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Nutrient-enriched formula versus standard formula for preterm infants following hospital discharge

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Authors

Lauren Young1, Nicholas D Embleton2, William McGuire3

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables & Graphs


1Paediatric Intensive Care Unit, Birmingham Children's Hospital, Birmingham, UK [top]
2Newcastle Neonatal Service, Newcastle Hospitals NHS Foundation Trust and University of Newcastle, Newcastle upon Tyne, UK [top]
3Centre for Reviews and Dissemination, York, UK [top]

Citation example: Young L, Embleton ND, McGuire W. Nutrient-enriched formula versus standard formula for preterm infants following hospital discharge. Cochrane Database of Systematic Reviews 2016, Issue 12. Art. No.: CD004696. DOI: 10.1002/14651858.CD004696.pub5.

Contact person

William McGuire

Centre for Reviews and Dissemination
The University of York
York
Y010 5DD
UK

E-mail: William.McGuire@hyms.ac.uk

Dates

Assessed as Up-to-date: 08 September 2016
Date of Search: 08 September 2016
Next Stage Expected: 08 September 2018
Protocol First Published: Issue 2, 2004
Review First Published: Issue 2, 2005
Last Citation Issue: Issue 12, 2016

What's new

Date / Event Description
08 September 2016
Updated

One new trial added (Roggero 2011)

08 September 2016
New citation: conclusions not changed

Search updated; 1 new trial added; conclusion unchanged

History

Date / Event Description
28 October 2011
Updated

This updates the review, "Nutrient-enriched formula versus standard term formula for preterm infants following hospital discharge" (McGuire 2007).

28 October 2011
New citation: conclusions changed

Updated search; included 8 new trials as reported by trial authors

Revised review structure; specified separate comparisons of preterm formula and postdischarge formula vs standard term formula

Modified conclusions

Added new review authors

28 April 2008
Amended

Converted to new review format

25 June 2007
New citation: conclusions not changed

Made substantive amendments

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Abstract

Background

Preterm infants are often growth-restricted at hospital discharge. Feeding nutrient-enriched formula rather than standard formula to infants after hospital discharge might facilitate 'catch-up' growth and might improve development.

Objectives

To compare the effects of nutrient-enriched formula versus standard formula on growth and development of preterm infants after 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 (2016, Issue 8) in the Cochrane Library, MEDLINE, Embase and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; to 8 September 2016), as well as conference proceedings and previous reviews.

Selection criteria

Randomised and quasi-randomised controlled trials that compared the effects of feeding nutrient-enriched formula (postdischarge formula or preterm formula) versus standard term formula to preterm infants after hospital discharge .

Data collection and analysis

Two review authors assessed trial eligibility and risk of bias and extracted data independently. We analysed treatment effects as described in the individual trials and reported risk ratios and risk differences for dichotomous data, and mean differences (MDs) for continuous data, with respective 95% confidence intervals (CIs). We used a fixed-effect model in meta-analyses and explored potential causes of heterogeneity by performing sensitivity analyses. We assessed quality of evidence at the outcome level using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.

Main results

We included 16 eligible trials with a total of 1251 infant participants. Trials were of variable methodological quality, with lack of allocation concealment and incomplete follow-up identified as major potential sources of bias. Trials (N = 11) that compared feeding infants with 'postdischarge 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 post term. GRADE assessments indicated that evidence was of moderate quality, and that inconsistency within pooled estimates was the main quality issue.

Trials (N = 5) that compared feeding with 'preterm formula' (about 80 kcal/100 mL) versus term formula found evidence of higher rates of growth throughout infancy (weighted mean differences at 12 to 18 months post term: about 500 g in weight, 5 to 10 mm in length, 5 mm in head circumference). GRADE assessments indicated that evidence was of moderate quality, and that imprecision of estimates was the main quality issue.

Few trials assessed neurodevelopmental outcomes, and these trials did not detect differences in developmental indices at 18 months post term. Data on growth or development through later childhood have not been provided.

Authors' conclusions

Recommendations to prescribe 'postdischarge formula' for preterm infants after hospital discharge are not supported by available evidence. Limited evidence suggests that feeding 'preterm formula' (which is generally available only for in-hospital use) to preterm infants after hospital discharge may increase growth rates up to 18 months post term.

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Plain language summary

Nutrient-enriched formula versus standard term formula for preterm infants following hospital discharge

 

Review question: Does feeding preterm infants formula enriched with extra nutrients versus standard formula (designed for term infants) after hospital discharge increase growth rate and improve development?

Background: By the time preterm infants are ready to go home from the hospital after receiving care since birth, many are smaller and weigh less than they would have had they stayed in the womb instead of being born early. It may be that feeding preterm infants a formula enriched with extra nutrients (rather than standard formula used to feed term infants) helps them grow more quickly (and catch up with infants born at term) while improving their development.

Study characteristics: We identified 16 eligible trials enrolling a total of 1251 infants through searches updated to 8 September 2016.

Key findings: These trials provide moderate-quality evidence that unrestricted feeding with nutrient-enriched (vs standard) formula does not have important effects on growth and development up to about 18 months of age. Long-term growth and development have not yet been assessed.

Conclusions: Current recommendations to prescribe nutrient-enriched formula for preterm infants after hospital discharge are not supported by available evidence.

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Background

Compared with term infants, preterm infants have limited nutrient reserves at birth. Also, preterm infants, especially very preterm and very low birth weight (VLBW) infants, are subject to a variety of physiological and metabolic stresses that increase their nutrient needs. Recommended nutrient requirements for preterm infants are based on intrauterine growth studies and assume that the optimal rate of postnatal growth should be about the same as that of uncompromised fetuses of an equivalent postmenstrual age. Evidence indicates, however, that recommended target levels of nutrient input are rarely achieved in practice, and that most very preterm or VLBW infants accumulate significant energy, protein, mineral and other nutrient deficits during their initial hospital stay (Embleton 2001). By the time they are ready to go home, typically at around 36 to 40 weeks' postmenstrual age, many infants are substantially growth-restricted relative to their term-born peers (Clark 2003; Dusick 2003; Lucas 1984).

Description of the condition

After hospital discharge, responsively (demand) fed preterm infants often consume relatively more milk than term infants to attain 'catch-up' growth (Lucas 1992a). Despite this, growth deficits can persist through childhood and adolescence (Bracewell 2008; Farooqi 2006; Ford 2000; Trebar 2007). Slow or incomplete catch-up growth is associated with higher risk of neurodevelopmental impairment in later childhood, and with poorer cognitive and educational outcomes (Cooke 2003; Hack 1991; Leppanen 2014). Preterm infants who have accumulated mineral deficits have higher risks of metabolic bone disease and slower skeletal growth compared with infants born at term, although uncertainty remains about long-term effects of such deficits on bone mass and health (Fewtrell 2011). Furthermore, nutritional deficiency and growth restriction in utero and during early infancy may have consequences for long-term metabolic and cardiovascular health (Embleton 2013; Lapillonne 2013).

Description of the intervention

Because slow or incomplete catch-up growth is associated with prolonged growth restriction and slower neurodevelopmental progression, attention has focused on nutritional interventions that might promote growth during the putative ‘critical window’ of early infancy in the post-hospital discharge period. Two broad strategies for nutritional interventions are known (Dusick 2003; Fewtrell 2003; Klingenberg 2011).

  • Multi-nutrient fortification of expressed milk for infants fed with human breast milk.
  • Nutrient-enriched formula for formula-fed infants.

Another Cochrane review addresses the question of whether multi-nutrient fortification of human breast milk affects growth and development in preterm infants after hospital discharge (McCormick 2013). This review focuses on the comparison of nutrient-enriched formula versus standard formula for formula-fed preterm infants after hospital discharge.

A variety of standard and nutrient-enriched formula preparations are available (Aggett 2006; Griffin 2007). These can be categorised broadly as:

  • 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, respectively) are not sufficient to satisfy recommended nutrient needs for stable and growing preterm infants;
  • postdischarge formula: specifically designed for preterm infants post discharge from the hospital. These are energy (about 72 to 74 kcal/100 mL) and protein (about 1.8 to 1.9 g/100 mL) enriched and are variably enriched with minerals, vitamins and trace elements compared with standard term formula. Expert bodies and authorities recommend these formulas for preterm infants for three to 12 months post discharge (Aggett 2006); and
  • preterm formula: energy-enriched (about 80 kcal/100 mL), protein-enriched (2.0 to 2.4 g/100 mL) and variably enriched with minerals, vitamins and trace elements to support intrauterine nutrient accretion rates. These formulas are commonly used for nutrition of preterm infants before hospital discharge and generally are not recommended for postdischarge feeding.

How the intervention might work

Feeding preterm infants after hospital discharge formula enriched with extra energy, protein, minerals and vitamins may be expected to promote rapid catch-up growth. However, because preterm infants fed in response to hunger and satiation cues (demand or responsive feeding) adjust their volume of intake according to the energy density of formula, infants may consume less nutrient-enriched milk than standard formula (Lucas 1992a). Consequently, infants fed responsively with preterm or postdischarge formula may not receive any more energy (or other nutrients, depending on the nutrient:energy ratio) than infants fed standard term formula.

Feeding of nutrient-enriched formula may be associated with disordered gastric motility and emptying (Hancock 1984; Siegel 1984). Nutrient-enriched formula may therefore be poorly tolerated, thereby reducing nutrient delivery and potentially removing any benefit for growth and development. Furthermore, catch-up growth with accelerated weight gain and crossing of body mass index (BMI) percentiles might be associated with altered fat distribution and related ‘programmed’ metabolic consequences that may increase the risk of insulin resistance and cardiovascular disease (Doyle 2004; Euser 2005; Euser 2008; Hack 2003; Saigal 2006).

Why it is important to do this review

Given the potential for postdischarge nutrition strategies to affect growth and development in preterm infants, and the fact that uncertainty surrounds the balance between putative benefits and harms, this review was undertaken to detect, appraise and synthesise available evidence from randomised controlled trials to inform practice and research.

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Objectives

To compare the effects of nutrient-enriched formula versus standard formula on growth and development of preterm infants after hospital discharge.

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Methods

Criteria for considering studies for this review

Types of studies

We included controlled trials using random or quasi-random patient allocation, including cluster-randomised controlled trials. We did not include cross-over trials. Studies published as abstracts were eligible for inclusion only if assessment of study quality was possible, and if other criteria for inclusion were fulfilled.

Types of participants

We included preterm infants fed formula (exclusively or as a supplement to human breast milk) after discharge from hospital. The intervention may have commenced up to one week before planned discharge from hospital. We did not include in this review trials that randomly assigned infants to nutrient-enriched formula versus standard term formula more than one week before hospital discharge (and then continued the intervention after hospital discharge).

Types of interventions

  • Standard term formula: energy content less than/or equal to 72 kcal/100 mL and protein content less than/or equal to 1.7 g/100 mL

versus

  • Postdischarge formula: energy content > 72 kcal/100 mL (but less than/or equal to 75 kcal/100 mL) and protein content > 1.7 g /100 mL; or
  • Preterm formula: energy content > 75 kcal/100 mL and protein content > 2.0 g/100 mL.

The formula could be fed as the sole diet or as a supplement to human breast milk. Infants in trial groups should have received similar care other than the type of formula. Target levels prescribed for volume of intake and advice or support for demand feeding should have been no different among groups.

Types of outcome measures

Primary outcomes
  • Growth: weight, length, head growth, skinfold thickness, BMI and measures of body composition (lean/fat mass) and growth restriction (proportion of infants who remain < 10th percentile for distribution of weight, length or head circumference in the index population). Long-term growth and growth restriction (proportion of infants who remain below the 10th percentile for distribution of weight, height or head circumference in the index population)
  • Development
    • Neurodevelopmental outcomes assessed by validated tools at greater than/or equal to 12 months' corrected age; classifications of disability, including non-ambulant cerebral palsy, developmental delay and auditory and visual impairment
    • Cognitive and educational outcomes at greater than/or equal to 5 years: intelligence quotient and/or indices of educational achievement measured by a validated tool (including school examination results)
Secondary outcomes
  • Feed intolerance such as vomiting or diarrhoea that necessitates ceasing the study formula
  • Measures of bone mineralisation such as serum alkaline phosphatase level, or assessment of bone mineral content by dual-energy X-ray absorptiometry and clinical or radiological evidence of rickets on long-term follow-up
  • Blood pressure on long-term follow-up
  • Body mass index or other measures of overweight or obesity on long-term follow-up

Search methods for identification of studies

We used the standard search strategy of the Cochrane Neonatal Review Group.

Electronic searches

We updated the search on 8 September 2016 using a combination of the following terms: (infant nutrition OR infant formula OR milk OR formula OR nutrient OR fortif* OR supplemt*) AND (postdischarge OR post-discharge OR discharge) plus the following database-specific terms limited by relevant search filters for clinical trials, as recommended in the Cochrane Handbook for Systematic Reviews of Interventions.

  • PubMed: ((infant, newborn[MeSH] OR newborn OR neonate OR neonatal OR premature OR low birth weight OR VLBW OR LBW or infan* or neonat*) AND (randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized [tiab] OR placebo [tiab] OR drug therapy [sh] OR randomly [tiab] OR trial [tiab] OR groups [tiab]) NOT (animals [mh] NOT humans [mh]))
  • Embase: (infant, newborn or newborn or neonate or neonatal or premature or very low birth weight or low birth weight or VLBW or LBW or Newborn or infan* or neonat*) AND (human not animal) AND (randomized controlled trial or controlled clinical trial or randomized or placebo or clinical trials as topic or randomly or trial or clinical trial)
  • Cumulative Index to Nursing and Allied Health Literature (CINAHL): (infant, newborn OR newborn OR neonate OR neonatal OR premature OR low birth weight OR VLBW OR LBW or Newborn or infan* or neonat*) AND (randomized controlled trial OR controlled clinical trial OR randomized OR placebo OR clinical trials as topic OR randomly OR trial OR PT clinical trial)
  • Cochrane Library: (infant or newborn or neonate or neonatal or premature or very low birth weight or low birth weight or VLBW or LBW)

We applied no language restrictions.

We searched ClinicalTrials.gov and Current Controlled Trials External Web Site Policy for completed and ongoing trials.

Searching other resources

We examined the references provided in studies identified as potentially relevant. We searched abstracts from annual meetings of the Pediatric Academic Societies (1993 to 2016), the European Society for Pediatric Research (1995 to 2016), the UK Royal College of Paediatrics and Child Health (2000 to 2016) and the Perinatal Society of Australia and New Zealand (2000 to 2016). We considered trials reported only as abstracts to be eligible if sufficient information was available from the report, or from contact with study authors, to fulfil the inclusion criteria.

Data collection and analysis

We used the standard methods of the Cochrane Neonatal Review Group.

Selection of studies

Two review authors screened the titles and abstracts of all studies identified by the above search strategy. We reassessed the full texts of potentially eligible reports and excluded studies that did not meet all of the inclusion criteria. We discussed disagreements until consensus was achieved.

Data extraction and management

We used a data collection form to aid extraction of relevant information from each included study. Two review authors extracted study data separately. We discussed disagreements until consensus was achieved and asked investigators for further information if data provided in the trial reports were insufficient.

Assessment of risk of bias in included studies

We used criteria and standard methods of the Cochrane Neonatal Review Group to assess the methodological quality of included trials. Two review authors conducted assessment of risk of bias and resolved disagreements by discussion. We requested additional information from trial authors to clarify methods and results if necessary.

We made explicit judgements about whether studies were at high risk of bias across four domains, according to the criteria suggested in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

  • Random sequence generation: We categorised the method used to generate the allocation sequence as:
    • low risk - any truly random process (e.g. random number table, computer random number generator);
    • high risk - any non-random process (e.g. odd or even date of birth, hospital or clinic record number); or
    • unclear risk - no or unclear information provided.
  • Allocation concealment: We categorised the method used to conceal the allocation sequence as:
    • low risk (e.g. telephone or central randomisation, consecutively numbered sealed opaque envelopes);
    • high risk - open random allocation (e.g. unsealed or non-opaque envelopes, alternation; date of birth); or
    • unclear - no or unclear information provided.
  • Blinding: We assessed blinding of participants, clinicians and caregivers and outcome assessors separately for different outcomes and categorised the methods as:
    • low risk;
    • high risk; or
    • unclear risk.
  • Incomplete outcome data: We described completeness of data, including attrition and exclusions from analysis for each outcome and reasons for attrition or exclusion, when reported. We assessed whether missing data were balanced across groups or were related to outcomes. When sufficient information was reported or was supplied by trial authors, we planned to reinstate missing data to the analyses. We categorised completeness as:
    • low risk: less than/or equal to 10% missing data;
    • high risk: > 10% missing data; or
    • unclear risk: no or unclear information provided.

We assessed the likely magnitude and direction of bias and whether we considered it likely for bias to impact study findings. We planned to explore the impact of the level of bias by performing sensitivity analyses.

Measures of treatment effect

We analysed treatment effects in individual trials by using Review Manager 5.3 and reported risk ratios (RRs) and risk differences (RDs) for dichotomous data and mean differences (MDs) for continuous data, with respective 95% confidence intervals (CIs). We determined the number needed to treat for an additional beneficial outcome (NNTB) or an additional harmful outcome (NNTH) for analyses with statistically significant differences among RDs.

Unit of analysis issues

The unit of analysis was the participating infant in individually randomised trials. For cluster-randomised trials (had we identified any for inclusion), we planned to undertake analyses at the level of the individual while accounting for clustering of data by using methods recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

Dealing with missing data

We requested additional data from trial investigators if data on important outcomes were missing or were reported unclearly. When data were still missing, we examined the impact of this on effect size estimates by performing sensitivity analyses.

Assessment of heterogeneity

We examined treatment effects in individual trials and heterogeneity between trial results by inspecting forest plots if more than one trial was included in a meta-analysis. We calculated the I² statistic for each analysis to quantify inconsistency across studies and to describe the percentage of variability in effect estimates that may be due to heterogeneity rather than to sampling error. If we detected moderate or high (I² > 50%) heterogeneity, we explored possible causes (e.g. differences in study design, participants or interventions; completeness of outcome assessments) by performing sensitivity analyses.

Assessment of reporting biases

If more than five trials were included in a meta-analysis, we conducted a funnel plot analysis.

Data synthesis

We used the fixed-effect model in RevMan 5.1 to perform meta-analysis.

Quality of evidence

We assessed the quality of evidence for the main comparison at the outcome level by using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach (Guyatt 2011a), which considers evidence from randomised controlled trials as of high quality that may be downgraded on the basis of consideration of any of five areas.

  • Design (risk of bias).
  • Consistency across studies.
  • Directness of the evidence.
  • Precision of estimates.
  • Presence of publication bias.

The GRADE approach is used to assess the quality of a body of evidence according to four grades (Schünemann 2013).

  • High: We are very confident that the true effect lies close to the estimate of effect.
  • Moderate: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of effect but may be substantially different.
  • Low: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of effect.
  • Very low: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.

Two review authors assessed independently the quality of the evidence for outcomes identified as critical or important for clinical decision making (growth, development).

In cases for which we considered risk of bias to arise from inadequate concealment of allocation, randomised assignment, complete follow-up or blinded outcome assessment, to reduce our confidence in the effect estimates, we downgraded the quality of evidence accordingly (Guyatt 2011b). We evaluated consistency on the basis of similarity of point estimates, extent of overlap of confidence intervals and statistical criteria, including measurement of heterogeneity (I²). We downgraded the quality of evidence when inconsistency across study results was large and unexplained (i.e. some studies suggested important benefit, and others no effect or harm with no explanation) (Guyatt 2011c). We assessed precision accordingly with the 95% confidence interval (CI) around the pooled estimation (Guyatt 2011d). When trials were conducted in populations other than the target population, we downgraded the quality of evidence because of indirectness (Guyatt 2011e).

We entered data (pooled estimates of effects and 95% CIs) and explicit judgements for each of the above aspects assessed into the Guideline Development Tool, the software used to create 'Summary of findings (SoF)' tables (GRADEpro 2008). We explained our assessment of study characteristics in footnotes in the SoF table.

Subgroup analysis and investigation of heterogeneity

We prespecified the following subgroup analyses.

  • Very preterm (< 32 weeks' gestation) or VLBW (< 1500 g) infants (vs infants at 32 to 36 weeks' gestation or birth weight 1500 to 2499 g).
  • Infants who were small for gestational age (< 10th percentile for weight) at hospital discharge (vs infants greater than/or equal to 10th percentile).
  • Infants with chronic lung disease receiving supplemental oxygen therapy at hospital discharge (vs infants without chronic lung disease).

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Results

Description of studies

We identified two potentially eligible study reports. We included one new trial (Roggero 2011). We have not yet been able to obtain the full article reporting a potentially eligible trial and have categorised this as a 'study awaiting classification' (Ekcharoen 2015). See Figure 1.

Included studies

In total, we identified 16 trials that fulfil review eligibility criteria (Agosti 2003; Atkinson 1999; Atkinson 2004; Carver 2001; Cooke 2001; De Curtis 2002; Jeon 2011; Koo 2006; Litmanovitz 2004; Lucas 1992; Lucas 2001; Peng 2004; Picaud 2005; Roggero 2011; Roggero 2012; Taroni 2009). See Characteristics of included studies.

Participants

Trials were undertaken within the past 20 years by investigators attached to perinatal centres in Europe, North America and the Middle East. In total, 1251 infants participated in these trials (range 20 to 229).

Most trials specified a maximum birth weight as the primary eligibility criterion.

Four trials specified gestational age as an eligibility criterion.

Three trials specifically recruited participants who were small for gestational age.

Although most reports of the other trials did not specify intrauterine or postnatal growth restriction as an exclusion criterion, it appears that very few participants in the trials were small for gestational age at birth or enrolment. Generally, infants with additional problems at discharge, particularly those with inadequate independent oral feeding or receipt of supplemental oxygen secondary to chronic lung disease, were not eligible to participate.

Interventions
Postdischarge formula versus standard term formula (Comparison 1)

Eleven trials (N = 885): Atkinson 1999; Atkinson 2004; Carver 2001; De Curtis 2002; Koo 2006; Litmanovitz 2004; Lucas 1992; Lucas 2001; Roggero 2011; Roggero 2012; Taroni 2009.

Preterm formula versus standard term formula (Comparison 2)

Five trials (N = 366): Agosti 2003; Cooke 2001; Jeon 2011; Peng 2004; Picaud 2005.

All participating infants were fed ad libitum. These feeds were intended to be the principal source of milk for a range of periods post term (or post hospital discharge).

Outcomes

The main outcomes assessed were growth parameters (weight, length and occipitofrontal head circumference) assessed up to 12 to 18 months' corrected age. Three trials assessed neurodevelopmental outcomes at 18 months using Bayley Scales of Infant Development II (Cooke 2001; Jeon 2011; Lucas 2001). One trial used Griffiths' Developmental Scales at six, nine and 12 months' corrected age (Agosti 2003).

Excluded studies

We excluded nine studies (Amesz 2010; Bernbaum 1989; Bhatia 1991; Brunton 1998; Chan 1994; Cooper 1985; Friel 1993; Lapillonne 2004; Wheeler 1996) and listed reasons for exclusion in the Characteristics of excluded studies table.

Risk of bias in included studies

Trials were of variable methodological quality (Figure 2).

Allocation (selection bias)

In eight trials (Atkinson 1999; Atkinson 2004; Cooke 2001; Koo 2006; Lucas 2001; Picaud 2005; Roggero 2011; Roggero 2012), the method of randomisation described was likely to ensure blinding of allocation. In the other trials, it is not clear whether allocation concealment was adequate. In one of these trials, substantial between-group differences in baseline demographic characteristics were evident, most likely due to allocation bias (Jeon 2011). This trial originally randomised participants to one of three intervention groups. We elected to discard data from the group in which infant characteristics were statistically significantly different from those of other groups at enrolment.

Blinding (performance bias and detection bias)

Most trials blinded families to the type of milk that the infant received. In three trials (Agosti 2003; Jeon 2011; Peng 2004), it is likely that families were aware of which type of milk their infant had been allocated to receive. It is unclear whether blinding was satisfactory in another four trials (Litmanovitz 2004; Roggero 2011; Roggero 2012; Taroni 2009).

Most trials blinded outcome assessors and investigators to the type of milk that the infant received, but in five trials (Jeon 2011; Litmanovitz 2004; Roggero 2011; Roggero 2012; Taroni 2009), it is unclear whether blinding was satisfactory. In one trial (Peng 2004), physicians were unblinded.

Incomplete outcome data (attrition bias)

Eleven trials (Atkinson 2004; Cooke 2001; De Curtis 2002; Jeon 2011; Litmanovitz 2004; Lucas 1992; Lucas 2001; Peng 2004; Roggero 2011; Roggero 2012; Taroni 2009) achieved complete or near-complete (> 90%) assessment. In two other trials (Atkinson 1999; Koo 2006), 75% of infants underwent outcome assessments at latest follow-up. In another two trials (Agosti 2003; Carver 2001), less than 50% of infants completed the planned 12-month follow-up assessment. In Picaud 2005, loss to follow-up by 12 months in the control group was substantial (35%) and was greater than in the intervention group (9%).

Effects of interventions

Postdischarge formula versus standard term formula (Comparison 1)

Growth (Outcomes 1.1 to 1.4)

Lucas 1992 detected no statistically significantly differences in weight, length or head circumference at the end of intervention and follow-up periods (nine months' corrected age).

Atkinson 1999 reported that infants who received postdischarge formula were statistically significantly heavier at six, nine and 12 months' corrected age, and researchers noted no statistically significant differences in length or head circumference.

Carver 2001 detected no statistically significant differences in weight, length or head circumference at six and 12 months' corrected age. Loss to follow-up during the trial was substantial, and as the published report does not state how many infants were assessed at various time points, we could not use data to calculate mean differences.

Lucas 2001 reported that at completion of the intervention period (nine months' corrected age), weight and length were statistically significantly greater among infants who received postdischarge formula but noted no statistically significant differences in head circumference. At 18 months, results showed no statistically significant differences in weight or head circumference. The group of infants who received postdischarge formula remained statistically significantly longer on average than infants in the control group (MD 9.0, 95% CI 0.3 to 17.7 mm).

De Curtis 2002 found no statistically significant differences in rate of gain of weight, length or head circumference during the two-month trial period.

Atkinson 2004 reported no statistically significant differences in rate of gain of weight, length or head circumference up to 12 months' corrected age (growth data reported as z scores).

Litmanovitz 2004 noted no statistically significant differences in weight, length or head circumference at six months' corrected age.

Koo 2006 reported that mean weight, head circumference and length were less in the nutrient-enriched formula group at six, nine and 12 months after hospital discharge.

Taroni 2009 found no statistically significant differences in weight, length or head circumference at one month corrected age.

Roggero 2011 reported no statistically significant differences in weight, length or head circumference at three, six or 12 months' corrected age.

Roggero 2012 noted no statistically significant differences in weight, length or head circumference at three, six or 12 months' corrected age.

Meta-analyses of growth data
  • Weight (Outcome 1.2; Figure 3): Meta-analyses detected no statistically significant differences in weight at three to four and six months' corrected age. At nine months, meta-analysis of data from four trials (Atkinson 1999; Koo 2006; Lucas 1992; Lucas 2001) indicated that infants in the postdischarge formula group were heavier (weighted mean difference (WMD) 244, 95% CI 17 to 471 g). At 12-month follow-up, results showed no statistically significant differences.
  • Length (Outcome 1.3; Figure 4): Meta-analyses detected no statistically significant differences in weight at three to four and six months' corrected age. At nine months, meta-analysis of data from four trials (Atkinson 1999; Koo 2006; Lucas 1992; Lucas 2001) indicated that infants in the postdischarge formula group were longer (WMD 7.3, 95% CI 1.8 to 12.9 mm). At 12-month follow-up, results showed no statistically significant differences.
  • Head circumference (Outcome 1.4; Figure 5): Meta-analyses detected no statistically significant differences at three to four, six, nine or 12 months.

All meta-analyses showed substantial statistical heterogeneity (I2 > 50%).

Development (Outcome 1.5)

Lucas 2001 did not detect a statistically significant difference in the Bayley Scales Mental or Psychomotor Development Index at 18 months' corrected age. None of the included trials assessed later cognitive and educational outcomes.

Feed intolerance

Only one trial assessed this outcome (Lucas 1992) and reported no statistically significant difference in the mean number of vomits or possets per day. None of the participating infants ceased taking a study formula because of feed intolerance.

Bone mineralisation (Outcome 1.6)

Atkinson 2004 found no statistically significant differences in bone mineral content assessed at 12 months' corrected age (numerical data not available).

De Curtis 2002 reported no statistically significant differences in bone mineral content nor in bone area at the end of the two-month study period.

Koo 2006 reported that at the end of the 12-month study period, infants who received nutrient-enriched formula had statistically significantly lower bone mass (measured by dual-energy X-ray absorptiometry). Investigators presented data in graphs only, and data could not be extracted or obtained for calculation of mean differences.

Lucas 1992 assessed bone width and bone mineral content of the radius at nine months' corrected age. Bone width was not statistically significantly different between groups. Bone mineral content was statistically significantly greater in the group of infants who received the postdischarge formula: mean difference 20.6, 95% CI 7.8 to 33.4 mg/cm.

Litmanovitz 2004 found no statistically significant differences in bone strength assessed as 'bone speed of sound' on measurement with ultrasonography, nor in serum levels of bone-specific alkaline phosphatase, at six months' corrected age.

No trials assessed the effect of the intervention on clinical or radiological evidence of rickets.

Blood pressure on long-term follow-up

No included trials performed this assessment.

Body mass index on long-term follow-up

No included trials performed this assessment.

Subgroup analyses
  • VLBW or very preterm infants: Two trials (Litmanovitz 2004; Taroni 2009) recruited exclusively VLBW infants. As described above, investigators found no statistically significant differences in weight, length or head circumference, nor in measures of bone mineralisation, up to six months' corrected age.
  • Infants who remain small for gestational age at hospital discharge: Three trials (Atkinson 2004; Roggero 2012; Taroni 2009) recruited infants who were growth-restricted at birth. These trials detected no statistically significant effects on weight up to 12 months' corrected age, but meta-analyses of data from the two trials that undertook follow-up at six months (Atkinson 2004; Roggero 2012) revealed statistically significant effects on crown-heel length (WMD 8.88, 95% CI 0.94 to 16.83 mm) and on head circumference (WMD 5.36, 95% CI 0.62 to 10.11 mm).
  • Infants with chronic lung disease requiring home supplemental oxygen therapy: No trials exclusively recruited infants with chronic lung disease. Subgroup data were not available.

Preterm formula versus standard term formula (Comparison 2)

Growth (Outcomes 2.1-2.4)

Cooke 2001 found no statistically significant differences in rate of weight gain during the trial period. Researchers presented data in graphs only, and data could not be extracted or obtained for calculation of the mean difference. At 18 months' corrected age, the nutrient-enriched formula group was statistically significantly heavier than the control group (MD 500, 95% CI 26 to 974 g), but investigators noted no statistically significant differences in length or head circumference.

Agosti 2003 reported no statistically significant differences in mean weight, length or head circumference at four, six and 12 months after hospital discharge.

Peng 2004 noted no statistically significant differences in mean weight, length or head circumference at monthly intervals up to six months' corrected age.

Picaud 2005 observed no statistically significant differences in rate of gain of weight, length or head circumference during the first four months of the trial period and no statistically significant differences in weight, length or head circumference between groups at four months. At 12 months post discharge, infants in the preterm formula group were heavier (MD 1007, 95% CI 211 to 1803 g) (Outcome 2.2), were longer (MD 27, 95% CI 2 to 52 mm) (Outcome 2.3) and had larger head circumference (MD 12, 95% CI 0.2 to 24 mm) (Outcome 2.4) than control infants. However, loss to follow-up by 12 months was substantial in the control group (35%) and was greater than that reported for the intervention group (9%).

Jeon 2011 found no statistically significant differences in mean weight, length or head circumference at three, 12 and 18 months after hospital discharge.

Meta-analyses of growth data
  • Weight (Outcome 2.2; Figure 6): Meta-analysis of data from four trials (Agosti 2003; Cooke 2001; Jeon 2011; Picaud 2005) showed statistically significantly higher weight in the preterm formula group at 12 months' corrected age (WMD 540, 95% CI 255 to 824 g). Meta-analysis of data from two trials (Cooke 2001; Jeon 2011) revealed statistically significantly higher weight in the preterm formula group at 18 months (WMD 491, 95% CI 142 to 839 g) (Outcome 2.2).
  • Length (Outcome 2.3; Figure 7): Meta-analysis of data from three trials (Agosti 2003; Jeon 2011; Picaud 2005) showed no 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) revealed statistically significantly longer crown-heel length in the preterm formula group at 18 months (WMD 11, 95% CI 2 to 20 mm).
  • Head circumference (Outcome 2.4; Figure 8): Meta-analysis of data from three trials (Agosti 2003; Jeon 2011; Picaud 2005) showed a statistically significantly 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) revealed a statistically significantly larger head circumference in the preterm formula group at 18 months (WMD 5.4, 95% CI 0.7 to 10.1 mm).
Development (Outcome 2.5)

Neither Cooke 2001 nor Jeon 2011 nor a meta-analysis of data from both trials detected a statistically significant difference in the Bayley Scales Mental Development Index (WMD -1.4, 95% CI -6.2 to 3.4) or in the Psychomotor Development Index (WMD -1.1, 95% CI -4.2 to 1.93). Agosti 2003 noted no statistically significant differences in Griffiths' Developmental Scale evaluations at six, nine and 12 months' corrected age (numerical data not available from report nor from trialists).

Feed intolerance

No included trials performed this assessment.

Bone mineralisation

Cooke 2001 assessed body composition with dual-energy X-ray absorptiometry at six and 12 months' corrected age and noted no statistically significant differences in bone area, bone mineral mass or bone mineral density measurements between groups. In the published report, all data were presented in graphs and could not be extracted for estimation of mean differences. Investigators also reported that they found no statistically significant differences in serum phosphorus, calcium and alkaline phosphatase levels measured at intervals during the study period (up to six months post term). These data were presented mainly in graphs and could not be extracted for estimation of mean differences.

Blood pressure on long-term follow-up

No included trials performed this assessment.

Body mass index on long-term follow-up

No included trials performed this assessment.

Subgroup analyses
  • VLBW or very preterm infants: Two trials (Agosti 2003; Jeon 2011) exclusively recruited VLBW infants. See details of findings described above. Subgroup data from the other trials were not available.
  • Infants who remain small for gestational age at hospital discharge: Subgroup data were not available.
  • Infants with chronic lung disease requiring home supplemental oxygen therapy: Subgroup data were not available.

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Discussion

Summary of main results

Data from 11 randomised controlled trials with a total of 885 participants provided no evidence that feeding postdischarge formula (~74 kcal/100 mL) versus standard term formula (~67 kcal/100 mL) to preterm infants after hospital discharge affects growth parameters up to 12 to 18 months post term.

The five trials that examined the effect of feeding preterm formula (~80 kcal/100 mL) versus standard term formula provided some evidence of an effect on growth parameters. Meta-analyses showed a weighted mean difference of about 500 g for weight, 11 mm for length and 5 to 6 mm for head circumference at 12 to 18 months post term. It is not yet known whether any of these differences persist through later childhood.

Evidence of the effects of nutrient-enriched formula on long-term development is unclear. The only trial of postdischarge versus term formula conducted to assess developmental outcomes showed no difference in the Bayley Scales Mental or Psychomotor Development Index assessed at 18 months' corrected age (Lucas 2001). Similarly, meta-analyses of data from two trials provided no evidence that feeding preterm versus term formula affects neurodevelopmental outcomes at 18 months' corrected age. Data on longer-term cognitive and educational outcomes are not yet available.

Overall completeness and applicability of evidence

We identified 11 eligible trials that compared feeding with postdischarge formula versus term formula, but studies generally were small and of variable methodological quality. Quantitative synthesis was limited, as only seven of these trials (Atkinson 1999; Koo 2006; Litmanovitz 2004; Lucas 1992; Lucas 2001; Roggero 2011; Roggero 2012) presented data that could be included in meta-analyses of growth outcomes. Interpretation of meta-analyses was further limited by heterogeneity. The source of heterogeneity is not clear, as these trials were of similar design (intervention given for six to 12 months) and methodological quality (satisfactory processes to ensure allocation concealment and achievement of about 70% to 80% follow-up at longer than six months post term). Meta-analyses of data from the five trials that compared preterm formula versus term formula were more complete and revealed no statistical heterogeneity.

Differences in measured effects on growth parameters between postdischarge formula and preterm formula may simply be related to total nutrient content and intake. An additional factor is that whereas postdischarge formula contains about 10% more calories and 20% to 25% more protein and bone minerals than term formula, preterm formula is about 20% energy-enriched and contains 40% to 60% more protein and minerals than term formula. Demand (responsively) fed infants regulate their volume of milk intake relative to its calorie density; therefore, infants in comparison groups may have had similar total energy intake. However, infants fed postdischarge formula would still have received about 10% more protein and minerals than those fed term formula, but infants fed preterm formula would have received up to about 25% more protein and minerals than those given term formula. It is possible that protein and mineral intake (per unit of energy) is the key factor in determining catch-up growth rates and, specifically, lean and skeletal growth, in this population of infants.

The applicability of currently available data is limited by the short duration of follow-up reported in clinical trials. No trials planned to undertake or undertook assessment of growth or development beyond 12 to 18 months' corrected age, and some trials reported growth outcomes only up to six months. Similarly, no trials have reported data related to possible adverse metabolic consequences of nutrient supplementation in early infancy, nor to any long-term measures of obesity (such as body mass index (BMI), fat mass) or risk factors for cardiovascular disease (such as elevated blood pressure).

Quality of the evidence

Interpretation of review findings is limited by methodological weaknesses associated with potential for bias in some trials (Figure 2). Methods used to preserve allocation concealment are uncertain for some trials. Only one trial (Jeon 2011) reported substantial between-group differences in baseline demographics that are likely due to allocation bias. We elected to exclude one arm of this three-arm trial because of substantial differences in mean birth weight, gestational age and proportion of growth-restricted infants. The other methodological limitation apparent in six trials was incomplete outcome assessment (loss to follow-up > 20%). In most of these trials (Atkinson 1999; Koo 2006; Peng 2004; Picaud 2005), loss to follow-up was less than 30% and was distributed evenly between intervention and control groups. In two trials (Agosti 2003; Carver 2001), loss to follow-up at 12-month assessment was greater than 50%. However, these trials did not contribute substantially to any meta-analyses.

The GRADE assessment revealed that evidence for key growth outcomes was of moderate quality because of inconsistency (moderate or high heterogeneity in meta-analyses of trials of postdischarge formula vs standard formula; Summary of findings table 1) and imprecision (few trials with low numbers of participants included in meta-analyses of preterm formula vs standard formula; Summary of findings table 2).

Potential biases in the review process

Our main concern with the review process is that findings may be subject to publication and other reporting biases, including greater availability of numerical data for inclusion in meta-analyses from trials that reported statistically significant or clinically important effects (Hopewell 2009). We attempted to minimise this threat by searching the proceedings of major international perinatal conferences to identify trial reports that were not (or were not yet) published in full form in academic journals. However, we cannot be sure whether other trials have been undertaken but not reported, and we remain concerned that such trials are less likely than published trials to have detected statistically significant or clinically important effects. The meta-analyses that we performed did not include sufficient trials to explore the symmetry of funnel plots as a means of identifying possible publication or reporting bias.

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Authors' conclusions

Implications for practice

These findings do not support expert group and consensus recommendations that formula-fed preterm infants should receive a postdischarge formula for up to 12 months after discharge from the hospital (Aggett 2006; Bhatia 2005; Carver 2005; Dusick 2003; Griffin 2007; Kleinman 2004). In contrast, available trial data indicate that feeding with 'preterm formula', which generally is licensed and available only for in-hospital use, may increase weight, length and head circumference growth up to 12 to 18 months post term.

Infants who participated in the trials included in this review were fed responsively (on demand), and study findings may not be applicable to infants who cannot feed responsively, for example, because of oro-motor dysmotility or chronic lung disease.

Implications for research

Follow-up of infants who participated in the trials identified in this review might provide further data on the effect of this intervention on growth through later childhood, specifically, whether final height is affected; on effects on later neurodevelopmental outcomes; and on long-term effects on metabolic or cardiovascular outcomes (Euser 2005; Greer 2007). If additional large randomised controlled trials are undertaken to evaluate the effects of feeding preterm infants with nutrient-enriched formula after hospital discharge, it may be appropriate to include in these research efforts preterm infants who are not able to feed ad libitum after hospital discharge, and who have extra metabolic demands, for example, because of severe growth restriction or chronic lung disease. Trials should aim to assess long-term clinically important outcomes such as final height and body composition and neurodevelopment (including cognitive and educational outcomes).

Further research is needed to determine which specific nutrients (including appropriate energy:protein balance) are key to promoting lean mass and linear growth and to improving developmental outcomes. As a first step, it may be worthwhile to review systematically trials that could not be included in this review because the nutrient-enriched formula examined differed only in protein and mineral content (but not in energy) from standard term formula.

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Acknowledgements

We thank Dr Litmanovitz for clarifying aspects of Litmanovitz 2004.

We thank Dr Roggero for kindly providing unpublished data from Roggero 2011 for inclusion in this review.

We thank Yolanda Brosseau and Colleen Ovelman of the Cochrane Neonatal Review Group for help in preparing this updated review.

Editorial support of the Cochrane Neonatal Review Group has been provided with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN275201100016C.

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Contributions of authors

William McGuire and Lauren Young undertook the electronic search and identified citations for possible inclusion. Lauren Young, William McGuire and Nick Embleton reviewed the citation list (title and abstract) for inclusion and undertook methodological appraisal and data extraction, entry and analysis. William McGuire acted as an arbiter for disagreements, reviewed data entered and analysed and completed the review.

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Declarations of interest

Nick Embleton has conducted research with support from manufacturers of infant formula including Nestec SA (Switzerland), Wyeth UK and Nutricia UK, but did not receive payment, support nor benefit in kind for contributions to this review.

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Differences between protocol and review

We added the methods and plan for Summary of findings tables and GRADE recommendations, which were not included in the original protocol nor in the previously published review.

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Published notes

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Characteristics of studies

Characteristics of included studies

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/100 mL, calcium and phosphorus content 100 mg/100 mL and 50 mg/100 mL, respectively) (N = 69) or standard term formula (energy content 70 kcal/100 mL, protein content 1.7 g/100 mL) (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: multi-centre trial in Italy (2001)

Research supported by Milupa (formula milk manufacturing company)

Numerical growth data obtained from primary investigators (June 2011)

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

Report states simply that infants were "randomised" to study groups.

Allocation concealment (selection bias) Unclear risk

Randomisation method was not mentioned.

Incomplete outcome data (attrition bias) High risk

Loss to follow-up was 34% at 6 months and 66% at 12 months.

Blinding of participants and personnel (performance bias) High risk

Families and caregivers were aware of which formula milk infants received.

Blinding of outcome assessment (detection bias) Low risk

Outcome assessors were unlikely to have been aware of which formula milk infants received.

Atkinson 1999

Methods

Randomised controlled trial

Participants

70 formula milk-fed preterm infants of birth weight < 1800 g and 'appropriate for gestational age'

Interventions

Postdischarge formula (energy content 74 kcal/100 mL, protein content 1.8 g/100 mL) (N = 34) vs 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 table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Random sequence was independently generated.

Allocation concealment (selection bias) Low risk

Allocation was drawn from sequential sealed opaque envelopes.

Incomplete outcome data (attrition bias) High risk

Growth outcome data to 12 months were available for 24 (71%) intervention group and 29 (81%) control group infants.

Blinding of participants and personnel (performance bias) Low risk

Families and caregivers were unaware of which formula milk infants received.

Blinding of outcome assessment (detection bias) Low risk

Outcome assessors were not aware of which formula milk infants received.

Atkinson 2004

Methods

Randomised controlled trial

Participants

53 formula milk-fed preterm 'small for gestational age' infants

Interventions

Postdischarge formula (energy content 74 kcal/100 mL, protein content 1.8 g/100 mL) (N = 24) vs 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

Notes

Published in abstract form only. Additional information and data courtesy of Dr Stephanie Atkinson

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Random sequence was independently generated.

Allocation concealment (selection bias) Low risk

Allocation was drawn from sequential sealed opaque envelopes.

Incomplete outcome data (attrition bias) Low risk

Follow-up growth parameter outcome assessments were completed.

Blinding of participants and personnel (performance bias) Low risk

Families and caregivers were unaware of which formula milk infants received.

Blinding of outcome assessment (detection bias) Low risk

Outcomes assessors were not aware of which formula milk infants received.

Carver 2001

Methods

Randomised controlled trial

Participants

125 preterm infants (birth weight < 1800 g or gestation < 37 weeks). Infants with severe bronchopulmonary dysplasia or cardiac, respiratory, gastrointestinal or other systemic diseases at time of discharge were not eligible to participate.

Interventions

Postdischarge formula (energy content 74 kcal/100 mL, protein content 1.9 g/100 mL, calcium and phosphorus content 78 mg/100 mL and 46 mg/100 mL, respectively) (N = 67) or standard term formula (energy content 68 kcal/100 mL, protein content 1.5 g/100 mL) (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 assessed at intervals until the end of the 12-month study period

Notes

Setting: multi-centre - 6 perinatal centres in North America

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Method used to generate random sequence was not described.

Allocation concealment (selection bias) Unclear risk

No information on randomisation method was provided.

Incomplete outcome data (attrition bias) High risk

31 of 67 in postdischarge formula group and 26 of 56 in standard term formula group left the study early (plus 2 other infants, who were randomised but did not take part in the study). Total loss of follow-up for growth parameters assessed at 12 months was 60% in the intervention group and 52% in the control group.

Infants exited the study early (without growth parameters measured) for a variety of reasons, including study non-compliance (not defined or described), gastrointestinal upset and "illness unrelated to the study feedings" (not defined or described).

Blinding of participants and personnel (performance bias) Low risk

Families and caregivers were unaware of which formula milk infants received.

Blinding of outcome assessment (detection bias) Low risk

Outcome assessors were not aware of which formula milk infants received.

Cooke 2001

Methods

Randomised controlled trial

Participants

103 preterm infants (birth weight < 1750 g or gestation < 35 weeks). Only infants who were 'growing normally' (rate of weight gain > 25 g/kg/d) at the time of discharge were eligible to participate.

Interventions

Preterm formula (energy content 80 kcal/100 mL, protein content 2.2 g/100 mL, calcium and phosphorus content 108 mg/100 mL and 54 mg/100 mL, respectively) (N = 49) or standard term formula (energy content 66 kcal/100 mL, protein content 1.4 g/100 mL) (N = 54) from hospital discharge until 6 months' corrected age

Outcomes

Anthropometric and developmental parameters (including Bayley Scales of Infant Development II), measures of bone mineralisation

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 data for inclusion in this review.

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Random sequence was centrally generated.

Allocation concealment (selection bias) Low risk

Sealed opaque envelopes were used.

Incomplete outcome data (attrition bias) Low risk

Follow-up was near complete (> 80%).

Blinding of participants and personnel (performance bias) Low risk

Families and caregivers were unaware of which formula milk infants received.

Blinding of outcome assessment (detection bias) Low risk

Outcome assessors were not aware of which formula milk infants received.

De Curtis 2002

Methods

Randomised controlled trial

Participants

33 formula milk-fed preterm infants (birth weight < 1750 g or gestation < 35 weeks)

Interventions

Postdischarge formula (energy content 74 kcal/100 mL, protein content 1.8 g/100 mL, calcium and phosphorus content 80 mg/100 mL and 40 mg/100 mL, respectively) (N = 16) or standard term formula (energy content 66 kcal/100 mL, protein content 1.4 g/100 mL) (N = 17) from hospital discharge until 2 months' corrected age

Outcomes

Growth parameters and bone mineralisation measured by dual-energy X-ray absorptiometry at the end of the 2-month study period

Notes

Setting: Department of Pediatrics, University of Liege, Belgium

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

Method used to generate random sequence was not described.

Allocation concealment (selection bias) Unclear risk

No information on randomisation method was provided.

Incomplete outcome data (attrition bias) Low risk

Follow-up was near complete (> 90%).

Blinding of participants and personnel (performance bias) Low risk

Families and caregivers were unaware of which formula milk infants received.

Blinding of outcome assessment (detection bias) Low risk

Outcome assessors were not aware of which formula milk infants received.

Jeon 2011

Methods

Randomised controlled trial

Participants

59 preterm very low birth weight infants

Interventions

Preterm formula (energy content 80 kcal/100 mL, protein content 2.3 g/100 mL, calcium and phosphorus content 128 mg/100 mL and 64 mg/100 mL, respectively) (N = 34) or standard term formula (energy content 67 kcal/100 mL, protein content 1.6 g/100 mL) (N = 34) from hospital discharge until 3 months post term, then both groups continued with standard term formula until at least 6 months post term

Outcomes

Growth parameters at 3-monthly intervals until 18 months post term, Bayley Scales of Infant Development II at 18 months' corrected age

Notes

Setting: multi-centre trial in 4 hospitals in South Korea

Research supported by Maeli Dairy Industry Co. Ltd. (formula milk manufacturer)

Initially, 3 groups were randomly allocated to receive (1) standard term formula, (2) preterm formula for 3 months or (3) preterm formula for 6 months. However, results showed substantial and significant between-group differences in baseline demographic characteristics, especially between group (3) and the other groups. Group (3) infants had statistically significantly lower birth weight 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) vs group (3).

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

Method used to generate random sequence was not described.

Allocation concealment (selection bias) Unclear risk

No information on randomisation method was provided.

Incomplete outcome data (attrition bias) Low risk

Growth outcome data to 18 months were available for 30 (88%) intervention group and 29 (85%) control group infants.

Blinding of participants and personnel (performance bias) High risk

Families and caregivers were likely to have been aware of which formula milk infants received.

Blinding of outcome assessment (detection bias) Unclear risk

Outcome assessors may have been aware of which formula milk infants received.

Koo 2006

Methods

Randomised controlled trial

Participants

89 preterm infants ready for hospital discharge (gestational age at birth < 35 weeks). Infants with major congenital malformation, previous gastrointestinal surgery or abnormal suck and swallow actions were not eligible to participate.

Interventions

Nutrient-enriched formula (energy content 74 kcal/100 mL, protein content 1.9 g/100 mL, calcium and phosphorus content 78 mg/100 mL and 46 mg/100 mL, respectively) (N = 44) or standard term formula (energy content 67 kcal/100 mL, protein content 1.5 g/100 mL) (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-month study period

Notes

Setting: Department of Pediatrics, Wayne State University, and Hutzel Hospital, Detroit, Michigan, USA

Research supported by Ross Products Division, Abbott Laboratories (formula milk manufacturer)

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

Method used to generate random sequence was not described.

Allocation concealment (selection bias) Low risk

Allocation was drawn from sequential sealed opaque envelopes.

Incomplete outcome data (attrition bias) High risk

Growth outcome data to 12 months were available for 31 (70%) intervention group and 36 (80%) control group infants.

Blinding of participants and personnel (performance bias) Low risk

Families and caregivers were unaware of which formula milk infants received.

Blinding of outcome assessment (detection bias) Low risk

Outcome assessors were not aware of which formula milk infants received.

Litmanovitz 2004

Methods

Randomised controlled trial

Participants

20 healthy very low birth weight infants at hospital discharge

Interventions

Nutrient-enriched formula (energy content 74 kcal/100 mL, protein content 1.9 g/100 mL) (N = 10) or standard term formula (energy content 67 kcal/100 mL, protein content 1.5 g/100 mL) (N = 10) after hospital discharge. Formula was intended to provide sole milk intake up to 6 months' corrected age.

Outcomes

Weight, length, head circumference and measures of bone mineralisation at term and at 6 months' corrected age

Notes

Setting: Meir General Hospital, Kfar-saba, Israel

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

Method used to generate random sequence was not described.

Allocation concealment (selection bias) Unclear risk

No information on randomisation method was provided.

Incomplete outcome data (attrition bias) Low risk

Follow-up was near complete (> 80%).

Blinding of participants and personnel (performance bias) Unclear risk

No information was provided on whether families and caregivers were aware of which formula milk infants received.

Blinding of outcome assessment (detection bias) Unclear risk

No information was provided on whether outcome assessors were aware of which formula milk infants received.

Lucas 1992

Methods

Randomised controlled trial

Participants

32 exclusively formula milk-fed preterm infants, birth weight < 1850 g, weight < 3000 g at hospital discharge

Interventions

Nutrient-enriched formula (energy content 72 kcal/100 mL, protein content 1.8 g/100 mL, calcium and phosphorus content 70 mg/100 mL and 35 mg/100 mL, respectively) (N = 16) or standard term formula (energy content 68 kcal/100 mL, protein content 1.4 g/100 mL) (N = 16) after hospital discharge. Formula was intended to provide sole milk intake up to 9 months' corrected age.

Outcomes

Measures of growth (weight, crown-heel length and head circumference), feed tolerance, bone mineralisation during 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 before planned hospital discharge and could not be included in follow-up assessments.

Data were presented graphically. We extracted numerical data (mean and SD) from the graphs to calculate mean differences.

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

Method used to generate random sequence was not described.

Allocation concealment (selection bias) Unclear risk

No information on randomisation method was provided.

Incomplete outcome data (attrition bias) Low risk

Follow-up was near complete (1 infant from the standard term formula group was withdrawn).

Blinding of participants and personnel (performance bias) Low risk

It is likely that families and caregivers were unaware of which formula milk infants received.

Blinding of outcome assessment (detection bias) Low risk

It is likely that outcome assessors were unaware of which formula milk infants received.

Lucas 2001

Methods

Randomised controlled trial

Participants

229 formula milk-fed preterm infants, birth weight < 1750 g, weight < 3000 g at hospital discharge

Interventions

Nutrient-enriched formula (energy content 72 kcal/100 mL, protein content 1.85 g/100 mL, calcium and phosphorus content 70 mg/100 mL and 35 mg/100 mL, respectively) (N = 113) or standard term formula (energy content 68 kcal/100 mL, protein content 1.5 g/100 mL) (N = 116) from hospital discharge until 9 months post term

Outcomes

Growth parameters up to 18 months post term, neurodevelopment (Bayley Scales) at 18 months' corrected age

Notes

Setting: 5 neonatal centres in the UK (1993-1995)

Research supported by Farley Health Products (formula milk company)

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

A member of the clinical team not involved in the trial prepared randomisation assignments.

Allocation concealment (selection bias) Low risk

Allocation was drawn from sequential sealed opaque envelopes.

Incomplete outcome data (attrition bias) Low risk

Growth and developmental outcomes were assessed in > 80% of participating infants.

Blinding of participants and personnel (performance bias) Low risk

Families and caregivers were unaware of which formula milk infants received.

Blinding of outcome assessment (detection bias) Low risk

Outcome assessors were unaware of which formula milk infants received.

Peng 2004

Methods

Randomised controlled trial

Participants

34 preterm infants with gestational age of less than/or equal to 35 weeks and birth weight less than/or equal to 1850 g

Interventions

Nutrient-enriched formula (energy content 81 kcal/100 mL, protein content 2.40 g/100 mL, calcium and phosphorus content 95 mg/100 mL and 53 mg/100 mL, respectively) (N = 19) or standard term formula (energy content 67.6 kcal/100 mL, protein content 1.4 g/100 mL) (N = 15) from hospital-discharge until 6 months' corrected age

Outcomes

Measures of growth (weight, crown-heel length and head circumference), feed tolerance, bone mineralisation during trial period

Notes

Setting: Mackay Memorial Hospital, Taipei, Taiwan

Research supported by Mead Johnson (formula milk company)

No differences were found between the 2 groups in weight, length or head circumference 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.

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

Method used to generate random sequence was not described.

Allocation concealment (selection bias) Unclear risk

No information on randomisation method was provided.

Incomplete outcome data (attrition bias) High risk

Growth outcome data to 6 months were available for 29 of the 40 infants initially enrolled (73%).

Blinding of participants and personnel (performance bias) High risk

Families and caregivers were likely to have been aware of which formula milk infants received, as parents were not blinded to infant assignment.

Blinding of outcome assessment (detection bias) High risk

Outcome assessors may have been aware of which formula milk infants received, as physicians were not blinded to infant assignment.

Picaud 2005

Methods

Randomised controlled trial

Participants

49 formula milk-fed preterm infants, birth weight < 1750 g or gestation at birth < 33 weeks

Interventions

Preterm formula (energy content 81 kcal/100 mL, protein content 2.3 g/100 mL, calcium and phosphorus content 100 mg/100 mL and 53 mg/100 mL, respectively) (N = 23) or standard term formula (energy content 67 kcal/100 mL, protein content 1.7 g/100 mL) (N = 26) from hospital discharge until 2 months post term

Outcomes

Growth parameters and measures of bone mineralisation up to 4 months' corrected age

Notes

Setting: 2 tertiary care neonatal units in France (2001-2004)

Research supported by Nestlé France (formula milk manufacturer)

From 2 months post discharge, both groups received standard term formula milk.

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Clinical trials unit was generated.

Allocation concealment (selection bias) Low risk

Pharmacy was coded.

Incomplete outcome data (attrition bias) High risk

Loss to follow-up by 12 months in the control group was substantial (35%) and was greater than in the intervention group (9%).

Blinding of participants and personnel (performance bias) Low risk

Families and caregivers were unaware of which formula milk infants received.

Blinding of outcome assessment (detection bias) Low risk

Outcome assessors were unaware of which formula milk infants received.

Roggero 2011

Methods

Randomised controlled trial

Participants

123 formula fed preterm infants who were 'appropriate (birth weight) for gestational age'

Interventions

Postdischarge formula (energy content 75 kcal/100 mL, protein content 2.0 g/100 mL, calcium and phosphorus content 100 mg/100 mL and 56 mg/100 mL, respectively) (N = 59) or standard term formula (energy content 67 kcal/100 mL, protein content 1.4 g/100 mL) (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

Trial was registered with Current Controlled Trials (http://www.controlledtrials.com/ISRCTN30189842).

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Randomisation was performed by an independent investigator using computer-generated randomisation lists.

Allocation concealment (selection bias) Low risk

Randomisation was performed by an independent investigator using computer-generated randomisation lists.

Incomplete outcome data (attrition bias) Unclear risk

Follow-up until 12 months post term was complete.

Blinding of participants and personnel (performance bias) Unclear risk

No information was provided.

Blinding of outcome assessment (detection bias) Unclear risk

No information was provided.

Roggero 2012

Methods

Randomised controlled trial

Participants

84 formula milk-fed preterm infants born 'small for gestational age' (< 10th percentile)

Interventions

Postdischarge formula (energy content 75 kcal/100 mL, protein content 2.0 g/100 mL, calcium and phosphorus content 100 mg/100 mL and 56 mg/100 mL, respectively) (N = 40) or standard term formula (energy content 67 kcal/100 mL, protein content 1.4 g/100 mL) (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 (2008-2010)
These trialists also conducted an RCT of nutrient-enriched vs standard formula in appropriate for gestational age infants (N = 123). These data are not yet published or available from study authors (referred to in conference abstract: Roggero 2011c).

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

No information was provided.

Allocation concealment (selection bias) Unclear risk

No information was provided.

Incomplete outcome data (attrition bias) Low risk

Follow-up until 6 months post term was complete.

Blinding of participants and personnel (performance bias) Unclear risk

No information was provided.

Blinding of outcome assessment (detection bias) Unclear risk

No information was provided.

Taroni 2009

Methods

Randomised controlled trial

Participants

27 formula milk-fed preterm infants, birth weight < 1500 g or gestation at birth < 33 weeks, 'small for gestational age' (< 10th percentile)

Interventions

Postdischarge formula (energy content 75 kcal/100 mL, protein content 2.0 g/100 mL, calcium and phosphorus content 100 mg/100 mL and 56 mg/100 mL, respectively) (N = 14) or standard term formula (energy content 67 kcal/100 mL, protein content 1.4 g/100 mL) (N = 13) from hospital discharge until 1 month corrected age

Outcomes

Growth parameters and fat mass up to 1 month corrected age

Notes

Setting: 4 Italian neonatal units (2008-2009)

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Random sequence was pre-prepared.

Allocation concealment (selection bias) Unclear risk

No information was provided.

Incomplete outcome data (attrition bias) Low risk

Follow-up until 1 month post term was complete.

Blinding of participants and personnel (performance bias) Unclear risk

No information was provided.

Blinding of outcome assessment (detection bias) Unclear risk

No information was provided.

Footnotes

PMA: postmenstrual age.
RCT: randomised controlled trial.
VLBW: very low birth weight.

Characteristics of excluded studies

Amesz 2010

Reason for exclusion

The protein content of both formula milks was less than/or equal to 1.7 g/100 mL.

Bernbaum 1989

Reason for exclusion

The energy content of both formula milks was < 70 kcal/100 mL.

Bhatia 1991

Reason for exclusion

The protein content of both formula milks was less than/or equal to 1.7 g/100 mL.

Brunton 1998

Reason for exclusion

Both formula milks were calorie-enriched (90 kcal/100 mL).

Chan 1994

Reason for exclusion

The energy content of both formula milks was < 70 kcal/100 mL.

Cooper 1985

Reason for exclusion

The energy content of both formula milks was < 70 kcal/100 mL.

Friel 1993

Reason for exclusion

The energy content of both formula milks was < 70 kcal/100 mL.

Lapillonne 2004

Reason for exclusion

Both formula milks were calorie-enriched (81 kcal/100 mL) and protein-enriched (> 2.0 g/100 mL).

Wheeler 1996

Reason for exclusion

The energy content of both formula milks was < 70 kcal/100 mL.

Characteristics of studies awaiting classification

Ekcharoen 2015

Methods

Randomised controlled trial

Participants

Preterm infants who had postconceptional age 35 to 36 weeks and weight 1.8 to 3 kg at hospital discharge

Interventions

Postdischarge formula vs high-energy, high-protein, medium-chain triglyceride-containing formula

Outcomes

Growth rate at days 28, 56 and 84 after hospital discharge

Notes

Abstract only; full-text article not available (study authors contacted September 2016)

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Summary of findings tables

1 Postdischarge formula compared with standard term formula for preterm infants after hospital discharge

Postdischarge formula compared with standard term formula for preterm infants after hospital discharge

Patient or population: preterm infants after hospital discharge
Setting: community
Intervention: postdischarge formula
Comparison: standard term formula

Outcomes

Anticipated absolute effects*

(95% CI)

Number of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Postdischarge formula vs standard term formula

Weight (grams) 3-4 months post term

MD 7.45 g lower
(141.84 lower to 126.93 higher)

523
(6 RCTs)

⊕⊕⊕⊝
Moderate

Downgraded for moderate inconsistency (I² = 62%)

Weight (grams) 6 months post term

MD 35.54 g higher
(113.71 lower to 184.78 higher)

576
(7 studies)

⊕⊕⊕⊝
Moderate

Downgraded for inconsistency moderate (I² = 64%).

Crown-heel length (mm) 3-4 months post term

MD 2.45 mm higher
(2.01 lower to 6.9 higher)

523
(6 RCTs)

⊕⊕⊕⊝
Moderate

Downgraded for high inconsistency (I² = 81%)

Crown-heel length (mm) 6 months post term

MD 2.12 mm higher
(2.16 lower to 6.41 higher)

576
(7 studies)

⊕⊕⊕⊝
Moderate

Downgraded for moderate inconsistency (I² = 75%)

Head circumference (mm) 3-4 months post term

MD 0.3 mm lower
(2.86 lower to 2.26 higher)

523
(6 studies)

⊕⊕⊕⊝
Moderate

Downgraded for moderate inconsistency (I² = 71%)

Head circumference (mm) 6 months post term

MD 2.28 mm higher
(0.28 lower to 4.83 higher)

576
(7 studies)

⊕⊕⊕⊝
Moderate

Downgraded for moderate inconsistency (I² = 69%)

Development - Bayley Scales of Infant Development II: Mental Development Index

MD 0.9 higher
(3.24 lower to 5.04 higher)

184
(1 RCT)

⊕⊕⊕⊕
High

 

2 Preterm formula compared with standard term formula for preterm infants after hospital discharge

Preterm formula compared with standard term formula for preterm infants after hospital discharge

Patient or population: preterm infants after hospital discharge
Setting: community
Intervention: preterm formula
Comparison: standard term formula

Outcomes

Anticipated absolute effects* (95% CI)

Number of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Preterm formula vs standard term formula

Weight (grams) 3-4 months post term

MD 74.41 g higher
(267.1 lower to 415.93 higher)

130
(3 RCTs)

⊕⊕⊕⊝
Moderate

Downgraded for imprecision

Weight (grams) 6 months post term

MD 74.6 g higher
(164.73 lower to 313.92 higher)

273
(4 RCTs)

⊕⊕⊕⊝
Moderate

Downgraded for imprecision

Crown-heel length (mm) 3-4 months post term

MD 2.27 mm lower
(13.09 lower to 8.56 higher)

130
(3 RCTs)

⊕⊕⊕⊝
Moderate

Downgraded for imprecision

Crown-heel length (mm) 6 months post term

MD 1.83 mm higher
(6.25 lower to 9.92 higher)

160
(3 RCTs)

⊕⊕⊕⊝
Moderate

Downgraded for imprecision

Head circumference (mm) 3-4 months post term

MD 3.61 mm higher
(2.09 lower to 9.31 higher)

130
(3 RCTs)

⊕⊕⊕⊝
Moderate

Downgraded for imprecision

Head circumference (mm) 6 months post term

MD 5.82 mm higher
(1.32 higher to 10.32 higher)

160
(3 RCTs)

⊕⊕⊕⊝
Moderate

Downgraded for imprecision

Development - Bayley Scales of Infant Development II: Mental Development Index

MD 1.44 lower
(6.22 lower to 3.35 higher)

143
(2 RCTs)

⊕⊕⊕⊕
High

 

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References to studies

Included studies

Agosti 2003

[CRSSTD: 3161394]

Agosti M, Vegni C, Calciolari G, Marini A; GAMMA Study Group. Post-discharge nutrition of the very low-birthweight infant: interim results of the multicentric GAMMA study. Acta Paediatrica Supplement 2003;91:39-43. [CRSREF: 3161395]

Atkinson 1999

[CRSSTD: 3161396]

Atkinson SA, Randall-Simpson J, Chang M, Paes B. Randomised trial of feeding nutrient-enriched versus standard formula to premature infants during the first year of life. Pediatric Research 1999;45:276A. [CRSREF: 3161397]

Atkinson 2004

[CRSSTD: 3161398]

Atkinson SA, Paes B, Saigal S, Hussey T, Lee D. Nutrient-enriched discharge formula compared to standard term formula does not benefit growth, bone mineral accretion or trace element status in preterm small for gestational age (SGA) infants to one year corrected age: an RCT. Pediatric Research 2004;55:383A. [CRSREF: 3161399]

Carver 2001

[CRSSTD: 3161400]

Carver JD, Wu PY, Hall RT, Ziegler EE, Sosa R, Jacobs J et al. Growth of preterm infants fed nutrient-enriched or term formula after hospital discharge. Pediatrics 2001;107:683-9. [CRSREF: 3161401]

Cooke 2001

[CRSSTD: 3161402]

* Cooke RJ, Embleton ND, Griffin IJ, Wells JC, McCormick KP. Feeding preterm infants after hospital discharge: growth and development at 18 months of age. Pediatric Research 2001;49:719-22. [CRSREF: 3161403]

Cooke RJ, Griffin IJ, McCormick K, Wells JC, Smith JS, Robinson SJ, Leighton M. Feeding preterm infants after hospital discharge: effect of dietary manipulation on nutrient intake and growth. Pediatric Research 1998;43:355-60. [CRSREF: 3161404]

Cooke RJ, Griffin IJ, McCormick K. Adiposity is not altered in preterm infants fed with a nutrient-enriched formula after hospital discharge. Pediatric Research 2010;67:660-4. [CRSREF: 3161405; PubMed: 20216105]

Cooke RJ, McCormick K, Griffin IJ, Embleton N, Faulkner K, Wells JC et al. Feeding preterm infants after hospital discharge: effect of diet on body composition. Pediatric Research 1999;46:461-4. [CRSREF: 3161406]

De Curtis 2002

[CRSSTD: 3161407]

De Curtis M, Pieltain C, Rigo J. Body composition in preterm infants fed standard term or enriched formula after hospital discharge. European Journal of Nutrition 2002;41:177-82. [CRSREF: 3161408]

Jeon 2011

[CRSSTD: 3161409]

Jeon GW, Jung YJ, Koh SY, Lee YK, Kim KA, Shin SM et al. Preterm infants fed nutrient-enriched formula until six months show improved growth and development. Pediatrics International 2011;53:683-8. [CRSREF: 3161410; PubMed: 21342352]

Koo 2006

[CRSSTD: 3161411]

Koo WW, Hockman EM. Posthospital discharge feeding for preterm infants: effects of standard compared with enriched milk formula on growth, bone mass, and body composition. American Journal of Clinical Nutrition 2006;84:1357-64. [CRSREF: 3161412]

Litmanovitz 2004

[CRSSTD: 3161413]

* Litmanovitz I, Dolfin T, Arnon S, Bauer S, Regev R, Shainkin-Kestenbaum R et al. Bone strength and growth of preterm infants fed nutrient-enriched or term formula after hospital discharge. Pediatric Research 2004;55:274A. [CRSREF: 3161414]

Litmanovitz I, Eliakim A, Arnon S, Regev R, Bauer S, Shainkin-Kestenbaum R et al. Enriched post-discharge formula versus term formula for bone strength in very low birth weight infants: a longitudinal pilot study. Journal of Perinatal Medicine 2007;35:431-5. [CRSREF: 3161415; PubMed: 17605597]

Lucas 1992

[CRSSTD: 3161416]

Bishop NJ, King FJ, Lucas A. Increased bone mineral content of preterm infants fed with a nutrient enriched formula after discharge from hospital. Archives of Disease in Childhood 1993;68:573-8. [CRSREF: 3161417]

* Lucas A, Bishop NJ, King FJ, Cole TJ. Randomised trial of nutrition for preterm infants after discharge. Archives of Disease in Childhood 1992;67:324-7. [CRSREF: 3161418]

Lucas 2001

[CRSSTD: 3161419]

Lucas A, Fewtrell MS, Morley R, Singhal A, Abbott RA, Isaacs E et al. Randomized trial of nutrient-enriched formula versus standard formula for postdischarge preterm infants. Pediatrics 2001;108:703-11. [CRSREF: 3161420]

Peng 2004

[CRSSTD: 3161421]

Peng CC, Hsu CH, Kao HA, Hung HY, Chang JH. Feeding with premature or infant formula in premature infants after discharge: comparison of growth and nutrition status. Acta Paediatrica Taiwanica 2004;45:151-7. [CRSREF: 3161422; PubMed: 15493734]

Picaud 2005

[CRSSTD: 3161423]

Picaud JC, Plan O, Pidoux O, Reygrobellet B. Chapuis F, Salle BL et al. Effect of post-discharge nutrition on growth and whole body mineralization in very low birth weight (VLBW) infants. In: Pediatric Academic Societies Conference Proceedings. PAS2005:57:1326. [CRSREF: 3161424]

Roggero 2011

Published data only (unpublished sought but not used) [CRSSTD: 3161425]

Gianni ML, Roggero P, Amato O, Picciolini O, Piemontese P, Liotto N et al. Randomized outcome trial of nutrient-enriched formula and neurodevelopment outcome in preterm infants. BMC Pediatrics 2014;14:74. [CRSREF: 3161426; PubMed: 24645671]

* Roggero P, Gianni ML, Amato O, Liotto N, Morlacchi L, Orsi A et al. Growth and fat-free mass gain in preterm infants after discharge: a randomized controlled trial. Pediatrics 2012;130:e1215-21. [CRSREF: 3161427; PubMed: 23109680]

Roggero 2012

[CRSSTD: 3161428]

Roggero P, Giannì ML, Liotto N, Taroni F, Morniroli D, Mosca F. Small for gestational age preterm infants: nutritional strategies and quality of growth after discharge. Journal of Maternal-Fetal and Neonatal Medicine 2011;24(Suppl 1):144-6. [CRSREF: 3161429; PubMed: 21888510]

Taroni 2009

[CRSSTD: 3161430]

Taroni E, Liotto N, Orsi A, Piemontese P, Amato O, Morlacchi L et al. Quality of post-discharge growth in small for gestational age preterm infants: an explorative study [Qualita della crescita post-dimissione in prematuri nati piccoli per eta gestazionale: studio esplorativo]. La Pediatria Medica e Chirurgica 2009;31:121-5. [CRSREF: 3161431; PubMed: 19739491]

Excluded studies

Amesz 2010

[CRSSTD: 3161432]

Amesz EM, Schaafsma A, Cranendonk A, Lafeber HN. Optimal growth and lower fat mass in preterm infants fed a protein-enriched postdischarge formula. Journal of Pediatric Gastroenterology and Nutrition 2010;50:200-7. [CRSREF: 3161433; PubMed: 19881394]

Bernbaum 1989

[CRSSTD: 3161434]

Bernbaum JC, Sasanow SR, Churella HR, Daft A. Growth and metabolic response of premature infants fed whey- or casein-dominant formulas after hospital discharge. Journal of Pediatrics 1989;115:652-6. [CRSREF: 3161435; PubMed: 2795362]

Bhatia 1991

[CRSSTD: 3161436]

Bhatia J, Rassin DK. Feeding the premature infant after hospital discharge: growth and biochemical responses. Journal of Pediatrics 1991;118:515-9. [CRSREF: 3161437]

Brunton 1998

[CRSSTD: 3161438]

Brunton JA, Saigal S, Atkinson SA. Growth and body composition in infants with bronchopulmonary dysplasia up to 3 months corrected age: a randomized trial of a high-energy nutrient-enriched formula fed after hospital discharge. Journal of Pediatrics 1988;133:340-5. [CRSREF: 3161439]

Chan 1994

[CRSSTD: 3161440]

Chan GM, Borschel MW, Jacobs JR. Effects of human milk or formula feeding on the growth, behavior, and protein status of preterm infants discharged from the newborn intensive care unit. American Journal of Clinical Nutrition 1994;60:710-6. [CRSREF: 3161441]

Chan GM. Growth and bone mineral status of discharged very low birth weight infants fed different formulas or human milk. Journal of Pediatrics 1993;123:439-43. [CRSREF: 3161442]

Cooper 1985

[CRSSTD: 3161443]

Cooper PA, Rothberg AD. Feeding of very-low-birth-weight infants with special formula - continued use beyond 2000 g and effects on growth to 1 year. South African Medical Journal 1985;67:716-8. [CRSREF: 3161444]

Friel 1993

[CRSSTD: 3161445]

Friel JK, Andrews WL, Matthew D, McKim E, French S, Long DR. Improved growth of very low birthweight infants. Nutrition Research 1993;13:611-20. [CRSREF: 3161446]

Lapillonne 2004

[CRSSTD: 3161447]

Lapillonne A, Salle BL, Glorieux FH, Claris O. Bone mineralization and growth are enhanced in preterm infants fed an isocaloric, nutrient-enriched preterm formula through term. American Journal of Clinical Nutrition 2004;80(6):1595-603. [CRSREF: 3161448; PubMed: 15585774]

Wheeler 1996

[CRSSTD: 3161449]

Wheeler RE, Hall RT. Feeding of premature infant formula after hospital discharge of infants weighing less than 1800 grams at birth. Journal of Perinatology 1996;16:111-6. [CRSREF: 3161450]

Studies awaiting classification

Ekcharoen 2015

[CRSSTD: 4486755]

Ekcharoen C, Tantibhaedhyangkul R. Comparing growth rates after hospital discharge of preterm infants fed with either post-discharge formula or high-protein, medium-chain triglyceride containing formula. Journal of the Medical Association of Thailand 2015;98(12):1179-86. [CRSREF: 4486756; PubMed: 27004302]

Ongoing studies

None noted.

[top]

Other references

Additional references

Aggett 2006

Aggett PJ, Agostoni C, Axelsson I, De Curtis M, Goulet O, Hernell O et al. Feeding preterm infants after hospital discharge: a commentary by the ESPGHAN Committee on Nutrition. Journal of Pediatric Gastroenterology and Nutrition 2006;42:596-603. [PubMed: 16707992]

Bhatia 2005

Bhatia J. Post-discharge nutrition of preterm infants. Journal of Perinatology 2005;25 Suppl 2:S15-6; discussion S17-8. [PubMed: 15861162]

Bracewell 2008

Bracewell MA, Hennessy EM, Wolke D, Marlow N. The EPICure study: growth and blood pressure at 6 years of age following extremely preterm birth. Archives of Disease in Childhood. Fetal and Neonatal Edition 2008;93:F108-14. [PubMed: 17660214]

Carver 2005

Carver JD. Nutrition for preterm infants after hospital discharge. Advances in Pediatrics 2005;52:23-47. [PubMed: 16124335]

Clark 2003

Clark RH, Thomas P, Peabody J. Extrauterine growth restriction remains a serious problem in prematurely born neonates. Pediatrics 2003;111:986-90.

Cooke 2003

Cooke RWI, Foulder-Hughes L. Growth impairment in the very preterm and cognitive and motor performance at 7 years. Archives of Disease in Childhood 2003;88:482-7.

Doyle 2004

Doyle LW, Faber B, Callanan C, Ford GW, Davis NM. Extremely low birth weight and body size in early adulthood. Archives of Disease in Childhood 2004;89:347-50. [PubMed: 15033844]

Dusick 2003

Dusick AM, Poindexter BB, Ehrenkranz RA, Lemons JA. Growth failure in the preterm infant: can we catch up? Seminars in Perinatology 2003;27(4):302-10. [PubMed: 14510321]

Embleton 2001

Embleton NE, Pang N, Cooke RJ. Postnatal malnutrition and growth retardation: an inevitable consequence of current recommendations in preterm infants? Pediatrics 2001;107:270-3.

Embleton 2013

Embleton ND. Early nutrition and later outcomes in preterm infants. World Review of Nutrition and Dietetics 2013;106:26-32. [PubMed: 23428677]

Euser 2005

Euser AM, Finken MJ, Keijzer-Veen MG, Hille ET, Wit JM, Dekker FW. Associations between prenatal and infancy weight gain and BMI, fat mass, and fat distribution in young adulthood: a prospective cohort study in males and females born very preterm. American Journal of Clinical Nutrition 2005;81:480-7. [PubMed: 15699238]

Euser 2008

Euser AM, de Wit CC, Finken MJ, Rijken M, Wit JM. Growth of preterm born children. Hormone Research 2008;70(6):319-28. [PubMed: 18953169]

Farooqi 2006

Farooqi A, Hagglof B, Sedin G, Gothefors L, Serenius F. Growth in 10- to 12-year-old children born at 23 to 25 weeks' gestation in the 1990s: a Swedish national prospective follow-up study. Pediatrics 2006;118:e1452-65. [PubMed: 17079546]

Fewtrell 2003

Fewtrell MS. Growth and nutrition after discharge. Seminars in Neonatology 2003;8(2):169-76. [PubMed: 15001153]

Fewtrell 2011

Fewtrell M. Early nutritional predictors of long-term bone health in preterm infants. Current Opinion in Clinical Nutrition and Metabolic Care 2011;14(3):297-301. [PubMed: 21378555]

Ford 2000

Ford GW, Doyle LW, Davis NM, Callanan C. Very low birth weight and growth into adolescence. Archives of Pediatrics and Adolescent Medicine 2000;154:778-84.

GRADEpro 2008

GRADEpro [Version 3.2 for Windows] [Computer program]. Brozek J, Oxman A, Schünemann H. The GRADE Working Group, 2008.

Greer 2007

Greer FR. Post-discharge nutrition: what does the evidence support? Seminars in Perinatology 2007;31:89-95. [PubMed: 17462493]

Griffin 2007

Griffin IJ, Cooke RJ. Nutrition of preterm infants after hospital discharge. Journal of Pediatric Gastroenterology and Nutrition 2007;45 Suppl 3:S195-203. [PubMed: 18185092]

Guyatt 2011a

Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J et al. GRADE guidelines: 1. Introduction - GRADE evidence profiles and summary of findings tables. Journal of Clinical Epidemiology 2011;64(4):383-94. [PubMed: 21195583]

Guyatt 2011b

Guyatt GH, Oxman AD, Vist G, Kunz R, Brozek J, Alonso-Coello P et al. GRADE guidelines: 4. Rating the quality of evidence - study limitations (risk of bias). Journal of Clinical Epidemiology 2011;64(4):407-15. [PubMed: 21247734]

Guyatt 2011c

Guyatt GH, Oxman AD, Kunz R, Brozek J, Alonso-Coello P, Rind D et al. GRADE guidelines 6. Rating the quality of evidence - imprecision. Journal of Clinical Epidemiology 2011;64(12):1283-93. [PubMed: 21839614]

Guyatt 2011d

Guyatt GH, Oxman AD, Kunz R, Woodcock J, Brozek J, Helfand M et al. GRADE guidelines: 7. Rating the quality of evidence - inconsistency. Journal of Clinical Epidemiology 2011;64(12):1294-302. [PubMed: 21803546]

Guyatt 2011e

Guyatt GH, Oxman AD, Kunz R, Woodcock J, Brozek J, Helfand M et al. GRADE guidelines: 8. Rating the quality of evidence - indirectness. Journal of Clinical Epidemiology 2011;64(12):1303-10. [PubMed: 21802903]

Hack 1991

Hack M, Breslau N, Weissman B, Aram D, Klein N, Borawski E. Effect of very low birthweight and subnormal head size on cognitive abilities at school age. New England Journal of Medicine 1991;325:231–7.

Hack 2003

Hack M, Schluchter M, Cartar L, Rahman M, Cuttler L, Borawski E. Growth of very low birth weight infants to age 20 years. Pediatrics 2003;112:e30–8.

Hancock 1984

Hancock PJ, Bancalari E. Gastric motility in premature infants fed two different formulas. Journal of Pediatric Gastroenterology and Nutrition 1984;3:696-9.

Higgins 2011

Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. www.cochrane-handbook.org.

Hopewell 2009

Hopewell S, Loudon K, Clarke MJ, Oxman AD, Dickersin K. Publication bias in clinical trials due to statistical significance or direction of trial results. Cochrane Database of Systematic Reviews 2009, Issue 1. Art. No.: MR000006. DOI: 10.1002/14651858.MR000006.pub3.

Kleinman 2004

Kleinman RE. Nutritional needs of the preterm infant. In: Pediatric Nutrition Handbook. 5th edition. Chicago, Illinois, USA: American Academy of Pediatrics, 2004.

Klingenberg 2011

Klingenberg C, Embleton ND, Jacobs SE, O'Connell LA, Kuschel CA. Enteral feeding practices in very preterm infants: an international survey. Archives of Disease in Childhood. Fetal and Neonatal Edition 2011;97:F56-61. [PubMed: 21856644]

Lapillonne 2013

Lapillonne A, Griffin IJ. Feeding preterm infants today for later metabolic and cardiovascular outcomes. Journal of Pediatrics 2013;162(3 Suppl):S7-16. [PubMed: 23445851]

Leppanen 2014

Leppanen M, Lapinleimu H, Lind A, Matomaki J, Lehtonen L, Haataja L et al. Antenatal and postnatal growth and 5-year cognitive outcome in very preterm infants. Pediatrics 2014;133(1):63-70. [PubMed: 24344103]

Lucas 1984

Lucas A, Gore SM, Cole TJ, Bamford MF, Dossetor JF, Barr I et al. Multicentre trial on feeding low birthweight infants: effects of diet on early growth. Archives of Disease in Childhood 1984;59:722-30.

Lucas 1992a

Lucas A, King F, Bishop NB. Postdischarge formula consumption in infants born preterm. Archives of Disease in Childhood 1992;67:691-2.

McCormick 2013

Young L, Embleton ND, McCormick FM, McGuire W. Multinutrient fortification of human breast milk for preterm infants following hospital discharge. Cochrane Database of Systematic Reviews 2013, Issue 2. Art. No.: CD004866. DOI: 10.1002/14651858.CD004866.pub3.

Saigal 2006

Saigal S, Stoskopf B, Streiner D, Paneth N, Pinelli J, Boyle M. Growth trajectories of extremely low birth weight infants from birth to young adulthood: a longitudinal, population-based study. Pediatric Research 2006;60:751-8. [PubMed: 17065570]

Schünemann 2013

Schünemann H, Brożek J, Guyatt G, Oxman A, editors; GWG. GRADE Handbook for Grading Quality of Evidence and Strength of Recommendations. www.guidelinedevelopment.org/handbook. Updated October 2013.

Siegel 1984

Siegel M, Lebenthal E, Krantz B. Effect of caloric density on gastric emptying in premature infants. Journal of Pediatrics 1984;104:118-22.

Trebar 2007

Trebar B, Traunecker R, Selbmann HK, Ranke MB. Growth during the first two years predicts pre-school height in children born with very low birth weight (VLBW): results of a study of 1,320 children in Germany. Pediatric Research 2007;62:209-14. [PubMed: 17597641]

Other published versions of this review

McGuire 2007

Henderson G, Fahey T, McGuire W. Nutrient-enriched formula versus standard formula for preterm infants following hospital discharge. Cochrane Database of Systematic Reviews 2007, Issue 4. Art. No.: CD004696. DOI: 10.1002/14651858.CD004696.pub3.

Young 2012

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.

Classification pending references

None noted.

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Data and analyses

1 Postdischarge formula versus standard term formula

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
1.1 Growth rates during trial period 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
  1.1.1 Weight gain (g/kg/d) 1 33 Mean Difference (IV, Fixed, 95% CI) 0.00 [-1.37, 1.37]
  1.1.2 Linear growth (mm/wk) 1 33 Mean Difference (IV, Fixed, 95% CI) 0.00 [-1.07, 1.07]
  1.1.3 Head circumference (mm/wk) 1 33 Mean Difference (IV, Fixed, 95% CI) 0.00 [-0.68, 0.68]
1.2 Weight (grams) 7 Mean Difference (IV, Fixed, 95% CI) Subtotals only
  1.2.1 3-4 months post term 6 523 Mean Difference (IV, Fixed, 95% CI) -7.45 [-141.84, 126.93]
  1.2.2 6 months post term 7 576 Mean Difference (IV, Fixed, 95% CI) 35.54 [-113.71, 184.78]
  1.2.3 9 months post term 4 347 Mean Difference (IV, Fixed, 95% CI) 244.09 [16.95, 471.23]
  1.2.4 12 months post term 4 314 Mean Difference (IV, Fixed, 95% CI) -14.87 [-243.18, 213.43]
  1.2.5 18-24 months post term 1 192 Mean Difference (IV, Fixed, 95% CI) 100.00 [-246.90, 446.90]
1.3 Crown-heel length (mm) 7 Mean Difference (IV, Fixed, 95% CI) Subtotals only
  1.3.1 3-4 months post term 6 523 Mean Difference (IV, Fixed, 95% CI) 2.45 [-2.01, 6.90]
  1.3.2 6 months post term 7 576 Mean Difference (IV, Fixed, 95% CI) 2.12 [-2.16, 6.41]
  1.3.3 9 months post term 4 347 Mean Difference (IV, Fixed, 95% CI) 7.33 [1.80, 12.87]
  1.3.4 12 months post term 4 314 Mean Difference (IV, Fixed, 95% CI) -0.66 [-6.43, 5.10]
  1.3.5 18-24 months post term 1 192 Mean Difference (IV, Fixed, 95% CI) 9.00 [0.32, 17.68]
1.4 Head circumference (mm) 7 Mean Difference (IV, Fixed, 95% CI) Subtotals only
  1.4.1 3-4 months post term 6 523 Mean Difference (IV, Fixed, 95% CI) -0.30 [-2.86, 2.26]
  1.4.2 6 months post term 7 576 Mean Difference (IV, Fixed, 95% CI) 2.28 [-0.28, 4.83]
  1.4.3 9 months post term 4 347 Mean Difference (IV, Fixed, 95% CI) 0.16 [-3.21, 3.53]
  1.4.4 12 months post term 4 314 Mean Difference (IV, Fixed, 95% CI) 2.11 [-1.52, 5.75]
  1.4.5 18-24 months post term 1 192 Mean Difference (IV, Fixed, 95% CI) -3.00 [-8.24, 2.24]
1.5 Development 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
  1.5.1 Bayley Scales of Infant Development II: Mental Development Index 1 184 Mean Difference (IV, Fixed, 95% CI) 0.90 [-3.24, 5.04]
  1.5.2 Bayley Scales of Infant Development II: Psychomotor Development Index 1 184 Mean Difference (IV, Fixed, 95% CI) 2.70 [-1.28, 6.68]
1.6 Bone mineralisation 3 Mean Difference (IV, Fixed, 95% CI) Subtotals only
  1.6.1 Bone area at 2 months post term (cm2) 1 33 Mean Difference (IV, Fixed, 95% CI) 7.00 [-15.46, 29.46]
  1.6.2 Bone mineral content at 2 months post term (grams) 1 33 Mean Difference (IV, Fixed, 95% CI) 3.20 [-4.73, 11.13]
  1.6.3 Bone 'speed of sound' assessed on ultrasonography at 6 months post term (mm/s) 1 20 Mean Difference (IV, Fixed, 95% CI) 45.00 [-18.48, 108.48]
  1.6.4 Bone specific serum alkaline phosphatase at 6 months post term (units/L) 1 20 Mean Difference (IV, Fixed, 95% CI) -9.00 [-42.01, 24.01]
  1.6.5 Bone width at 9 months post term (cm) 1 31 Mean Difference (IV, Fixed, 95% CI) 0.05 [-0.01, 0.11]
  1.6.6 Bone mineral content at 9 months post term (mg/cm) 1 31 Mean Difference (IV, Fixed, 95% CI) 20.60 [7.78, 33.42]
 

2 Preterm formula versus standard term formula

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
2.1 Growth rates during trial period 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
  2.1.1 Weight gain (g/d) 1 42 Mean Difference (IV, Fixed, 95% CI) 3.70 [-0.16, 7.56]
  2.1.2 Linear growth (mm/wk) 1 42 Mean Difference (IV, Fixed, 95% CI) 1.00 [0.09, 1.91]
  2.1.3 Head circumference (mm/wk) 1 42 Mean Difference (IV, Fixed, 95% CI) 0.50 [-0.04, 1.04]
2.2 Weight (grams) 5 Mean Difference (IV, Fixed, 95% CI) Subtotals only
  2.2.1 3-4 months post term 3 130 Mean Difference (IV, Fixed, 95% CI) 74.41 [-267.10, 415.93]
  2.2.2 6 months post term 4 273 Mean Difference (IV, Fixed, 95% CI) 74.60 [-164.73, 313.92]
  2.2.3 9 months post term 1 59 Mean Difference (IV, Fixed, 95% CI) 112.00 [-482.69, 706.69]
  2.2.4 12 months post term 4 265 Mean Difference (IV, Fixed, 95% CI) 539.48 [255.03, 823.92]
  2.2.5 18 months post term 2 162 Mean Difference (IV, Fixed, 95% CI) 490.81 [142.19, 839.44]
2.3 Crown-heel length (mm) 5 Mean Difference (IV, Fixed, 95% CI) Subtotals only
  2.3.1 3-4 months post term 3 130 Mean Difference (IV, Fixed, 95% CI) -2.27 [-13.09, 8.56]
  2.3.2 6 months post term 3 160 Mean Difference (IV, Fixed, 95% CI) 1.83 [-6.25, 9.92]
  2.3.3 9 months post term 1 59 Mean Difference (IV, Fixed, 95% CI) -3.00 [-17.03, 11.03]
  2.3.4 12 months post term 3 152 Mean Difference (IV, Fixed, 95% CI) 5.13 [-4.23, 14.49]
  2.3.5 18 months post term 2 162 Mean Difference (IV, Fixed, 95% CI) 11.00 [1.89, 20.11]
2.4 Head circumference (mm) 5 Mean Difference (IV, Fixed, 95% CI) Subtotals only
  2.4.1 3-4 months post term 3 130 Mean Difference (IV, Fixed, 95% CI) 3.61 [-2.09, 9.31]
  2.4.2 6 months post term 3 160 Mean Difference (IV, Fixed, 95% CI) 5.82 [1.32, 10.32]
  2.4.3 9 months post term 1 59 Mean Difference (IV, Fixed, 95% CI) 8.00 [0.85, 15.15]
  2.4.4 12 months post term 3 152 Mean Difference (IV, Fixed, 95% CI) 6.07 [1.07, 11.06]
  2.4.5 18 months post term 2 162 Mean Difference (IV, Fixed, 95% CI) 5.42 [0.69, 10.14]
2.5 Development 2 Mean Difference (IV, Fixed, 95% CI) Subtotals only
  2.5.1 Bayley Scales of Infant Development II: Mental Development Index 2 143 Mean Difference (IV, Fixed, 95% CI) -1.44 [-6.22, 3.35]
  2.5.2 Bayley Scales of Infant Development II: Psychomotor Development Index 2 143 Mean Difference (IV, Fixed, 95% CI) -1.13 [-4.19, 1.93]
 

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Figures

Figure 1

Refer to Figure 1 caption below.

Study flow diagram: review update (Figure 1).

Figure 2

Refer to Figure 2 caption below.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies (Figure 2).

Figure 3 (Analysis 1.2)

Refer to Figure 3 caption below.

Forest plot of comparison: 1 Postdischarge formula versus standard term formula, outcome: 1.2 Weight (grams) (Figure 3).

Figure 4 (Analysis 1.3)

Refer to Figure 4 caption below.

Forest plot of comparison: 1 Postdischarge formula versus standard term formula, outcome: 1.3 Crown-heel length (mm) (Figure 4).

Figure 5 (Analysis 1.4)

Refer to Figure 5 caption below.

Forest plot of comparison: 1 Postdischarge formula versus standard term formula, outcome: 1.4 Head circumference (mm) (Figure 5).

Figure 6 (Analysis 2.2)

Refer to Figure 6 caption below.

Forest plot of comparison: 2 Preterm formula versus standard term formula, outcome: 2.2 Weight (grams) (Figure 6).

Figure 7 (Analysis 2.3)

Refer to Figure 7 caption below.

Forest plot of comparison: 2 Preterm formula versus standard term formula, outcome: 2.3 Crown-heel length (mm) (Figure 7).

Figure 8 (Analysis 2.4)

Refer to Figure 8 caption below.

Forest plot of comparison: 2 Preterm formula versus standard term formula, outcome: 2.4 Head circumference (mm) (Figure 8).

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Sources of support

Internal sources

  • Centre for Reviews and Dissemination, University of York, UK
  • Royal Victoria Infirmary, Newcastle upon Tyne, UK

External sources

  • NIHR, UK

    This report is independent research funded by a UK National Institute of Health Research Grant (NIHR) Cochrane Programme Grant (13/89/12). The views expressed in this publication are those of the review authors and are not necessarily those of the NHS, the NIHR or the UK Department of Health.

  • Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, USA

    Editorial support of the Cochrane Neonatal Review Group has been provided by Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN275201600005C.


This review is published as a Cochrane review in The Cochrane Library, Issue 12, 2016 (see http://www.thecochranelibrary.com External Web Site Policy for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback. The Cochrane Library should be consulted for the most recent recent version of the review.