1 POST-DISCHARGE FORMULA VERSUS STANDARD TERM FORMULA, Outcome 1
Growth rates during trial period. . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
Weight (g). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Crown heel length (mm). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
Head circumference (mm). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
Development. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
Bone mineralization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
Analysis 2.1. Comparison 2 PRETERM FORMULA VERSUS STANDARD TERM FORMULA, Outcome 1 Growth
rates during trial period. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
Analysis 2.2. Comparison 2 PRETERM FORMULA VERSUS STANDARD TERM FORMULA, Outcome 2 Weight
(g). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
Analysis 2.3. Comparison 2 PRETERM FORMULA VERSUS STANDARD TERM FORMULA, Outcome 3 Crown
heel length (mm). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
Analysis 2.4. Comparison 2 PRETERM FORMULA VERSUS STANDARD TERM FORMULA, Outcome 4 Head
circumference (mm). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
Analysis 2.5. Comparison 2 PRETERM FORMULA VERSUS STANDARD TERM FORMULA, Outcome 5
Development. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . 52
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
Nutrient-enriched formula versus standard term formula for preterm infants following hospital discharge (Review) i
[Intervention Review]
Nutrient-enriched formula versus standard term formula for

preterm infants following hospital discharge
Lauren Young1 , Jessie Morgan1 , Felicia M McCormick2 , William McGuire1

1 Hull York Medical School & Centre for Reviews and Dissemination, University of York, York, UK. 2 Mother and Infant Research
Unit, Department of Health Sciences, University of York, York, UK
Contact address: William McGuire, Hull York Medical School & Centre for Reviews and Dissemination, University of York, York,
Y010 5DD, UK. William.McGuire@hyms.ac.uk.
Editorial group: Cochrane Neonatal Group.

Publication status and date: New search for studies and content updated (conclusions changed), published in Issue 3, 2012.
Review content assessed as up-to-date: 30 September 2011.
Citation: Young L, Morgan J, McCormick FM, McGuire W. Nutrient-enriched formula versus standard term formula for
preterm infants following hospital discharge. Cochrane Database of Systematic Reviews 2012, Issue 3. Art. No.: CD004696. DOI:
10.1002/14651858.CD004696.pub4.
ABSTRACT
Background
Preterm infants are often growth-restricted at hospital discharge. Feeding infants after hospital discharge with nutrient-enriched formula
rather than standard term formula might facilitate “catch-up” growth and improve development.
Objectives
To determine the effect of feeding nutrient-enriched formula compared with standard term formula on growth and development for
preterm infants following hospital discharge.
Search methods
We used the standard search strategy of the Cochrane Neonatal Review Group. This included searches of the Cochrane Central Register
of Controlled Trials (The Cochrane Library, 2011, Issue 4), MEDLINE, EMBASE, and CINAHL (to September 2011), conference
proceedings and previous reviews.
Selection criteria
Randomised or quasi-randomised controlled trials that compared the effect of feeding preterm infants following hospital discharge
with nutrient-enriched formula (post-discharge formula or preterm formula) compared with standard term formula.
Data collection and analysis
We extracted data using the standard methods of the Cochrane Neonatal Review Group, with separate evaluation of trial quality and
data extraction by two review authors.
Main results
We found 15 eligible trials in which a total of 1128 preterm infants participated. The trials were of variable methodological quality
with lack of allocation concealment and incomplete follow-up in some trials being the major potential sources of bias. The trials (N =
10) that compared feeding infants with “post-discharge formula” (energy density about 74 kcal/100 ml) versus standard term formula
(about 67 kcal/100 ml) did not find consistent evidence of effects on growth parameters up to 12 to 18 months corrected age. The trials
Nutrient-enriched formula versus standard term formula for preterm infants following hospital discharge (Review) 1
(N = 5) that compared feeding with “preterm formula” (about 80 kcal/100 ml) versus term formula found some evidence of higher
rates of growth through infancy: weighted mean differences at 12 to 18 months corrected age about 500 g in weight, 5 to10 mm in
length, and 5 mm in head circumference. Few trials assessed neurodevelopmental outcomes and these did not detect any statistically
significant differences in developmental indices at 18 months corrected age. There are not yet any data on growth or development
through later childhood.
Authors’ conclusions
Current recommendations to prescribe “post-discharge formula” for preterm infants following hospital discharge are not supported by
the available evidence. Some limited evidence exists that feeding preterm infants following hospital discharge with “preterm formula”
(which is generally only available for in-hospital use) may increase growth rates up to 18 months corrected age.
PLAIN LANGUAGE SUMMARY
Nutrient-enriched formula versus standard term formula for preterm infants following hospital discharge
Preterm infants are often much smaller than term infants by the time that they are discharged home from hospital. This review
attempted to identify trial evidence about whether feeding these infants with formula enriched with nutrients rather than ordinary
formula designed for term infants increased growth rates and improved development. We found 15 trials but these did not provide
strong or consistent evidence that unrestricted feeding with nutrient-enriched formula affects growth and development up to about 18
months of age. Long-term growth and development has not yet been assessed.
BACKGROUND catch up growth in preterm infants, especially of the head, is as-

Compared with term infants, preterm infants have limited nutri- sociated with a higher risk of neurodevelopmental impairment in
ent reserves at birth. Preterm infants, especially very preterm or later childhood, as well as with poorer cognitive and educational
very low birth weight (VLBW) infants, are additionally subject to outcomes (Hack 1991; Cooke 2003). Preterm infants who have
a variety of physiological and metabolic stresses that increase their accumulated deficits in calcium and phosphate are at higher risk of
nutrient needs. Recommended nutrient requirements for preterm poor bone mineralization, metabolic bone disease, and a reduced
infants are based on intrauterine growth studies and assume that rate of skeletal growth compared to infants born at term (Rigo
the optimal rate of postnatal growth should be about the same as 2000).
that of normal, uncompromised fetuses of an equivalent postmen-
strual age. However, evidence exists that in practice the recom-
mended target levels of nutrient input are rarely achieved and most Description of the intervention
very preterm or VLBW infants accumulate significant energy, pro- Because slow or incomplete catch up growth is associated with
tein, mineral, and other nutrient deficits during their hospital stay prolonged growth restriction and with slower neuro-developmen-
(Embleton 2001). Consequently, many preterm infants and most tal progression, attention has focused on nutritional interventions
very preterm or VLBW infants are growth restricted by the time that might promote growth during the putative ‘critical window’
they are ready for hospital discharge (Lucas 1984; Clark 2003). of early infancy in the post-discharge period. Two broad strategies
for nutritional interventions exist (Dusick 2003; Fewtrell 2003;
Klingenberg 2011):
Description of the condition • multi-nutrient fortification of expressed milk for infants fed
with human breast milk
Following hospital discharge, ad libitum (demand) fed preterm
• nutrient-enriched formula for formula fed infants
infants often consume more milk than term infants in order to at-
tain some “catch up” growth (Lucas 1992a). Despite this, growth Another Cochrane review addresses the question of whether
deficits can persist through childhood and adolescence (Ford 2000; multi-nutrient fortification of human breast milk affects growth
Farooqi 2006; Trebar 2007; Bracewell 2008). Slow or incomplete and development in preterm infants following hospital discharge
(McCormick 2010). This review focuses on the comparison of Why it is important to do this review
nutrient-enriched formula milk versus standard term formula for
Given the potential for post-discharge nutrition strategies to affect
formula fed preterm infants following hospital discharge.
growth and development in preterm infants, and since uncertainty
A variety of standard and nutrient-enriched formula preparations
exists about the balance between the putative benefits and harms,
are available (Aggett 2006; Griffin 2007). These can be categorised
an attempt to detect, appraise, and synthesise evidence from ran-
broadly as:
domised controlled trials is needed.
• standard term formula: designed for term infants, based on
the composition of mature human breast milk. The typical
energy content is 66 to 68 kcal/100 ml. The concentration of
protein, approximately 1.4 to 1.7 g/100 ml, and calcium and
phosphate content (about 50 mg/100 ml and 30 mg/100 ml OBJECTIVES
respectively) are not sufficient to provide the recommended To determine how feeding preterm infants following hospital dis-
nutrient needs for stable and growing preterm infants. charge with nutrient-enriched formula (preterm formula or post-
• post-discharge formula: specifically designed for preterm discharge formula) compared with standard term formula affects
infants post-discharge from hospital. These are energy (about 72 growth and development.
to 74 kcal/100 ml) and protein (about 1.8 to 1.9 g/100 ml)
enriched, and variably enriched with minerals, vitamins, and
trace elements compared to standard term formula. Expert METHODS
bodies and authorities recommend these formulae for preterm
infants for three to twelve months post-discharge (Aggett 2006).
• preterm formula: energy-enriched (about 80 kcal/100 ml),
Criteria for considering studies for this review
protein-enriched (2.0 to 2.4 g/100 ml), and variably enriched
with minerals, vitamins, and trace elements to support intra-
uterine nutrient accretion rates. These formulae are commonly
Types of studies
used for nutrition of preterm infants prior to hospital discharge
and are not generally recommended for post-discharge feeding. Controlled trials using random or quasi-random patient alloca-
tion. Studies published as abstracts were only eligible for inclusion
if assessment of study quality was possible and if other criteria for
inclusion were fulfilled.
How the intervention might work Types of participants

In theory, feeding preterm infants following hospital discharge Preterm infants fed with formula (exclusively or as a supplement to
with formula enriched with extra energy, protein, minerals and vi- human breast milk) following discharge from hospital. The inter-
tamins may be expected to promote more rapid catch up growth. vention may have commenced up to one week prior to planned dis-
However, because preterm infants fed in response to hunger and charge from hospital. Trials that randomly assigned infants to nu-
satiation cues (ad libitum or demand) adjust their volume of intake trient-enriched formula versus standard term formula more than
depending upon the energy-density of the formula, infants may one week prior to hospital discharge (and then continued the in-
consume less nutrient-enriched milk than standard term formula tervention after hospital discharge) were not to be included in this
(Lucas 1992a). Consequently, infants fed ad libitum with preterm review.
or post-discharge formula may not receive any more nutrients than
infants who receive standard term formula. Feeding with nutrient-
enriched formula may also be associated with disordered gastric Types of interventions
motility and emptying (Hancock 1984; Siegel 1984). Nutrient- • Standard term formula: energy content < 72 kcal/100 ml,
enriched formula may therefore be more poorly tolerated, so re- and protein content < 1.7 g/100 ml.
ducing nutrient delivery, and potentially removing any benefits for
versus either
growth and development. Furthermore, concern exists that catch
• Post-discharge formula: energy content > 72 kcal/100 ml
up growth with accelerated weight gain and crossing of body mass
(but < 75 kcal/100 ml) and protein content > 1.7 g /100 ml.
index (BMI) percentiles might be associated with altered fat dis-
• Preterm formula: energy content between > 75 kcal/100 ml
tribution and related ‘programmed’ metabolic consequences that
and protein content > 2.0 g/100 ml).
may increase the risk of insulin resistance and cardiovascular dis-
ease (Hack 2003; Doyle 2004; Euser 2005; Saigal 2006; Euser The formulae could be fed either as sole diet or as a supplement
2008). to human breast milk. Infants in the trial groups should have
received similar care other than the type of formula. For example, Infant, Premature OR Infant, Low Birth Weight OR infan* OR
there should not have been any differences between groups in neonat*] AND [“Infant-Nutrition”/ all subheadings OR Infant
the prescription of target levels of volume of intake, or advice or Formula OR milk OR formula OR post-discharge OR fortif* OR
support for demand feeding. supplement*].
The search outputs were limited with the relevant search filters for
clinical trials as recommended in the Cochrane Handbook. We
Types of outcome measures did not apply any language restriction.
We searched ClinicalTrials.gov and Current Controlled Trials for
completed or ongoing trials.
Primary outcomes
1. Growth: Weight, length, head growth, skinfold thickness,
BMI and measures of body composition (lean/fat mass) and Searching other resources
growth-restriction (proportion of infants who remain < 10th We examined the references in studies identified as potentially rel-
percentile for the index population’s distribution of weight, evant. We also searched the abstracts from the annual meetings
length, or head circumference). Long-term growth and growth- of the Pediatric Academic Societies (1993 to 2011), the European
restriction (proportion of infants who remain below the tenth Society for Pediatric Research (1995 to 2011), the UK Royal Col-
percentile for the index population’s distribution of weight, lege of Paediatrics and Child Health (2000 to 2011), and the Peri-
height, or head circumference). natal Society of Australia and New Zealand (2000 to 2011). We
2. Development: considered trials reported only as abstracts to be eligible if suffi-
i) Neurodevelopmental outcomes assessed using cient information was available from the report, or from contact
validated tools at > 12 months corrected age, and classifications with the authors, to fulfil the inclusion criteria.
of disability, including non-ambulant cerebral palsy,
developmental delay, auditory and visual impairment
ii) Cognitive and educational outcomes at > 5 years: Data collection and analysis
Intelligence quotient and/or indices of educational achievement
measured using a validated tool (including school examination We used the standard methods of the Cochrane Neonatal Review
results). Group.
Secondary outcomes Selection of studies
1. Feed intolerance such as vomiting or diarrhoea that Two review authors screened the title and abstract of all studies
necessitates ceasing the study formula. identified by the above search strategy. We reassessed the full text
2. Measures of bone mineralization such as serum alkaline of any potentially eligible reports and excluded those studies that
phosphatase level, or bone mineral content assessed by dual did not meet all of the inclusion criteria. We discussed any dis-
energy x ray absorptiometry and clinical or radiological evidence agreements until consensus was achieved.
of rickets on long term follow-up.
3. Blood pressure on long term follow-up.
Data extraction and management
4. Body mass index or other measures of overweight or obesity
on long term follow-up. We used a data collection form to aid extraction of relevant infor-
mation from each included study. Two review authors extracted
the data separately. We discussed any disagreements until consen-
sus was achieved. We asked the investigators for further informa-
Search methods for identification of studies tion if data from the trial reports were insufficient.
We used the standard search strategy of the Cochrane Neonatal
Review Group.
Assessment of risk of bias in included studies
We used the criteria and standard methods of the Cochrane
Electronic searches Neonatal Review Group to assess the methodological quality of
We searched the Cochrane Central Register of Controlled Trials any included trials. Additional information from the trial authors
(CENTRAL, The Cochrane Library, Issue 4, 2011), MEDLINE was requested to clarify methodology and results as necessary. We
(1966 September 2011), EMBASE (1980 to September 2011), evaluated and reported the following issues in the Risk of Bias
and CINAHL (1982 to September 2011) using a combination of tables:
the following text words and MeSH terms: [Infant, Newborn OR
1. Sequence generation: We categorised the method used to the possible causes (for example, differences in study design, par-
generate the allocation sequence as: ticipants, interventions, or completeness of outcome assessments)
i) low risk (any random process e.g. random number in sensitivity analyses.
table; computer random number generator);
ii) high risk (any non random process e.g. odd or even
date of birth; patient case-record number); Assessment of reporting biases
iii) unclear. If more than five trials were included in a meta-analysis, we con-
2. Allocation concealment: We categorised the method used ducted a funnel plot analysis.
to conceal the allocation sequence as:
i) low risk (e.g. telephone or central randomisation;
consecutively numbered sealed opaque envelopes); Data synthesis
ii) high risk (open random allocation; unsealed or non- We used the fixed effect model in RevMan 5.1 for meta-analysis.
opaque envelopes, alternation; date of birth);
iii) unclear.
3. Blinding: We assessed blinding separately for different Subgroup analysis and investigation of heterogeneity
outcomes and categorised the methods as: We pre-specified the following sub-group analyses:
i) low risk, high risk or unclear for 1. very preterm (< 32 weeks) or VLBW (< 1500 g) infants;
a) participants; 2. infants who were small for gestational age (< 10th percentile
b) clinicians and caregivers and; for weight) at hospital discharge;
c) outcome assessors. 3. infants with chronic lung disease receiving supplemental
4. Incomplete outcome data: We described the completeness oxygen therapy at hospital discharge.
of data including attrition and exclusions from the analysis for
each outcome and any reasons for attrition or exclusion where
reported. We assessed whether missing data were balanced across
groups or were related to outcomes. Where sufficient information
was reported or supplied by the trial authors, re-included missing RESULTS
data in the analyses. We categorised completeness as:
i) low risk (< 20% missing data);
ii) high risk (> 20% missing data); Description of studies
iii) unclear.
See: Characteristics of included studies; Characteristics of excluded
studies; Characteristics of studies awaiting classification.
Measures of treatment effect
We calculated relative risk (RR) and risk difference (RD) for di-
Included studies
chotomous data and weighted mean difference (WMD) for con-
tinuous data, with respective 95% confidence intervals (CI). We We identified 15 trials that fulfilled the eligibility criteria (Lucas
determined the number needed to treat for benefit (NNTB) or 1992; Atkinson 1999; Lucas 2001; Cooke 2001; Carver 2001;
harm (NNTH) for a statistically significant difference in the RD. De Curtis 2002; Agosti 2003; Litmanovitz 2004; Atkinson 2004;
Peng 2004; Picaud 2005; Koo 2006; Taroni 2009; Roggero 2011a;
Jeon 2011; see Characteristics of included studies).
Unit of analysis issues Participants
The unit of analysis is the participating infant in individually ran- The trials were undertaken within the last 20 years by investigators
domised trials and the neonatal unit for cluster randomised trials. attached to perinatal centres in Europe, North America and the
middle-East. In total, 1128 infants have participated in these trials
(range 20 to 229).
Assessment of heterogeneity Most trials specified a maximum birth weight as the primary eli-
If more than one trial was included in a meta-analysis, we exam- gibility criterion:
ined the treatment effects of individual trials and heterogeneity • 1500 g: Agosti 2003; Litmanovitz 2004;Taroni 2009; Jeon
between trial results by inspecting the forest plots. We calculated 2011
the I² statistic for each analysis to quantify inconsistency across • 1750 g: Lucas 2001; Cooke 2001; De Curtis 2002; Picaud
studies and describe the percentage of variability in effect estimates 2005
that may be due to heterogeneity rather than sampling error. If • 1800 g: Atkinson 1999; Carver 2001
substantial (I² > 50%) heterogeneity was detected, we explored • 1850 g: Lucas 1992; Peng 2004
Three trials specified gestational age as an eligibility criterion: periods post term (or post hospital discharge):
• < 35 weeks: Koo 2006 • one month:Taroni 2009
• < 37 weeks: Atkinson 2004; Roggero 2011a • two months: De Curtis 2002; Picaud 2005
• three months: Agosti 2003; Jeon 2011
Three trials specifically recruited participants who were small for • six months: Cooke 2001; Litmanovitz 2004; Peng 2004;
gestational age: Roggero 2011a
• birth weight < 5th percentile: Atkinson 2004 • nine months: Lucas 1992; Lucas 2001
• birth weight <10th percentile: Taroni 2009; Roggero 2011a • up to 12 months: Atkinson 1999; Carver 2001; Atkinson
2004; Koo 2006
Of the other trials, although most reports did not specify intra-
Outcomes
uterine or postnatal growth restriction as exclusion criteria, it ap-
The main outcomes assessed were growth parameters (weight,
pears that very few participants in the trials were small for gesta-
length, and occipito-frontal head circumference) assessed up to
tional age at birth or enrolment.
12 to 18 months corrected age. Three trials assessed neuro-devel-
Generally, infants with additional problems at discharge, partic-
opmental outcomes at 18 months using Bayley Scales of Infant
ularly inadequate independent oral feeding or receipt of supple-
Development II (Lucas 2001; Cooke 2001; Jeon 2011). One trial
mental oxygen secondary to chronic lung disease, were not eligible
assessed Griffiths’ Developmental Scales at six, nine and twelve
to participate.
months corrected age(Agosti 2003).
Interventions
POST-DISCHARGE FORMULA VERSUS STANDARD
TERM FORMULA (Comparison 1) Excluded studies
10 trials (N = 762): Lucas 1992; Atkinson 1999; Carver 2001; We excluded nine studies (Cooper 1985; Bernbaum 1989; Bhatia
Lucas 2001; De Curtis 2002; Atkinson 2004; Litmanovitz 2004; 1991; Friel 1993; Chan 1994; Wheeler 1996; Brunton 1998;
Koo 2006;Taroni 2009; Roggero 2011a. Lapillonne 2004; Amesz 2010). The reasons for exclusion are listed
PRETERM FORMULA VERSUS STANDARD TERM FOR- in the table, Characteristics of excluded studies.
MULA (Comparison 2)
5 trials (N = 366): Cooke 2001; Agosti 2003; Peng 2004; Picaud
2005; Jeon 2011.
All of the participating infants were fed ad libitum. These feeds
Risk of bias in included studies
were intended to be the principal source of milk for a range of The trials were of variable methodological quality (Figure 1).
Figure 1. Risk of bias graph: review authors’ judgements about each risk of bias item presented as
percentages across all included studies.
Allocation Atkinson 1999 reported that infants who received post-discharge
In seven trials, the described method of randomisation was likely to formula were statistically significantly heavier at six, nine and
ensure blinding of allocation (Atkinson 1999; Cooke 2001; Lucas twelve months corrected age. There were not any statistically sig-
2001; Atkinson 2004; .Picaud 2005; Koo 2006; Cooke 2001). In nificant differences in length or head circumference.
the other trials, it is not clear whether allocation concealment was Carver 2001 did not detect any statistically significant differences
adequate. In one of these trials, substantial between-group differ- in weight, length, or head circumference at six and twelve months
ences in baseline demographic characteristics existed, most likely corrected age. There was substantial loss to follow-up during the
due to allocation bias (Jeon 2011). This trial originally randomised trial and since published report does not state how many infants
participants to one of three intervention groups. We elected to were assessed at the various time points the data could not be used
discard data from the group where infants’ characteristics were sta- to calculate mean differences.
tistically significantly different from other groups at enrolment. Lucas 2001 reported that at completion of the intervention pe-
riod (nine months corrected age), weight and length were statis-
tically significantly greater in infants who received post-discharge
Blinding formula but that there was not a statistically significant difference
Most of the trials blinded families to the type of milk that the in head circumference. At 18 months, there were not any statisti-
infant received. In two trials, the families are likely to have been cally significant differences in weight or head circumference. The
aware which type of milk their infant had been allocated to receive ( group of infants who received post-discharge formula remained
Agosti 2003; Peng 2004; Jeon 2011). It is unclear whether blinding statistically significantly longer on average than the control group
was satisfactory in another three trials (Litmanovitz 2004; Taroni [mean difference 9.0 (95% CI 0.3 to 17.7) mm].
2009; Roggero 2011a). De Curtis 2002 did not find any statistically significant differences
Most of the trials blinded outcomes assessors and investigators in the rate of gain of weight, length, or head circumference during
to the type of milk that the infant received but in four of the the two months trial period.
trials it is unclear if this was satisfactory (Litmanovitz 2004;Taroni Atkinson 2004 did not find any statistically significant differences
2009; Jeon 2011; Roggero 2011a), and in one trial physicians were in the rate of gain of weight, length, or head circumference up to
unblinded (Peng 2004). 12 months corrected age (growth data reported as z scores).
Litmanovitz 2004 did not find any statistically significant differ-
ences in the weight, length, or head circumference at six months
Incomplete outcome data corrected age.
Ten of the trials achieved complete or near-complete (> 80%) Koo 2006 reported that the mean weight, head circumference,
follow-up assessment (Lucas 1992; Lucas 2001; Cooke 2001; and length was lower in the nutrient-enriched formula group at
De Curtis 2002; Atkinson 2004; Litmanovitz 2004; Peng 2004; six, nine and twelve months after hospital discharge.
Taroni 2009; Roggero 2011a; Jeon 2011). In two of the other trials, Taroni 2009 did not find any statistically significant differences
75% of infants underwent outcomes assessments at latest follow- in weight, length, or head circumference at one month corrected
up (Atkinson 1999; Koo 2006). In another two trials, < 50% of age.
infants completed the planned 12 months follow-up assessment Roggero 2011a did not find any statistically significant differences
(Carver 2001; Agosti 2003). In Picaud 2005, loss to follow-up by in weight, length, or head circumference at six months corrected
12 months in the control group was substantial (35%) and greater age.
than that in the intervention group (9%). Meta-analyses of growth data
• Weight (Outcome 1.2; Figure 2): Meta-analyses did not
detect any statistically significant differences in weight at three to
Effects of interventions
four and six months corrected age. At nine months, meta-
POST-DISCHARGE FORMULA VERSUS STANDARD analysis of data from four trials (Lucas 1992; Atkinson 1999;
TERM FORMULA (COMPARISON 1) Koo 2006; Lucas 2001) indicated that infants in the post-
Growth (Outcomes 1.1- 1.4) discharge formula group were heavier [WMD: 244 (95% CI 17
Lucas 1992 did not detect any statistically significantly differences to 471) g]. At follow-up at 12 months, there was not a
in weight, length or head circumference at the end of the inter- statistically significant difference.
vention and follow-up period (nine months corrected age).
Figure 2. Forest plot of comparison: 1 POST-DISCHARGE FORMULA VERSUS STANDARD TERM
FORMULA, outcome: 1.2 Weight (g).
• Length (Outcome 1.3; Figure 3): Meta-analyses did not

detect any statistically significant differences in weight at three to
four and six months corrected age. At nine months, meta-
analysis of data from four trials (Lucas 1992; Atkinson 1999;
Koo 2006; Lucas 2001) indicated that infants in the post-
discharge formula group were longer [WMD: 7.3 (95% CI 1.8
to 12.9) mm]. At follow-up at 12 months, there was not a
statistically significant difference.
FORMULA, outcome: 1.3 Crown heel length (mm).
• Head circumference (Outcome 1.4; Figure 4): Meta-

analyses did not detect any statistically significant differences at
three to four, six, nine or twelve months.
FORMULA, outcome: 1.4 Head circumference (mm).
in bone mineral content assessed at 12 months corrected age (nu-

These meta-analyses all contained substantial statistical hetero-
merical data not available).
geneity (I2 > 50%).
De Curtis 2002 did not find any statistically significant differences
Development (Outcome 1.5)
in the bone mineral content or the bone area at the end of the two
Lucas 2001 did not detect a statistically significant difference in the
months study period.
Bayley Scales Mental or Psychomotor Development Index assessed
Koo 2006 reported that at the end of the 12 months study period
at 18 months corrected age. None of the included trials assessed
the infants who received nutrient-enriched formula had statisti-
later cognitive and educational outcomes.
cally significantly lower bone mass (measured using dual-energy X-
Feed intolerance
ray absorptiometry). The data were presented in graphs and could
Only one trial assessed this outcome (Lucas 1992). There was not
not be extracted or obtained for calculation of mean differences.
a statistically significant difference in the mean number of vomits
Lucas 1992 assessed bone width and bone mineral content of the
or possets per day. None of the participating infants ceased taking
radius at nine months corrected age. The bone width was not
a study formula because of feed intolerance.
statistically significantly different between the groups. The bone
Bone mineralization (Outcome 1.6:)
mineral content was statistically significantly higher in the group of
Atkinson 2004 did not find any statistically significant differences
infants who received the post-discharge formula: Mean difference graphs only and were not able to be extracted to allow calculation
20.6 (95% CI 7.8 to 33.4) mg/cm. of the mean difference. At 18 months corrected age, the nutrient-
Litmanovitz 2004 did not find any statistically significant differ- enriched formula group was statistically significantly heavier than
ences in bone strength assessed as “bone speed of sound” measured the control group [mean difference: 500 (95% CI 26 to 974) g],
with ultrasound or in serum levels of bone specific alkaline phos- but there were not any statistically significant differences in length
phatase at six months corrected age. or head circumference.
None of the trials assessed the effect of the intervention on clinical Agosti 2003 did not find any statistically significant differences in
or radiological evidence of rickets. mean weight, length, or head circumference at four, six and twelve
Blood pressure on long term follow-up months after hospital discharge.
Not assessed by any of the included trials. Peng 2004 did not find any statistically significant differences in
Boby mass index on long term follow-up mean weight, length, or head circumference at monthly intervals
Not assessed by any of the included trials. up to six months corrected age.
Sub-group analyses: Picaud 2005 did not find any statistically significant differences in
1. VLBW or very preterm infants: Two trials recruited the rate of gain of weight, length, or head circumference during
exclusively VLBW infants (Litmanovitz 2004;Taroni 2009). As the initial four months trial period. There were not any statisti-
described above, the investigators did not find any statistically cally significant differences in weight, length or head circumfer-
significant difference in the weight, length, or head ence between the groups at four months. At 12 months post-dis-
circumference, or in measures of bone mineralization up to six charge, infants in the preterm formula group were heavier [mean
months corrected age. difference:1007 (95% CI 211 to 1803) g] (Outcome 2.2), longer
2. Infants who remain small for gestational age at hospital [mean difference: 27 (95% CI 2 to 52) mm] (Outcome 2.3), and
discharge: Three trials recruited growth-restricted at birth infants had larger head circumferences [mean difference:12 (95% CI 0.2
(Atkinson 2004; Taroni 2009; Roggero 2011a).These trials did to 24) mm] (Outcome 2.4) than control infants. However, loss
not detect any statistically significant effects on weight up to 12 to follow-up by 12 months in the control group was substantial
months corrected age, but meta-analyses of data from the two (35%) and greater than that in the intervention group (9%).
trials that undertook follow-up at six months found statistically Jeon 2011 did not find any statistically significant differences in
significant effects on crown heel length (WMD 8.88 [95% CI mean weight, length, or head circumference at three, twelve and
0.94 to 16.83] mm) and head circumference (5.36 [95% CI eighteen months after hospital discharge.
0.62 to 10.11] mm) (Atkinson 2004; Roggero 2011a). Meta-analyses of growth data
3. Infants with chronic lung disease requiring home • Weight (Outcome 2.2; Figure 5): Weight (Outcome 2.2;
supplemental oxygen therapy: None of the trials recruited Figure 5): Meta-analysis of data from four trials (Cooke 2001;
exclusively infants with chronic lung disease. Subgroup data were Agosti 2003; Picaud 2005; Jeon 2011) found a statistically
not available. significant higher weight in the preterm formula group at 12
PRETERM FORMULA VERSUS STANDARD TERM FOR- months corrected age [WMD: 540 (95% CI 255 to 824) g].
MULA (COMPARISON 2) Meta-analysis of data from two trials (Cooke 2001; Jeon 2011)
Growth (Outcomes 2.1- 2.4) found a statistically significant higher weight in the preterm
Cooke 2001 did not find a statistically significant difference in rate formula group at 18 months [WMD: 491 (95% CI 142 to 839)
of weight gain during the trial period. These data were presented in g] (Outcome 2.2).
Figure 5. Forest plot of comparison: 2 PRETERM FORMULA VERSUS STANDARD TERM FORMULA,
outcome: 2.2 Weight (g).
• Length (Outcome 2.3; Figure 6): Meta-analysis of data

from three trials (Agosti 2003; Picaud 2005; Jeon 2011) did not
detect a statistically significant difference at 12 months corrected
age [WMD: 5.1 (95% CI -4.2 to 14.5) mm]. Meta-analysis of
data from two trials (Cooke 2001; Jeon 2011) found a
statistically significant higher crown heel length in the preterm
formula group at 18 months [WMD:11 (95% CI 2 to 20) mm]
outcome: 2.3 Crown heel length (mm).
• Head circumference (Outcome 2.4; Figure 7): Meta-

analysis of data from three trials (Agosti 2003; Jeon 2011; Picaud
2005) found a statistically significant larger head circumference
in the preterm formula group at 12 months corrected age
[WMD: 6.1 (95% CI 1.1 to 11.1) mm]. Meta-analysis of data
from two trials (Cooke 2001; Jeon 2011) found a statistically
significant larger head circumference in the preterm formula
group at 18 months [WMD: 5.4 (95% CI 0.7 to 10.1) mm].
outcome: 2.4 Head circumference (mm).
groups. In the published report, all of these data were presented in

Development (Outcome 2.5)
graphs and could not be extracted for estimation of mean differ-
Neither Cooke 2001 or Jeon 2011, nor a meta-analysis of data
ences. The investigators also reported that there were not any sta-
from both trials detected a statistically significant difference in the
tistically significant differences in the serum phosphorus, calcium
Bayley Scales Mental Development Index [WMD -1.4 (95% CI
and alkaline phosphatase levels measured at intervals during the
-6.2 to 3.4)] or Psychomotor Development Index [WMD -1.1
study period (up to six months post term). These data were pre-
(95% CI -4.2 to 1.93)]. Agosti 2003 did not detect any statistically
sented mainly in graphs and could not be extracted for estimation
significant differences in the Griffiths’ Developmental Scale eval-
of mean differences.
uations at six, nine and twelve months corrected age (numerical
Blood pressure on long term follow-up
data not available from report or trialists).
Not assessed by any of the included trials.
Feed intolerance
Boby mass index on long term follow-up
Bone mineralization
Sub-group analyses
Cooke 2001 assessed body composition with dual energy x-ray ab-
1. VLBW or very preterm infants: Two trials recruited
sorptiometry at six and twelve months corrected age. There were
exclusively VLBW infants (Agosti 2003; Jeon 2011). See above
not any statistically significant differences in the bone area, bone
for details of findings. Subgroup data from the other trials were
mineral mass, or bone mineral density measurements between the
not available. concealment and all achieved about 70% to 80% follow-up at >
2. Infants who remain small for gestational age (less than 10th 6 months corrected age). The meta-analyses of data from the five
percentile for weight) at hospital discharge: Subgroup data were trials that compared preterm formula versus term formula were
not available. more complete and did not demonstrate statistical heterogeneity.
3. Infants with chronic lung disease requiring home The explanation for the difference in the measured effect on
supplemental oxygen therapy: Subgroup data were not available. growth parameters of post-discharge formula and preterm formula
may simply be related to total nutrient content and intake. An
additional factor is that whereas post-discharge formula contains
about 10% more calories and 20% to 25% more protein and bone
DISCUSSION minerals than term formula, preterm formula is about 20% en-
ergy-enriched and contains 40% to 60% more protein and miner-
als than term formula. Since ad libitum fed infants regulate their
Summary of main results
volume of milk intake relative to its calorie-density, infants in the
Data from ten randomised controlled trials with a total of 762 par- comparison groups may have received similar total energy intakes.
ticipants did not provide consistent evidence that feeding preterm However, infants fed with post-discharge formula would still have
infants after hospital discharge with post-discharge formula (~74 received about 10% more protein and minerals than term formula
Kcal/100 ml) versus standard term formula (~67 Kcal/100 ml) fed infants, whereas infants fed with preterm formula would have
affects growth parameters up to 12 to 18 months corrected age. received up to about 25% more protein and minerals than term
The five trials that examined the effect of feeding with preterm formula-fed infants. It is possible that the protein and mineral in-
formula (~80 Kcal/100 mL) versus standard term formula pro- take (per unit of energy) is the key factor in determining catch-
vided stronger evidence of an effect on growth parameters. Meta- up growth rates, and specifically lean and skeletal growth, in this
analyses found a weighted mean difference of about 500 grams for population of infants.
weight, 11 mm for length, and 5 to 6 mm for head circumference The applicability of the currently available data is limited by the
at 12 to 18 months corrected age. However, it is not yet known short duration of follow-up in the trials. None of the trials planned
whether any of these differences persist through later childhood. or undertook any assessment of growth or development beyond
The evidence of the effect of nutrient-enriched formula on long 12 to 18 months corrected age and some of the trials have only
term development is also unclear. The only trial of post-discharge reported growth outcomes up to six months. Similarly, none of
versus term formula to assess developmental outcomes did not de- the trials have reported data related to possible adverse metabolic
tect a statistically significant difference in the Bayley Scales Mental consequences of nutrient-supplementation in early infancy or any
or Psychomotor Development Index assessed at 18 months cor- long term measures of obesity (BMI, fat mass) or cardiovascular
rected age (Lucas 2001). However, the 95% confidence intervals disease risk factors (such as elevated blood pressure).
for the estimates of effect are wide and do no exclude modest but
potentially important effect sizes. Similarly, meta-analyses of data
from two trials (Cooke 2001; Jeon 2011) did not provide evidence
that feeding with preterm versus term formula affects neurodevel- Quality of the evidence
opmental outcomes at 18 months corrected age. There are not yet
any data on longer-term cognitive and educational outcomes. The interpretation of the review findings is limited by the existence
in some of the trials of methodological weaknesses associated with
potential for bias. The main concern is lack of evidence of use of
methods to preserve allocation concealment in many of the trials.
Overall completeness and applicability of However, only one trial had substantial between-group differences
evidence in baseline demographics that is likely to be due to allocation
Although we identified ten eligible trials that compared feeding bias (Jeon 2011). We elected to exclude one arm of this three-
with post-discharge formula versus term formula, these were gen- arm trial because of substantial differences in mean birth weight,
erally small and of variable methodological quality. Quantitative gestational age, and proportion of growth-restricted infants. The
synthesis was limited as only six of the trials presented data that other methodological limitation present in six of the trials was
could be included in meta-analyses of growth outcomes (Lucas incomplete outcome assessment (loss to follow-up > 20%). In most
1992; Atkinson 1999; Lucas 2001; Litmanovitz 2004; Koo 2006; of these trials, loss to follow-up was < 30% and was distributed
Roggero 2011a). Interpretation of the meta-analyses was further evenly between intervention and control groups (Atkinson 1999;
limited by substantial and statistically significant heterogeneity. Koo 2006; Peng 2004; Picaud 2005). In two trials, loss to follow-
The source of heterogeneity is not clear as these trials were of sim- up at 12 months assessment was > 50% (Agosti 2003; Carver
ilar design (intervention given for 6 to 12 months) and method- 2001). However, these trial did not contribute substantially to any
ological quality (all had satisfactory processes to ensure allocation of the meta-analyses.
Potential biases in the review process Implications for research
The main concern with the review process is the possibility that Follow-up of infants who participated in the trials identified in this
the findings are subject to publication and other reporting biases review might provide further data on the effect of this interven-
including more availability of numerical data for inclusion in meta- tion on growth through later childhood, specifically whether final
analyses in trials which reported statistically significant or clinically height is affected, on later neurodevelopmental outcomes, and on
important effects (Hopewell 2009). We attempted to minimise any long term effects on metabolic or cardiovascular outcomes
this threat by searching the proceedings of the major international (Euser 2005; Greer 2007). If further large randomised controlled
perinatal conferences to identify trial reports that are not (or not trials to evaluate the effects of feeding preterm infants with nu-
yet) published in full form in academic journals. However, we trient-enriched formulae following hospital discharge are under-
cannot be sure that other trials have been undertaken but not taken then it may be appropriate to include in any research efforts
reported and the concern remains that such trials are less likely those preterm infants who are not able to feed ad libitum follow-
than published trials to have detected statistically significant or ing hospital discharge, and who have extra metabolic demands,
clinically important effects. The meta-analyses that we performed for example because of severe growth restriction or chronic lung
did not contain sufficient trials to explore symmetry of funnel disease. Trials should aim to assess long-term clinically important
plots as a means of identifying possible publication or reporting outcomes including final height and body composition and neu-
bias. rodevelopment (including cognitive and educational outcomes).
Further research is needed to determine which specific nutrients
(including appropriate energy:protein balance) are key to promot-
ing lean mass and linear growth and to improving developmental
AUTHORS’ CONCLUSIONS outcomes. As a first step, it may be worthwhile reviewing system-
atically trials that could not be included in this review because the
Implications for practice nutrient-enriched formula differed only in protein and mineral
content (but not energy) from standard term formula.
The findings of this review do not support expert group and con-
sensus recommendations that formula-fed preterm infants should
receive a post-discharge formula for up to 12 months post-dis-
charge (Dusick 2003; Kleinman 2004; Bhatia 2005; Carver 2005;
Aggett 2006; Griffin 2007). In contrast, the available trial data in-
ACKNOWLEDGEMENTS
dicate that feeding with “preterm formula”, which is generally only We thank Dr Litmanovitz for clarification of aspects of
licensed and available for in-hospital use, may increase weight, Litmanovitz 2004. We thank Tom Fahey for contributing to the
length and head circumference growth up to 12 to 18 months previous version of this review (McGuire 2005).
corrected age.
Editorial support of the Cochrane Neonatal Review Group has
The infants who participated in the trials included in this review been funded with Federal funds from the Eunice Kennedy Shriver
were fed ad libitum and the findings may not be applicable to National Institute of Child Health and Human Development Na-
infants who cannot feed ab libitum, for example because of oro- tional Institutes of Health, Department of Health and Human
motor dysmotility or chronic lung disease. Services, USA, under Contract No. HHSN275201100016C.
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1984;104:118–22.
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during the first two years predicts pre-school height in
Klingenberg 2011 children born with very low birth weight (VLBW): results
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Henderson G, Fahey T, McGuire W. Calorie and protein-
Lucas A, Gore SM, Cole TJ, Bamford MF, Dossetor JF,
enriched formula versus standard term formula for
Barr I, et al.Multicentre trial on feeding low birthweight
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Lucas 1992a 10.1002/14651858.CD004696.pub3]
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consumption in infants born preterm. Archives of Disease in Henderson G, Fahey T, McGuire W. Nutrient-enriched
Childhood 1992;67:691–2. formula versus standard formula for preterm infants
McCormick 2010 following hospital discharge. Cochrane Database of
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Multinutrient fortification of human breast milk for preterm 14651858.CD004696.pub3]
infants following hospital discharge. Cochrane Database ∗
Indicates the major publication for the study
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Agosti 2003
Methods Randomised controlled trial
Participants 121 formula milk-fed VLBW (<1500 g) infants
Interventions Preterm formula (energy content 80 kcal/100 ml, protein content 2.4 g/100ml, and
calcium and phosphorus content 100 mg/100ml and 50 mg/100ml respectively) (N=
69) or standard term formula (energy content 70 kcal/100ml, protein content 1.7 g/
100ml) (N=52). The intention was for the allocated formula to be the only milk source
from 40 weeks until 55 weeks postmenstrual age (PMA)
Outcomes Growth parameters and “Griffiths Developmental Scale” at 40 weeks, 55 weeks PMA,
and 6 and 12 months corrected age
Notes Setting: multicentre trial in Italy (2001)

Research supported by Milupa (formula milk manufacturing company)
Numerical growth data obtained from primary investigators (June 2011)
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection Unclear risk Report simply states that infants were ’randomized’ to
bias) study groups
Allocation concealment (selection bias) Unclear risk No mention of randomisation method
Incomplete outcome data (attrition bias) High risk Loss to follow-up was 34% at 6 months and 66% at 12
All outcomes months
Blinding of participants and personnel High risk Families and care givers were aware of which formula
(performance bias) milk infants received
All outcomes
Blinding of outcome assessment (detection Low risk Outcomes assessors are unlikely to have been aware of
bias) which formula milk infants received
All outcomes
Atkinson 1999
Participants 70 formula milk-fed preterm infants of birth weight < 1800 g and ’appropriate for
gestational age’
Interventions Post-discharge formula (energy content 74 kcal/100ml, protein content 1.8 g/100ml)
(N= 34) versus standard term formula (N=36) for 12 months post-discharge
Outcomes Growth parameters at 6, 9 and 12 months corrected age
Notes Published in abstract form only. Additional information and data courtesy of Dr
Stephanie Atkinson
Risk of bias
Random sequence generation (selection Low risk Independent generation of random sequence
bias)
Allocation concealment (selection bias) Low risk Allocation drawn from sequential sealed opaque en-
velopes
Incomplete outcome data (attrition bias) High risk Growth outcomes data to 12 months were available for 24
All outcomes (71%) intervention group and 29 (81%) control group
infants
Blinding of participants and personnel Low risk Families and care givers were unaware of which formula
All outcomes
Blinding of outcome assessment (detection Low risk Outcomes assessors not aware of which formula milk
bias) infants received
All outcomes
Atkinson 2004
Participants 53 formula milk-fed preterm ’small for gestational age’ infants
Interventions Post-discharge formula (energy content 74 kcal/100ml, protein content 1.8 g/100ml
(N=24) versus standard term formula (Ross Similac with Fe) (N=29) for 12 months
post-discharge
Outcomes Growth parameters at 6, 9 and 12 months corrected age
Atkinson 2004 (Continued)
Notes Published in abstract form only. Additional information and data courtesy of Dr
Stephanie Atkinson
Risk of bias
Random sequence generation (selection Low risk Independent generation of random sequence
bias)
velopes
Incomplete outcome data (attrition bias) Low risk Follow-up growth parameter outcome assessments were
All outcomes complete
All outcomes
All outcomes
Carver 2001
Participants 125 preterm infants (birth weight <1800 g or gestation <37 weeks). Infants with severe
bronchopulmonary dysplasia, cardiac, respiratory, gastrointestinal or other systemic dis-
eases at time of discharge were not eligible to participate
Interventions Post-discharge formula (energy content 74 kcal/100ml, protein content 1.9 g/100ml,
and calcium and phosphorus content 78 mg/100ml and 46 mg/100ml respectively) (N=
100ml) (N=56). The intention was for the allocated formula to be the main milk source
from hospital discharge until 12 months corrected age
Outcomes Growth parameters at intervals until the end of the 12 months study period
Notes Setting: Multi-centre, six perinatal centres in North America
Risk of bias
Carver 2001 (Continued)
Random sequence generation (selection Low risk No description of method used to generate random se-
bias) quence
Allocation concealment (selection bias) Unclear risk No information on randomisation method
Incomplete outcome data (attrition bias) High risk 31 of 67 in post-discharge formula group and 26 of 56
All outcomes in standard term formula group left the study early (plus
two other infants who were randomised but did not take
part in the study). The total loss of follow-up at growth
parameters assessment at 12 months was 60% in the in-
tervention group and 52% in the controls
Infants exited the study early (and did not have growth
parameters measured) for a variety of reasons including
study non-compliance (not defined or described), gastro-
intestinal upset, and “illness unrelated to the study feed-
ings” (not defined or described)
All outcomes
All outcomes
Cooke 2001
Participants 103 preterm infants (birth weight < 1750 g or gestation < 35 weeks). Only infants who
were “growing normally” (rate of weight gain more than 25 g/kg/day) at time of discharge
were eligible to participate
Interventions Preterm formula (energy content 80 kcal/100ml, protein content 2.2 g/100ml, and
49) or a standard term formula (energy content 66 kcal/100ml, protein content 1.4 g/
100ml) (N=54) from hospital discharge until six months corrected age
Outcomes Anthropometric and developmental parameters (including Bayley Scales of Infant De-
velopment II) and measures of bone mineralization
Notes Setting: Royal Victoria Hospital, Newcastle upon Tyne, UK

Research supported by Nutricia (formula milk manufacturer)
Article reported growth data for boys and girls separately. We combined the data for
inclusion in this review
Risk of bias
Cooke 2001 (Continued)
Random sequence generation (selection Low risk Random sequence centrally generated
bias)
Allocation concealment (selection bias) Low risk Sealed opaque envelopes
Incomplete outcome data (attrition bias) Low risk Follow-up was near complete (> 80%)
All outcomes
All outcomes
All outcomes
De Curtis 2002
Participants 33 formula milk-fed preterm infants (birth weight < 1750 grams or gestation < 35 weeks)
100ml) (N=17) from hospital discharge until two months corrected age
Outcomes Growth parameters and bone mineralization measured using dual energy x-ray absorp-
tiometry at the end of the 2 months study period
Notes Setting: Department of Pediatrics, University of Liege, Belgium
Risk of bias
Random sequence generation (selection Unclear risk No description of method used to generate random se-
bias) quence
All outcomes
De Curtis 2002 (Continued)
All outcomes
All outcomes
Jeon 2011
Participants 59 preterm very low birth weight infants
100ml) (N=34) from hospital discharge until three months post term then both groups
continuing with standard term formula until at least 6 months post term
Outcomes Growth parameters at 3 monthly intervals until 18 months post term and Bayley Scales
of Infant Development II at 18 months corrected age
Notes Setting: Multicentre trial in four hospitals in South Korea

Research supported by Maeli Dairy Industry Co. Ltd, (formula milk manufacturer)
Initially three groups were randomly allocated to receive either (1) standard term for-
mula, (2) preterm formula for 3 months, or (3) preterm formula for 6 months. How-
ever, there were substantial and significant between-group differences in the baseline
demographic characteristics, especially between group (3) and the other groups. Group
(3) infants had statistically significantly lower birth weights and were more likely to be
small for gestational age. We therefore chose to discard data from this arm and to restrict
comparison of outcomes to group (1) versus group (3)
Risk of bias
bias) quence
Incomplete outcome data (attrition bias) Low risk Growth outcomes data to 18 months were available for 30
infants
Jeon 2011 (Continued)
Blinding of participants and personnel High risk Families and care givers were likely to have been aware of
(performance bias) which formula milk infants received
All outcomes
Blinding of outcome assessment (detection Unclear risk Outcomes assessors may have been aware of which for-
bias) mula milk infants received
All outcomes
Koo 2006
Participants 89 preterm infants ready for hospital discharge (gestational age at birth < 35 weeks).
Infants with major congenital malformation, previous gastrointestinal surgery, or abnor-
mal suck and swallow actions were not eligible to participate
Interventions Nutrient-enriched formula (energy content 74 kcal/100ml, protein content 1.9 g/100ml,
100ml) (N=45). The intention was for the allocated formula to be fed ad libitum until
12 months after discharge
Outcomes Growth parameters and bone mineral content at intervals until the end of the 12 months
study period
Notes Setting: Department of Pediatrics, Wayne State University and Hutzel Hospital, Detroit,
USA
Research supported by Ross Products Division, Abbott Laboratories (formula milk man-
ufacturer)
Risk of bias
bias) quence
velopes
infants
All outcomes
Koo 2006 (Continued)
All outcomes
Litmanovitz 2004
Participants 20 healthy very low birth weight infants at hospital discharge
Interventions Nutrient-enriched formula (energy content 74 kcal/100ml, protein content 1.9 g/100ml
(N=10) or a standard term formula (energy content 67 kcal/100ml, protein content 1.5
g/100ml) (N=10) following hospital discharge. The formulas were intended to provide
the sole milk intake up to 6 months corrected age
Outcomes Weight, length, head circumference, and measures of bone mineralization at term and
at 6 months corrected age
Notes Setting: Meir General Hospital, Kfar-saba, Israel
Risk of bias
bias) quence
All outcomes
Blinding of participants and personnel Unclear risk No information on whether families and care givers were
(performance bias) aware of which formula milk infants received
All outcomes
Blinding of outcome assessment (detection Unclear risk No information on whether outcomes assessors were
bias) aware of which formula milk infants received
All outcomes
Lucas 1992
Participants 32 exclusively formula milk-fed preterm infants, birth weight < 1850 g, and weight <
3000 g at hospital discharge
Lucas 1992 (Continued)
Interventions Nutrient-enriched formula (energy content 72 kcal/100ml, protein content 1.8 g/100ml,
100ml) (N=16) following hospital discharge. The formulas were intended to provide the
sole milk intake up to 9 months corrected age
Outcomes Measures of growth (weight, crown-heel length and head circumference), feed tolerance,
and bone mineralization during the trial period
Notes Setting: Department of Paediatrics, Rosie Maternity Hospital, Cambridge

Research supported by Farley Health Products (formula milk company)
One infant who was randomised to the standard term formula group was transferred to
another hospital prior to the planned hospital discharge and could not be included in
any follow-up assessments
Data were presented graphically. We extracted numerical data (mean and SD) from the
graphs in order to calculate mean differences
Risk of bias
bias) quence
Incomplete outcome data (attrition bias) Low risk Follow-up was near complete (one infant from the stan-
All outcomes dard term formula group was withdrawn)
Blinding of participants and personnel Low risk It is likely that families and care givers were unaware of
(performance bias) which formula milk infants received
All outcomes
Blinding of outcome assessment (detection Low risk It is likely that outcomes assessors were unaware of which
bias) formula milk infants received
All outcomes
Lucas 2001
Participants 229 formula milk-fed preterm infants, birth weight <1750 g, and weight < 3000 g at
hospital discharge
Interventions Nutrient-enriched formula (energy content 72 kcal/100ml, protein content 1.85 g/

100ml, and calcium and phosphorus content 70 mg/100ml and 35 mg/100ml respec-
tively) (N=113) or standard term formula (energy content 68 kcal/100ml, protein con-
tent 1.5 g/100ml) (N=116) from hospital-discharge until 9 months post-term
Lucas 2001 (Continued)
Outcomes Growth parameters up to 18 months post term, and neurodevelopment (Bayley Scales)
at 18 months corrected age
Notes Setting: Five neonatal centres in the UK (1993-5)

Research supported by Farley Health Products (formula milk company)
Risk of bias
Random sequence generation (selection Low risk A member of the clinical team not involved in the trial
bias) prepared the randomisation assignments
velopes
Incomplete outcome data (attrition bias) Low risk Growth and developmental outcomes assessed in >80%
All outcomes of participating infants
All outcomes
Blinding of outcome assessment (detection Low risk Outcomes assessors unaware of which formula milk in-
bias) fants received
All outcomes
Peng 2004
Participants 34 preterm infants with a gestational age of < 35 weeks and birth weight < 1850 g
Interventions Nutrient-enriched formula (energy content 81 kcal/100ml, protein content 2.40 g/

100ml, and calcium and phosphorus content 95 mg/100ml and 53 mg/100ml respec-
tively) (N=19) or standard term formula (energy content 67.6 kcal/100ml, protein con-
tent 1.4 g/100ml) (N=15) from hospital-discharge until 6 months corrected age
Outcomes Measures of growth (weight, crown-heel length and head circumference), feed tolerance,
and bone mineralization during the trial period
Notes Setting: Mackay Memorial Hospital, Taipei, Taiwan

Research supported by Mead Johnson (formula milk company)
No differences were found between the two groups in weight, length, or head circumfer-
ence at baseline or on follow-up. Infants fed premature formula had higher blood urea
nitrogen and phosphorus at 3 months corrected age. Those on the premature formula
also had higher energy intake at 1 month corrected age
Peng 2004 (Continued)
Risk of bias
bias) quence
All outcomes of the 40 infants initially enrolled (73%)
Blinding of participants and personnel High risk Families and care givers were likely to have been aware of
(performance bias) which formula milk infants received as parents were not
All outcomes blinded to the infants’ assignment
Blinding of outcome assessment (detection High risk Outcomes assessors may have been aware of which for-
bias) mula milk infants received as physicians were not blinded
All outcomes to the infants’ assignment
Picaud 2005
Participants 49 formula milk-fed preterm infants, birth weight <1750 g or gestation at birth <33
weeks
100ml) (N=26) from hospital discharge until 2 months post term
Outcomes Growth parameters and measures of bone mineralization up to 4 months corrected age
Notes Setting: two tertiary care neonatal units in France (2001-04)

Research supported by Nestlé France (formula milk manufacturer)
From 2 months post-discharge both groups received standard term formula milk
Risk of bias
Random sequence generation (selection Low risk Clinical trials unit generated
bias)
Allocation concealment (selection bias) Low risk Pharmacy coded
Picaud 2005 (Continued)
Incomplete outcome data (attrition bias) High risk Loss to follow-up by 12 months in the control group was
All outcomes substantial (35%) and greater than that in the interven-
tion group (9%)
All outcomes
Blinding of outcome assessment (detection Low risk Outcomes assessors unaware of which formula milk in-
bias) fants received
All outcomes
Roggero 2011a
Participants 84 formula milk-fed preterm infants born “small for gestational age” (<10th percentile)
and calcium and phosphorus content 100 mg/100ml and 56 mg/100ml respectively)
(N=40) or a standard term formula (energy content 67 kcal/100ml, protein content 1.
4 g/100ml) (N=44) from hospital discharge until 6 months corrected age
Outcomes Growth parameters and fat mass up to 6 months corrected age
Notes Setting: Neonatal Intensive Care Unit, Department of Maternal and Paediatric Sciences,
Milan, Italy (2008-10).
These trialists also conducted an RCT of nutrient-enriched versus standard formula in
appropriate for gestational age infants (N= 123). These data are not yet published or
available from the authors (referred to in conference abstract: Roggero 2011b)
Risk of bias
Random sequence generation (selection Unclear risk No information provided

bias)
Allocation concealment (selection bias) Unclear risk No information provided
Incomplete outcome data (attrition bias) Low risk Follow-up until 6 months post term was complete
All outcomes
Blinding of participants and personnel Unclear risk No information provided

(performance bias)
All outcomes
Roggero 2011a (Continued)
Blinding of outcome assessment (detection Unclear risk No information provided

bias)
All outcomes
Taroni 2009
Participants 27 formula milk-fed preterm infants, birth weight <1500 g or gestation at birth <33
weeks, and “small for gestational age” (<10th percentile)
and calcium and phosphorus content 100 mg/100ml and 56 mg/100ml respectively)
(N= 14) or a standard term formula (energy content 67 kcal/100ml, protein content 1.
4 g/100ml) (N= 13) from hospital discharge until 1 month corrected age
Outcomes Growth parameters and fat mass up to 1 month corrected age
Notes Setting: Four Italian neonatal units (2008-9)
Risk of bias
Random sequence generation (selection Low risk Pre-prepared random sequence

bias)
Allocation concealment (selection bias) Unclear risk No information provided
Incomplete outcome data (attrition bias) Low risk Follow-up until 1 month post term was complete
All outcomes
Blinding of participants and personnel Unclear risk No information provided

(performance bias)
All outcomes
Blinding of outcome assessment (detection Unclear risk No information provided

bias)
All outcomes
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Amesz 2010 The protein content of both formula milks was <1.7 g/100ml
Bernbaum 1989 The energy content of both formula milks was <70 kcal/100ml
Bhatia 1991 The protein content of both formula milks was <1.7 g/100ml
Brunton 1998 Both of the formula milks were calorie-enriched (90 kcal/100ml)
Chan 1994 The energy content of both formula milks was <70 kcal/100ml
Cooper 1985 The energy content of both formula milks was <70 kcal/100ml
Friel 1993 The energy content of both formula milks was <70 kcal/100ml
Lapillonne 2004 Both of the formula milks were calorie-enriched (81kcal/100ml) and protein-enriched (>2.0 grams/100ml
Wheeler 1996 The energy content of both formula milks was <70 kcal/100ml
Characteristics of studies awaiting assessment [ordered by study ID]
Roggero 2011b
Participants 123 formula fed preterm infants who were “appropriate (birth weight) for gestational age”
Interventions Post-discharge formula (energy content 75 kcal/100ml, protein content 2.0 g/100ml, and calcium and phosphorus
content 100 mg/100ml and 56 mg/100ml respectively) (N= 59) or a standard term formula (energy content 67 kcal/
100ml, protein content 1.4 g/100ml) (N= 64) from hospital discharge until 6 months corrected age
Outcomes Growth parameters and fat mass up to (at least) 12 months corrected age
Notes This has been presented as an abstract at the European Society for Paediatric Research annual scientific meeting in
Newcastle (October 2011). When published in full, or if sufficient data are available from the investigators, this trial
is likely to be included in this Cochrane review
DATA AND ANALYSES
Comparison 1. POST-DISCHARGE FORMULA VERSUS STANDARD TERM FORMULA
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 Growth rates during trial period 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
1.1 Weight gain 1 33 Mean Difference (IV, Fixed, 95% CI) 0.0 [-1.37, 1.37]
(grams/kilogram/day)
1.2 Linear growth 1 33 Mean Difference (IV, Fixed, 95% CI) 0.0 [-1.07, 1.07]
(millimetres/week)
1.3 Head circumference 1 33 Mean Difference (IV, Fixed, 95% CI) 0.0 [-0.68, 0.68]
(millimetres/week)
2 Weight (g) 6 Mean Difference (IV, Fixed, 95% CI) Subtotals only
2.1 3-4 months post term 5 408 Mean Difference (IV, Fixed, 95% CI) -3.76 [-156.67, 149.
15]
2.2 6 months post term 6 461 Mean Difference (IV, Fixed, 95% CI) 56.23 [-111.53, 223.
98]
2.3 9 months post term 4 347 Mean Difference (IV, Fixed, 95% CI) 244.09 [16.95, 471.
23]
12]
90]
3 Crown heel length (mm) 6 Mean Difference (IV, Fixed, 95% CI) Subtotals only
3.1 3- 4 months post term 5 408 Mean Difference (IV, Fixed, 95% CI) 4.18 [-0.77, 9.13]
3.2 6 months post term 6 461 Mean Difference (IV, Fixed, 95% CI) 3.46 [-1.21, 8.13]
3.3 9 months post term 4 347 Mean Difference (IV, Fixed, 95% CI) 7.33 [1.80, 12.87]
3.4 12 months post term 2 120 Mean Difference (IV, Fixed, 95% CI) -0.83 [-9.00, 9.34]
4 Head circumference (mm) 6 Mean Difference (IV, Fixed, 95% CI) Subtotals only
4.1 3- 4 months post term 5 408 Mean Difference (IV, Fixed, 95% CI) -0.87 [-3.73, 1.99]
4.3 9 months post-term 4 347 Mean Difference (IV, Fixed, 95% CI) 0.16 [-3.21, 3.53]
4.4 12 months post-term 2 120 Mean Difference (IV, Fixed, 95% CI) 0.25 [-5.50, 6.01]
4.5 18 months post-term 1 192 Mean Difference (IV, Fixed, 95% CI) -3.0 [-8.24, 2.24]
5 Development 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
5.1 Bayley Scales of Infant 1 184 Mean Difference (IV, Fixed, 95% CI) 0.90 [-3.24, 5.04]
Development II: Mental
Development Index
5.2 Bayley Scales of Infant 1 184 Mean Difference (IV, Fixed, 95% CI) 2.70 [-1.28, 6.68]
Development II: Psychomotor
Development Index
6 Bone mineralization 3 Mean Difference (IV, Fixed, 95% CI) Subtotals only
6.1 Bone area at 2 months 1 33 Mean Difference (IV, Fixed, 95% CI) 7.0 [-15.46, 29.46]
post-term (cm2 )
6.2 Bone mineral content at 2 1 33 Mean Difference (IV, Fixed, 95% CI) 3.20 [-4.73, 11.13]
months post-term (g)
6.3 Bone ”speed of sound” 1 20 Mean Difference (IV, Fixed, 95% CI) 45.0 [-18.48, 108.
assessed with ultrasound at 6 48]
months post-term (mm/s)
6.4 Bone specific serum 1 20 Mean Difference (IV, Fixed, 95% CI) -9.0 [-42.01, 24.01]
alkaline phosphatase at 6
months post-term (units/L)
6.5 Bone width at 9 months 1 31 Mean Difference (IV, Fixed, 95% CI) 0.05 [-0.01, 0.11]
post-term (cm)
6.6 Bone mineral content at 9 1 31 Mean Difference (IV, Fixed, 95% CI) 20.60 [7.78, 33.42]
months post-term (mg/cm)
Comparison 2. PRETERM FORMULA VERSUS STANDARD TERM FORMULA
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 Growth rates during trial period 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
1.1 Weight gain (grams/day) 1 42 Mean Difference (IV, Fixed, 95% CI) 3.70 [-0.16, 7.56]
1.2 Linear growth 1 42 Mean Difference (IV, Fixed, 95% CI) 1.0 [0.09, 1.91]
(millimetres/week)
1.3 Head circumference 1 42 Mean Difference (IV, Fixed, 95% CI) 0.5 [-0.04, 1.04]
(millimetres/week)
2 Weight (g) 5 Mean Difference (IV, Fixed, 95% CI) Subtotals only
2.1 3- 4 months post term 3 130 Mean Difference (IV, Fixed, 95% CI) 74.41 [-267.10, 415.
93]
92]
69]
2.4 12 months post term 4 265 Mean Difference (IV, Fixed, 95% CI) 539.48 [255.03,
823.92]
2.5 18 months post term 2 162 Mean Difference (IV, Fixed, 95% CI) 490.81 [142.19,
839.44]
3 Crown heel length (mm) 5 Mean Difference (IV, Fixed, 95% CI) Subtotals only
3.1 3- 4 months post term 3 130 Mean Difference (IV, Fixed, 95% CI) -2.27 [-13.09, 8.56]
3.3 9 months post term 1 59 Mean Difference (IV, Fixed, 95% CI) -3.0 [-17.03, 11.03]
4 Head circumference (mm) 5 Mean Difference (IV, Fixed, 95% CI) Subtotals only
4.1 3- 4 months post term 3 130 Mean Difference (IV, Fixed, 95% CI) 3.61 [-2.09, 9.31]
5 Development 2 Mean Difference (IV, Fixed, 95% CI) Subtotals only
5.1 Bayley Scales of Infant 2 143 Mean Difference (IV, Fixed, 95% CI) -1.44 [-6.22, 3.35]
Development II: Mental
Development Index
5.2 Bayley Scales of Infant 2 143 Mean Difference (IV, Fixed, 95% CI) -1.13 [-4.19, 1.93]
Development II: Psychomotor
Development Index
Analysis 1.1. Comparison 1 POST-DISCHARGE FORMULA VERSUS STANDARD TERM FORMULA,

Outcome 1 Growth rates during trial period.
Review: Nutrient-enriched formula versus standard term formula for preterm infants following hospital discharge
Comparison: 1 POST-DISCHARGE FORMULA VERSUS STANDARD TERM FORMULA
Outcome: 1 Growth rates during trial period
Post-
discharge Mean Mean
Study or subgroup formula Term formula Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI
1 Weight gain (grams/kilogram/day)

De Curtis 2002 16 10 (2) 17 10 (2) 100.0 % 0.0 [ -1.37, 1.37 ]
Subtotal (95% CI) 16 17 100.0 % 0.0 [ -1.37, 1.37 ]

Heterogeneity: not applicable
Test for overall effect: Z = 0.0 (P = 1.0)
2 Linear growth (millimetres/week)
De Curtis 2002 16 10 (1) 17 10 (2) 100.0 % 0.0 [ -1.07, 1.07 ]
Subtotal (95% CI) 16 17 100.0 % 0.0 [ -1.07, 1.07 ]

3 Head circumference (millimetres/week)
De Curtis 2002 16 6 (1) 17 6 (1) 100.0 % 0.0 [ -0.68, 0.68 ]
Subtotal (95% CI) 16 17 100.0 % 0.0 [ -0.68, 0.68 ]

Test for subgroup differences: Chi2 = 0.0, df = 2 (P = 1.00), I2 =0.0%
-1 -0.5 0 0.5 1
Favours term formula Favours postdischarge for
Outcome 2 Weight (g).
Outcome: 2 Weight (g)
Post-
discharge Mean Mean
1 3-4 months post term

Koo 2006 31 5170 (784) 36 5826 (918) 14.1 % -656.00 [ -1063.54, -248.46 ]
Litmanovitz 2004 10 5471 (1050) 10 5700 (595) 4.2 % -229.00 [ -977.01, 519.01 ]
Lucas 1992 16 5900 (1400) 15 5500 (1350) 2.5 % 400.00 [ -568.15, 1368.15 ]
Lucas 2001 103 5370 (740) 103 5210 (790) 53.5 % 160.00 [ -49.04, 369.04 ]
Roggero 2011a 40 4793 (700) 44 4783 (708) 25.7 % 10.00 [ -291.37, 311.37 ]
Subtotal (95% CI) 200 208 100.0 % -3.76 [ -156.67, 149.15 ]

Heterogeneity: Chi2 = 13.22, df = 4 (P = 0.01); I2 =70%
2 6 months post term
Atkinson 1999 24 7783 (928) 29 7182 (912) 11.3 % 601.00 [ 102.99, 1099.01 ]
Koo 2006 31 6492 (1024) 36 7210 (1156) 10.3 % -718.00 [ -1240.05, -195.95 ]
Litmanovitz 2004 10 6948 (975) 10 7313 (694) 5.1 % -365.00 [ -1106.75, 376.75 ]
Lucas 1992 16 7150 (1500) 15 6700 (1400) 2.7 % 450.00 [ -570.86, 1470.86 ]
Lucas 2001 103 7200 (910) 103 7010 (900) 46.1 % 190.00 [ -57.17, 437.17 ]
Roggero 2011a 40 6233 (736) 44 6310 (850) 24.4 % -77.00 [ -416.27, 262.27 ]
Subtotal (95% CI) 224 237 100.0 % 56.23 [ -111.53, 223.98 ]

Atkinson 1999 24 8788 (1011) 29 8137 (1005) 17.3 % 651.00 [ 105.66, 1196.34 ]
Koo 2006 31 7765 (1120) 36 8629 (1297) 15.4 % -864.00 [ -1442.75, -285.25 ]
Lucas 1992 16 8250 (1400) 15 7600 (1350) 5.5 % 650.00 [ -318.15, 1618.15 ]
Lucas 2001 98 8360 (1100) 98 7990 (960) 61.7 % 370.00 [ 80.94, 659.06 ]
Subtotal (95% CI) 169 178 100.0 % 244.09 [ 16.95, 471.23 ]

-1000 -500 0 500 1000

(Continued . . . )
(. . . Continued)
Post-
discharge Mean Mean
Atkinson 1999 24 9571 (1016) 29 8853 (1031) 56.4 % 718.00 [ 164.80, 1271.20 ]
Koo 2006 31 8562 (1300) 36 9328 (1324) 43.6 % -766.00 [ -1395.66, -136.34 ]
Subtotal (95% CI) 55 65 100.0 % 71.53 [ -344.06, 487.12 ]

Lucas 2001 96 10200 (1280) 96 10100 (1170) 100.0 % 100.00 [ -246.90, 446.90 ]
Subtotal (95% CI) 96 96 100.0 % 100.00 [ -246.90, 446.90 ]

-1000 -500 0 500 1000

Outcome 3 Crown heel length (mm).
Outcome: 3 Crown heel length (mm)
Post-
discharge Mean Mean
1 3- 4 months post term

Koo 2006 31 554 (22) 36 576 (29) 16.4 % -22.00 [ -34.24, -9.76 ]
Litmanovitz 2004 10 589 (37) 10 586 (29) 2.9 % 3.00 [ -26.14, 32.14 ]
Lucas 1992 16 610 (27) 15 590 (25) 7.3 % 20.00 [ 1.69, 38.31 ]
Lucas 2001 103 580 (25) 103 574 (26) 50.5 % 6.00 [ -0.97, 12.97 ]
Roggero 2011a 40 558 (26) 44 544 (22) 22.9 % 14.00 [ 3.65, 24.35 ]
Subtotal (95% CI) 200 208 100.0 % 4.18 [ -0.77, 9.13 ]

Atkinson 1999 24 662 (20) 29 651 (23) 16.3 % 11.00 [ -0.58, 22.58 ]
Koo 2006 31 612 (24.5) 36 636 (27.6) 14.0 % -24.00 [ -36.48, -11.52 ]
Litmanovitz 2004 10 659 (36) 10 656 (20) 3.3 % 3.00 [ -22.52, 28.52 ]
Lucas 1992 16 660 (36) 15 645 (34) 3.6 % 15.00 [ -9.64, 39.64 ]
Lucas 2001 103 658 (28) 103 651 (23) 44.5 % 7.00 [ 0.00, 14.00 ]
Roggero 2011a 40 625 (26) 44 618 (25) 18.3 % 7.00 [ -3.93, 17.93 ]
Subtotal (95% CI) 224 237 100.0 % 3.46 [ -1.21, 8.13 ]

Atkinson 1999 24 705 (23) 29 696 (26) 17.6 % 9.00 [ -4.20, 22.20 ]
Koo 2006 31 668 (30.6) 36 695 (35.4) 12.3 % -27.00 [ -42.80, -11.20 ]
Lucas 1992 16 720 (18) 15 705 (16) 21.4 % 15.00 [ 3.03, 26.97 ]
Lucas 2001 98 709 (32) 98 697 (24) 48.8 % 12.00 [ 4.08, 19.92 ]
Subtotal (95% CI) 169 178 100.0 % 7.33 [ 1.80, 12.87 ]

-20 -10 0 10 20
(Continued . . . )
(. . . Continued)
Post-
discharge Mean Mean
Atkinson 1999 24 742 (23) 29 729 (26) 59.3 % 13.00 [ -0.20, 26.20 ]
Koo 2006 31 714 (32.3) 36 735 (34.2) 40.7 % -21.00 [ -36.94, -5.06 ]
Subtotal (95% CI) 55 65 100.0 % -0.83 [ -11.00, 9.34 ]

Lucas 2001 96 806 (34) 96 797 (27) 100.0 % 9.00 [ 0.32, 17.68 ]
Subtotal (95% CI) 96 96 100.0 % 9.00 [ 0.32, 17.68 ]

-20 -10 0 10 20
Outcome 4 Head circumference (mm).
Outcome: 4 Head circumference (mm)
Post-
discharge Mean Mean

Koo 2006 31 395 (16) 36 406 (17) 13.1 % -11.00 [ -18.91, -3.09 ]
Litmanovitz 2004 10 399 (19) 10 404 (8) 5.0 % -5.00 [ -17.78, 7.78 ]
Lucas 1992 16 411 (18) 15 408 (13) 6.8 % 3.00 [ -8.00, 14.00 ]
Lucas 2001 103 400 (14) 103 402 (14) 55.9 % -2.00 [ -5.82, 1.82 ]
Roggero 2011a 40 401 (17) 44 392 (13) 19.2 % 9.00 [ 2.48, 15.52 ]
Subtotal (95% CI) 200 208 100.0 % -0.87 [ -3.73, 1.99 ]

Atkinson 1999 24 447 (13) 29 440 (13) 16.3 % 7.00 [ -0.03, 14.03 ]
Koo 2006 31 419 (18) 36 429 (19) 10.2 % -10.00 [ -18.87, -1.13 ]
Litmanovitz 2004 10 430 (18) 10 440 (22) 2.6 % -10.00 [ -27.62, 7.62 ]
Lucas 1992 16 440 (18) 15 432 (13) 6.6 % 8.00 [ -3.00, 19.00 ]
Lucas 2001 103 433 (16) 103 434 (15) 44.8 % -1.00 [ -5.24, 3.24 ]
Roggero 2011a 40 423 (15) 44 419 (15) 19.5 % 4.00 [ -2.42, 10.42 ]
Subtotal (95% CI) 224 237 100.0 % 0.72 [ -2.12, 3.56 ]

3 9 months post-term
Atkinson 1999 24 461 (13) 29 455 (13) 23.0 % 6.00 [ -1.03, 13.03 ]
Koo 2006 31 439 (19) 36 450 (19) 13.6 % -11.00 [ -20.12, -1.88 ]
Lucas 1992 16 460 (20) 15 456 (16) 7.0 % 4.00 [ -8.71, 16.71 ]
Lucas 2001 98 456 (17) 98 456 (15) 56.4 % 0.0 [ -4.49, 4.49 ]
Subtotal (95% CI) 169 178 100.0 % 0.16 [ -3.21, 3.53 ]

-20 -10 0 10 20
(Continued . . . )
(. . . Continued)
Post-
discharge Mean Mean
Atkinson 1999 24 472 (14) 29 465 (14) 57.8 % 7.00 [ -0.57, 14.57 ]
Koo 2006 31 451 (18) 36 460 (19) 42.2 % -9.00 [ -17.87, -0.13 ]
Subtotal (95% CI) 55 65 100.0 % 0.25 [ -5.50, 6.01 ]

Lucas 2001 96 476 (18) 96 479 (19) 100.0 % -3.00 [ -8.24, 2.24 ]
Subtotal (95% CI) 96 96 100.0 % -3.00 [ -8.24, 2.24 ]

-20 -10 0 10 20
Outcome 5 Development.
Outcome: 5 Development
Post-
discharge Mean Mean
1 Bayley Scales of Infant Development II: Mental Development Index

Lucas 2001 91 92.3 (14.7) 93 91.4 (13.9) 100.0 % 0.90 [ -3.24, 5.04 ]
Subtotal (95% CI) 91 93 100.0 % 0.90 [ -3.24, 5.04 ]

2 Bayley Scales of Infant Development II: Psychomotor Development Index
Lucas 2001 91 91.7 (12.7) 93 89 (14.8) 100.0 % 2.70 [ -1.28, 6.68 ]
Subtotal (95% CI) 91 93 100.0 % 2.70 [ -1.28, 6.68 ]

-10 -5 0 5 10
Outcome 6 Bone mineralization.
Outcome: 6 Bone mineralization
Post-
discharge Mean Mean
1 Bone area at 2 months post-term (cm2 )

De Curtis 2002 16 351 (21) 17 344 (42) 100.0 % 7.00 [ -15.46, 29.46 ]
Subtotal (95% CI) 16 17 100.0 % 7.00 [ -15.46, 29.46 ]

2 Bone mineral content at 2 months post-term (g)
De Curtis 2002 16 68.2 (10.6) 17 65 (12.6) 100.0 % 3.20 [ -4.73, 11.13 ]
Subtotal (95% CI) 16 17 100.0 % 3.20 [ -4.73, 11.13 ]

3 Bone ”speed of sound” assessed with ultrasound at 6 months post-term (mm/s)
Litmanovitz 2004 10 3032 (60) 10 2987 (83) 100.0 % 45.00 [ -18.48, 108.48 ]
Subtotal (95% CI) 10 10 100.0 % 45.00 [ -18.48, 108.48 ]

4 Bone specific serum alkaline phosphatase at 6 months post-term (units/L)
Litmanovitz 2004 10 125 (41) 10 134 (34) 100.0 % -9.00 [ -42.01, 24.01 ]
Subtotal (95% CI) 10 10 100.0 % -9.00 [ -42.01, 24.01 ]

5 Bone width at 9 months post-term (cm)
Lucas 1992 16 0.67 (0.09) 15 0.62 (0.09) 100.0 % 0.05 [ -0.01, 0.11 ]
Subtotal (95% CI) 16 15 100.0 % 0.05 [ -0.01, 0.11 ]

6 Bone mineral content at 9 months post-term (mg/cm)
Lucas 1992 16 115.3 (21.6) 15 94.7 (14.3) 100.0 % 20.60 [ 7.78, 33.42 ]
Subtotal (95% CI) 16 15 100.0 % 20.60 [ 7.78, 33.42 ]

Test for subgroup differences: Chi2 = 13.06, df = 5 (P = 0.02), I2 =62%
-100 -50 0 50 100

Growth rates during trial period.
Comparison: 2 PRETERM FORMULA VERSUS STANDARD TERM FORMULA
Outcome: 1 Growth rates during trial period
Mean Mean
Study or subgroup Preterm formula Term formula Difference Weight Difference
1 Weight gain (grams/day)

Picaud 2005 21 31.8 (7.3) 21 28.1 (5.3) 100.0 % 3.70 [ -0.16, 7.56 ]
Subtotal (95% CI) 21 21 100.0 % 3.70 [ -0.16, 7.56 ]

2 Linear growth (millimetres/week)
Picaud 2005 21 13 (1.5) 21 12 (1.5) 100.0 % 1.00 [ 0.09, 1.91 ]
Subtotal (95% CI) 21 21 100.0 % 1.00 [ 0.09, 1.91 ]

3 Head circumference (millimetres/week)
Picaud 2005 21 7 (0.9) 21 6.5 (0.9) 100.0 % 0.50 [ -0.04, 1.04 ]
Subtotal (95% CI) 21 21 100.0 % 0.50 [ -0.04, 1.04 ]

-4 -2 0 2 4
Favours term Favours preterm
Weight (g).
Outcome: 2 Weight (g)
Mean Mean

Jeon 2011 30 6030 (973) 29 6219 (864) 53.0 % -189.00 [ -658.16, 280.16 ]
Peng 2004 16 6150 (1254) 13 6100 (864) 19.5 % 50.00 [ -723.39, 823.39 ]
Picaud 2005 21 6139 (1254) 21 5540 (863) 27.5 % 599.00 [ -52.07, 1250.07 ]
Subtotal (95% CI) 67 63 100.0 % 74.41 [ -267.10, 415.93 ]

Agosti 2003 38 7113 (825) 34 7056 (1053) 29.5 % 57.00 [ -383.55, 497.55 ]
Cooke 2001 56 7242 (1124) 57 7078 (935) 39.3 % 164.00 [ -217.55, 545.55 ]
Jeon 2011 30 7644 (1013) 29 7723 (1025) 21.2 % -79.00 [ -599.16, 441.16 ]
Peng 2004 16 7100 (1013) 13 7000 (1053) 10.0 % 100.00 [ -657.64, 857.64 ]
Subtotal (95% CI) 140 133 100.0 % 74.60 [ -164.73, 313.92 ]

Heterogeneity: Chi2 = 0.56, df = 3 (P = 0.91); I2 =0.0%
Jeon 2011 30 8848 (1211) 29 8736 (1119) 100.0 % 112.00 [ -482.69, 706.69 ]
Subtotal (95% CI) 30 29 100.0 % 112.00 [ -482.69, 706.69 ]

Agosti 2003 31 9717 (1192) 24 9256 (1146) 20.9 % 461.00 [ -160.52, 1082.52 ]
Cooke 2001 56 9203 (1213) 57 8649 (943) 50.3 % 554.00 [ 152.92, 955.08 ]
Jeon 2011 30 9667 (1520) 29 9444 (1260) 16.0 % 223.00 [ -488.44, 934.44 ]
Picaud 2005 21 9486 (1310) 17 8479 (1189) 12.8 % 1007.00 [ 211.15, 1802.85 ]
Subtotal (95% CI) 138 127 100.0 % 539.48 [ 255.03, 823.92 ]

-1000 -500 0 500 1000

Favours term formula Favours preterm formula
(Continued . . . )
(. . . Continued)
Mean Mean
Cooke 2001 49 10400 (1400) 54 9900 (1000) 54.1 % 500.00 [ 25.87, 974.13 ]
Jeon 2011 30 10713 (895) 29 10233 (1106) 45.9 % 480.00 [ -34.40, 994.40 ]
Subtotal (95% CI) 79 83 100.0 % 490.81 [ 142.19, 839.44 ]

-1000 -500 0 500 1000

Crown heel length (mm).
Outcome: 3 Crown heel length (mm)
Mean Mean

Jeon 2011 30 598 (30) 29 609 (26) 57.2 % -11.00 [ -25.31, 3.31 ]
Peng 2004 16 620 (36) 13 610 (35) 17.4 % 10.00 [ -15.94, 35.94 ]
Picaud 2005 21 598 (36) 21 589 (35) 25.4 % 9.00 [ -12.47, 30.47 ]
Subtotal (95% CI) 67 63 100.0 % -2.27 [ -13.09, 8.56 ]

Agosti 2003 38 656 (31) 34 653 (25) 38.9 % 3.00 [ -9.95, 15.95 ]
Jeon 2011 30 667 (25) 29 669 (22) 45.3 % -2.00 [ -14.01, 10.01 ]
Peng 2004 16 680 (31) 13 670 (25) 15.7 % 10.00 [ -10.38, 30.38 ]
-50 -25 0 25 50
(Continued . . . )
(. . . Continued)
Mean Mean
Subtotal (95% CI) 84 76 100.0 % 1.83 [ -6.25, 9.92 ]
Jeon 2011 30 720 (28) 29 723 (27) 100.0 % -3.00 [ -17.03, 11.03 ]
Subtotal (95% CI) 30 29 100.0 % -3.00 [ -17.03, 11.03 ]

Agosti 2003 31 756 (22) 24 747 (30) 42.9 % 9.00 [ -5.28, 23.28 ]
Jeon 2011 30 753 (28) 29 759 (28) 42.9 % -6.00 [ -20.29, 8.29 ]
Picaud 2005 21 747 (42) 17 720 (36) 14.2 % 27.00 [ 2.19, 51.81 ]
Subtotal (95% CI) 82 70 100.0 % 5.13 [ -4.23, 14.49 ]

Cooke 2001 49 801 (29) 54 790 (29) 65.9 % 11.00 [ -0.21, 22.21 ]
Jeon 2011 30 812 (22) 29 801 (37) 34.1 % 11.00 [ -4.60, 26.60 ]
Subtotal (95% CI) 79 83 100.0 % 11.00 [ 1.89, 20.11 ]

-50 -25 0 25 50
Head circumference (mm).
Outcome: 4 Head circumference (mm)
Mean Mean

Jeon 2011 30 405 (18) 29 400 (14) 48.2 % 5.00 [ -3.21, 13.21 ]
Peng 2004 16 415 (18) 13 418 (16) 21.2 % -3.00 [ -15.39, 9.39 ]
Picaud 2005 21 407 (18) 21 401 (16) 30.6 % 6.00 [ -4.30, 16.30 ]
Subtotal (95% CI) 67 63 100.0 % 3.61 [ -2.09, 9.31 ]

Agosti 2003 38 433 (12) 34 427 (19) 36.5 % 6.00 [ -1.44, 13.44 ]
Jeon 2011 30 435 (14) 29 426 (13) 42.6 % 9.00 [ 2.11, 15.89 ]
Peng 2004 16 426 (14) 13 427 (13) 20.9 % -1.00 [ -10.85, 8.85 ]
Subtotal (95% CI) 84 76 100.0 % 5.82 [ 1.32, 10.32 ]

Jeon 2011 30 451 (14) 29 443 (14) 100.0 % 8.00 [ 0.85, 15.15 ]
Subtotal (95% CI) 30 29 100.0 % 8.00 [ 0.85, 15.15 ]

Agosti 2003 31 464 (15) 24 461 (17) 33.6 % 3.00 [ -5.61, 11.61 ]
Jeon 2011 30 460 (13) 29 454 (15) 48.5 % 6.00 [ -1.17, 13.17 ]
Picaud 2005 21 465 (19) 17 453 (18) 17.9 % 12.00 [ 0.20, 23.80 ]
Subtotal (95% CI) 82 70 100.0 % 6.07 [ 1.07, 11.06 ]

Cooke 2001 49 485 (15) 54 480 (17) 58.5 % 5.00 [ -1.18, 11.18 ]
Jeon 2011 30 470 (11) 29 464 (17) 41.5 % 6.00 [ -1.33, 13.33 ]
-20 -10 0 10 20
(Continued . . . )
(. . . Continued)
Mean Mean
Subtotal (95% CI) 79 83 100.0 % 5.42 [ 0.69, 10.14 ]
-20 -10 0 10 20
Development.
Outcome: 5 Development
Mean Mean
1 Bayley Scales of Infant Development II: Mental Development Index

Cooke 2001 49 102 (14) 54 103 (14) 78.2 % -1.00 [ -6.41, 4.41 ]
Jeon 2011 21 98 (16) 19 101 (17) 21.8 % -3.00 [ -13.26, 7.26 ]
Subtotal (95% CI) 70 73 100.0 % -1.44 [ -6.22, 3.35 ]

2 Bayley Scales of Infant Development II: Psychomotor Development Index
Cooke 2001 49 102 (8) 54 103 (9) 86.9 % -1.00 [ -4.28, 2.28 ]
Jeon 2011 21 109 (16) 19 111 (11) 13.1 % -2.00 [ -10.44, 6.44 ]
Subtotal (95% CI) 70 73 100.0 % -1.13 [ -4.19, 1.93 ]

-10 -5 0 5 10
WHAT’S NEW
Last assessed as up-to-date: 30 September 2011.
Date Event Description
28 October 2011 New search has been performed This updates the review “Nutrient-enriched formula ver-
sus standard term formula for preterm infants following
hospital discharge” published in the Cochrane Database
of Systematic reviews (McGuire 2007).
28 October 2011 New citation required and conclusions have changed Updated search and availability of new information from
trial authors allowed inclusion of eight additional trials
Revised review structure specified separate comparisons
of preterm formula and post-discharge formula versus
standard term formula
Conclusions modified.
New authorship.
HISTORY
Protocol first published: Issue 2, 2004
Review first published: Issue 2, 2005
Date Event Description
28 April 2008 Amended Converted to new review format.
25 June 2007 New citation required but conclusions have not changed Substantive amendment
CONTRIBUTIONS OF AUTHORS
Lauren Young and Jessie Morgan undertook the electronic search and identified citations for possible inclusion. Lauren Young, Jessie
Morgan and Felicia McCormick reviewed the citation list (title and abstract) for inclusion and undertook methodological appraisal,
data extraction, entry and analysis. William McGuire acted as an arbiter for any disagreements, reviewed data entry and analysis and
completed the review.
DECLARATIONS OF INTEREST
None.
SOURCES OF SUPPORT
Internal sources
• Centre for Reviews and Dissemination, Department of Health Sciences, & Hull York Medical School, University of York, UK.
External sources
• Tenovus, Scotland, UK.
• NIHR, UK.
Lauren Young and Jessie Morgan are NIHR Academic Clinical Fellows.
DIFFERENCES BETWEEN PROTOCOL AND REVIEW

We elected to undertake separate comparisons of post-discharge formula and preterm formula versus standard term formula having
previously specified a joint comparison with subgroup analysis.
INDEX TERMS
Medical Subject Headings (MeSH)

Child Development [∗ physiology]; Dietary Proteins [administration & dosage]; Energy Intake [∗ physiology]; Infant Formula
[∗ administration & dosage; standards]; Infant Nutritional Physiological Phenomena; Infant, Low Birth Weight [growth & develop-
ment]; Infant, Newborn; Infant, Premature [∗ growth & development]; Patient Discharge; Randomized Controlled Trials as Topic
MeSH check words

Humans

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Nutrient-enriched formula versus standard term formula for

preterm infants following hospital discharge (Review)

Young L, Morgan J, McCormick FM, McGuire W

Nutrient-enriched formula versus standard term formula for

Lauren Young1 , Jessie Morgan1 , Felicia M McCormick2 , William McGuire1

Unit, Department of Health Sciences, University of York, York, UK

Editorial group: Cochrane Neonatal Group.

PLAIN LANGUAGE SUMMARY

BACKGROUND catch up growth in preterm infants, especially of the head, is as-

How the intervention might work Types of participants

Secondary outcomes Selection of studies

• Length (Outcome 1.3; Figure 3): Meta-analyses did not

• Head circumference (Outcome 1.4; Figure 4): Meta-

in bone mineral content assessed at 12 months corrected age (nu-

• Length (Outcome 2.3; Figure 6): Meta-analysis of data

• Head circumference (Outcome 2.4; Figure 7): Meta-

groups. In the published report, all of these data were presented in

Characteristics of included studies [ordered by study ID]

Methods Randomised controlled trial

Participants 121 formula milk-fed VLBW (<1500 g) infants

Notes Setting: multicentre trial in Italy (2001)

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk No mention of randomisation method

Methods Randomised controlled trial

Outcomes Growth parameters at 6, 9 and 12 months corrected age

Bias Authors’ judgement Support for judgement

Methods Randomised controlled trial

Participants 53 formula milk-fed preterm ’small for gestational age’ infants

Outcomes Growth parameters at 6, 9 and 12 months corrected age

Bias Authors’ judgement Support for judgement

Methods Randomised controlled trial

Notes Setting: Multi-centre, six perinatal centres in North America

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk No information on randomisation method

Methods Randomised controlled trial

Notes Setting: Royal Victoria Hospital, Newcastle upon Tyne, UK

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Low risk Sealed opaque envelopes

Methods Randomised controlled trial

Notes Setting: Department of Pediatrics, University of Liege, Belgium

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk No information on randomisation method

Methods Randomised controlled trial

Participants 59 preterm very low birth weight infants

Notes Setting: Multicentre trial in four hospitals in South Korea

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk No information on randomisation method

Methods Randomised controlled trial

Bias Authors’ judgement Support for judgement

Methods Randomised controlled trial

Participants 20 healthy very low birth weight infants at hospital discharge

Notes Setting: Meir General Hospital, Kfar-saba, Israel

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk No information on randomisation method

Methods Randomised controlled trial

Notes Setting: Department of Paediatrics, Rosie Maternity Hospital, Cambridge

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk No information on randomisation method