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

  • Conclusions changed
  • Review
  • Intervention

Authors


Abstract

Background

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

Objectives

To determine the effect of feeding nutrient-enriched formula compared with standard term formula on growth and development for preterm infants following hospital discharge.

Search methods

We used the standard search strategy of the Cochrane Neonatal Review Group. This included searches of the Cochrane Central Register of Controlled Trials (The Cochrane Library, 2011, Issue 4), MEDLINE, EMBASE, and CINAHL (to September 2011), conference proceedings and previous reviews.

Selection criteria

Randomised or quasi-randomised controlled trials that compared the effect of feeding preterm infants following hospital discharge with nutrient-enriched formula (post-discharge formula or preterm formula) compared with standard term formula.

Data collection and analysis

We extracted data using the standard methods of the Cochrane Neonatal Review Group, with separate evaluation of trial quality and data extraction by two review authors.

Main results

We found 15 eligible trials in which a total of 1128 preterm infants participated. The trials were of variable methodological quality with lack of allocation concealment and incomplete follow-up in some trials being the major potential sources of bias. The trials (N = 10) that compared feeding infants with "post-discharge formula" (energy density about 74 kcal/100 ml) versus standard term formula (about 67 kcal/100 ml) did not find consistent evidence of effects on growth parameters up to 12 to 18 months corrected age. The trials (N = 5) that compared feeding with "preterm formula" (about 80 kcal/100 ml) versus term formula found some evidence of higher rates of growth through infancy: weighted mean differences at 12 to 18 months corrected age about 500 g in weight, 5 to10 mm in length, and 5 mm in head circumference. Few trials assessed neurodevelopmental outcomes and these did not detect any statistically significant differences in developmental indices at 18 months corrected age. There are not yet any data on growth or development through later childhood.

Authors' conclusions

Current recommendations to prescribe "post-discharge formula" for preterm infants following hospital discharge are not supported by the available evidence. Some limited evidence exists that feeding preterm infants following hospital discharge with "preterm formula" (which is generally only available for in-hospital use) may increase growth rates up to 18 months corrected age.

Résumé scientifique

Préparations enrichies en nutriments versus préparations ordinaires pour les nouveau-nés prématurés après la sortie de l'hôpital

Contexte

Les nouveau-nés prématurés présentent souvent un retard de croissance à leur sortie de l'hôpital. L'alimentation des nouveau-nés après leur sortie de l'hôpital avec une préparation enrichie en nutriments plutôt qu'avec une préparation ordinaire pourrait faciliter une croissance de « rattrapage » et améliorer le développement.

Objectifs

Déterminer l'effet de l'alimentation avec une préparation enrichie en nutriments comparé à une préparation ordinaire sur la croissance et le développement de nouveau-nés prématurés après leur sortie de l'hôpital.

Stratégie de recherche documentaire

Nous avons utilisé la stratégie de recherche standard du Groupe thématique Cochrane sur la néonatologie. Celle-ci comprenait des recherches dans le registre Cochrane des essais contrôlés (The Cochrane Library, 2011, numéro 4), MEDLINE, EMBASE et CINAHL (jusqu'en septembre 2011), dans des actes de conférences et des revues antérieures.

Critères de sélection

Les essais contrôlés randomisés ou quasi-randomisés qui comparaient l'effet de l'alimentation de nouveau-nés prématurés après leur sortie de l'hôpital avec une préparation enrichie en nutriments (préparation de suite ou préparation pour prématurés) comparé à une préparation ordinaire.

Recueil et analyse des données

Nous avons extrait les données en utilisant les méthodes standard du Groupe thématique Cochrane sur la néonatologie avec une évaluation de la qualité des essais et une extraction des données séparées par deux auteurs de la revue.

Résultats principaux

Nous avons trouvé 15 essais éligibles auxquels ont participé un total de 1 128 nouveau-nés prématurés. Les essais étaient de qualité méthodologique variable, les principales sources de biais étant l'absence d'assignation secrète et un suivi incomplet dans certains essais. Les essais (N = 10) qui comparaient l'alimentation de nouveau-nés avec des « préparations de suite » (densité énergétique d'environ 74 kcal/100 ml) versus des préparations ordinaires (environ 67 kcal/100 ml) n'ont pas trouvé de preuves cohérentes d'effets sur les paramètres de croissance jusqu'à 12 à 18 mois d'âge corrigé. Les essais (N = 5) qui comparaient l'alimentation avec des « préparations pour prématurés » (environ 80 kcal/100 ml) versus des préparations ordinaires ont trouvé des preuves de taux de croissance plus élevés au cours de la petite enfance : différences moyennes pondérées à 12 à 18 mois d'âge corrigé environ 500 g en poids, 5 à 10 mm en longueur et 5 mm en périmètre crânien. Peu d'essais ont évalué les résultats de développement neurologique et ceux-ci n'ont détecté aucune différence statistiquement significative dans les indices de développement à 18 mois d'âge corrigé. Aucune donnée n'est encore disponible concernant la croissance ou le développement au cours de l'enfance.

Conclusions des auteurs

Les recommandations actuelles de prescription de « préparations de suite » pour les nouveau-nés prématurés après leur sortie d'hôpital ne sont pas corroborées par les preuves disponibles. Il existe des preuves limitées indiquant que l'alimentation des nouveau-nés prématurés après leur sortie d'hôpital avec des « préparations pour prématurés » (qui ne sont généralement disponibles qu'en usage hospitalier) peut augmenter la croissance jusqu'à 18 mois d'âge corrigé.

Plain language summary

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

Preterm infants are often much smaller than term infants by the time that they are discharged home from hospital. This review attempted to identify trial evidence about whether feeding these infants with formula enriched with nutrients rather than ordinary formula designed for term infants increased growth rates and improved development. We found 15 trials but these did not provide strong or consistent evidence that unrestricted feeding with nutrient-enriched formula affects growth and development up to about 18 months of age. Long-term growth and development has not yet been assessed.

Résumé simplifié

Préparations enrichies en nutriments versus préparations ordinaires pour les nouveau-nés prématurés après la sortie de l'hôpital

Les nouveau-nés prématurés sont souvent beaucoup plus petits que les enfants nés à terme à leur sortie de l'hôpital. Cette revue a tenté d'identifier des preuves issues d'essais indiquant si l'alimentation de ces nouveau-nés avec une préparation enrichie en nutriments plutôt qu'avec une préparation ordinaire conçue pour les enfants nés à terme augmentait la croissance et améliorait le développement. Nous avons trouvé 15 essais, mais ceux-ci n'ont pas apporté de preuves solides ou cohérentes indiquant qu'une alimentation à volonté avec une préparation enrichie en nutriments affectait la croissance et le développement jusqu'à environ 18 mois. La croissance et le développement à long terme n'ont pas encore été évalués.

Notes de traduction

Traduit par: French Cochrane Centre 18th May, 2012
Traduction financée par: Ministère du Travail, de l'Emploi et de la Santé Français

Ringkasan bahasa mudah

Formula yang diperkayakan nutrien berbanding formula term yang standard untuk bayi pramatang selepas discaj dari hospital.

Bayi pramatang biasanya lebih kecil dari bayi cukup bulan (term) pada waktu mereka discaj dari hospital. Ulasan ini cuba mengenalpasti bukti dari kajian samada menyusu bayi pramatang dengan formula yang diperkayakan dengan nutrien atau formula biasa yang dihasilkan untuk bayi term dapat meningkatkan kadar pembesaran dan perkembangan. Kami telah menjumpai 15 kajian tetapi kajian-kajian ini tidak dapat memberi bukti kukuh atau tetap yang penyusuan tanpa had dengan formula yang diperkayakan dengan nutrien mempengaruhi pembesaran dan perkembangan sehingga umur 18 bulan. Pembesaran dan perkembangan jangka masa panjang belum dinilai lagi.

Catatan terjemahan

Diterjemahkan oleh Foo Sook Lee (Penang Medical College). Disunting oleh Tan May Loong (Penang Medical College). Untuk sebarang pertanyaan mengenai terjemahan ini sila hubungi fslee@pmc.edu.my. 

Background

Compared with term infants, preterm infants have limited nutrient reserves at birth. Preterm infants, especially very preterm or very low birth weight (VLBW) infants, are additionally 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 normal, uncompromised fetuses of an equivalent postmenstrual age. However, evidence exists that in practice the recommended target levels of nutrient input are rarely achieved and most very preterm or VLBW infants accumulate significant energy, protein, mineral, and other nutrient deficits during their hospital stay (Embleton 2001). Consequently, many preterm infants and most very preterm or VLBW infants are growth restricted by the time they are ready for hospital discharge (Lucas 1984; Clark 2003).

Description of the condition

Following hospital discharge, ad libitum (demand) fed preterm infants often consume more milk than term infants in order to attain some "catch up" growth (Lucas 1992a). Despite this, growth deficits can persist through childhood and adolescence (Ford 2000; Farooqi 2006; Trebar 2007; Bracewell 2008). Slow or incomplete catch up growth in preterm infants, especially of the head, is associated with a higher risk of neurodevelopmental impairment in later childhood, as well as with poorer cognitive and educational outcomes (Hack 1991; Cooke 2003). Preterm infants who have accumulated deficits in calcium and phosphate are at higher risk of poor bone mineralization, metabolic bone disease, and a reduced rate of skeletal growth compared to infants born at term (Rigo 2000).

Description of the intervention

Because slow or incomplete catch up growth is associated with prolonged growth restriction and with slower neuro-developmental progression, attention has focused on nutritional interventions that might promote growth during the putative ‘critical window’ of early infancy in the post-discharge period. Two broad strategies for nutritional interventions exist (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 following hospital discharge (McCormick 2010). This review focuses on the comparison of nutrient-enriched formula milk versus standard term formula for formula fed preterm infants following 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 provide the recommended nutrient needs for stable and growing preterm infants.

  • post-discharge formula: specifically designed for preterm infants post-discharge from hospital. These are energy (about 72 to 74 kcal/100 ml) and protein (about 1.8 to 1.9 g/100 ml) enriched, and variably enriched with minerals, vitamins, and trace elements compared to standard term formula. Expert bodies and authorities recommend these formulae for preterm infants for three to twelve months post-discharge (Aggett 2006).

  • preterm formula: energy-enriched (about 80 kcal/100 ml), protein-enriched (2.0 to 2.4 g/100 ml), and variably enriched with minerals, vitamins, and trace elements to support intra-uterine nutrient accretion rates. These formulae are commonly used for nutrition of preterm infants prior to hospital discharge and are not generally recommended for post-discharge feeding.

How the intervention might work

In theory, feeding preterm infants following hospital discharge with formula enriched with extra energy, protein, minerals and vitamins may be expected to promote more rapid catch up growth. However, because preterm infants fed in response to hunger and satiation cues (ad libitum or demand) adjust their volume of intake depending upon the energy-density of the formula, infants may consume less nutrient-enriched milk than standard term formula (Lucas 1992a). Consequently, infants fed ad libitum with preterm or post-discharge formula may not receive any more nutrients than infants who receive standard term formula. Feeding with nutrient-enriched formula may also be associated with disordered gastric motility and emptying (Hancock 1984; Siegel 1984). Nutrient-enriched formula may therefore be more poorly tolerated, so reducing nutrient delivery, and potentially removing any benefits for growth and development. Furthermore, concern exists that 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 (Hack 2003; Doyle 2004; Euser 2005; Saigal 2006; Euser 2008).

Why it is important to do this review

Given the potential for post-discharge nutrition strategies to affect growth and development in preterm infants, and since uncertainty exists about the balance between the putative benefits and harms, an attempt to detect, appraise, and synthesise evidence from randomised controlled trials is needed.

Objectives

To determine how feeding preterm infants following hospital discharge with nutrient-enriched formula (preterm formula or post-discharge formula) compared with standard term formula affects growth and development.

Methods

Criteria for considering studies for this review

Types of studies

Controlled trials using random or quasi-random patient allocation. Studies published as abstracts were only eligible for inclusion if assessment of study quality was possible and if other criteria for inclusion were fulfilled.

Types of participants

Preterm infants fed with formula (exclusively or as a supplement to human breast milk) following discharge from hospital. The intervention may have commenced up to one week prior to planned discharge from hospital. Trials that randomly assigned infants to nutrient-enriched formula versus standard term formula more than one week prior to hospital discharge (and then continued the intervention after hospital discharge) were not to be included in this review.

Types of interventions

  • Standard term formula: energy content < 72 kcal/100 ml, and protein content < 1.7 g/100 ml.

versus either

  • Post-discharge formula: energy content > 72 kcal/100 ml (but < 75 kcal/100 ml) and protein content > 1.7 g /100 ml.

  • Preterm formula: energy content between > 75 kcal/100 ml and protein content > 2.0 g/100 ml).

The formulae could be fed either as sole diet or as a supplement to human breast milk. Infants in the trial groups should have received similar care other than the type of formula. For example, there should not have been any differences between groups in the prescription of target levels of volume of intake, or advice or support for demand feeding.

Types of outcome measures

Primary outcomes
  1. 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 the index population's distribution of weight, length, or head circumference). Long-term growth and growth-restriction (proportion of infants who remain below the tenth percentile for the index population's distribution of weight, height, or head circumference).

  2. Development:

    1. Neurodevelopmental outcomes assessed using validated tools at > 12 months corrected age, and classifications of disability, including non-ambulant cerebral palsy, developmental delay, auditory and visual impairment

    2. Cognitive and educational outcomes at > 5 years: Intelligence quotient and/or indices of educational achievement measured using a validated tool (including school examination results).

Secondary outcomes
  1. Feed intolerance such as vomiting or diarrhoea that necessitates ceasing the study formula.

  2. Measures of bone mineralization such as serum alkaline phosphatase level, or bone mineral content assessed by dual energy x ray absorptiometry and clinical or radiological evidence of rickets on long term follow-up.

  3. Blood pressure on long term follow-up.

  4. 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 searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 4, 2011), MEDLINE (1966 September 2011), EMBASE (1980 to September 2011), and CINAHL (1982 to September 2011) using a combination of the following text words and MeSH terms: [Infant, Newborn OR Infant, Premature OR Infant, Low Birth Weight OR infan* OR neonat*] AND ["Infant-Nutrition"/ all subheadings OR Infant Formula OR milk OR formula OR post-discharge OR fortif* OR supplement*].
The search outputs were limited with the relevant search filters for clinical trials as recommended in the Cochrane Handbook. We did not apply any language restriction.

We searched ClinicalTrials.gov and Current Controlled Trials for completed or ongoing trials.

Searching other resources

We examined the references in studies identified as potentially relevant. We also searched the abstracts from the annual meetings of the Pediatric Academic Societies (1993 to 2011), the European Society for Pediatric Research (1995 to 2011), the UK Royal College of Paediatrics and Child Health (2000 to 2011), and the Perinatal Society of Australia and New Zealand (2000 to 2011). We considered trials reported only as abstracts to be eligible if sufficient information was available from the report, or from contact with the 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 title and abstract of all studies identified by the above search strategy. We reassessed the full text of any potentially eligible reports and excluded those studies that did not meet all of the inclusion criteria. We discussed any 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 the data separately. We discussed any disagreements until consensus was achieved. We asked the investigators for further information if data from the trial reports were insufficient.

Assessment of risk of bias in included studies

We used the criteria and standard methods of the Cochrane Neonatal Review Group to assess the methodological quality of any included trials. Additional information from the trial authors was requested to clarify methodology and results as necessary. We evaluated and reported the following issues in the Risk of Bias tables:

  1. Sequence generation: We categorised the method used to generate the allocation sequence as:

    1. low risk (any random process e.g. random number table; computer random number generator);

    2. high risk (any non random process e.g. odd or even date of birth; patient case-record number);

    3. unclear.

  2. Allocation concealment: We categorised the method used to conceal the allocation sequence as:

    1. low risk (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);

    2. high risk (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth);

    3. unclear.

  3. Blinding: We assessed blinding separately for different outcomes and categorised the methods as:

    1. low risk, high risk or unclear for

      1. participants;

      2. clinicians and caregivers and;

      3. outcome assessors.

  4. Incomplete outcome data: We described the completeness of data including attrition and exclusions from the analysis for each outcome and any reasons for attrition or exclusion where reported. We assessed whether missing data were balanced across groups or were related to outcomes. Where sufficient information was reported or supplied by the trial authors, re-included missing data in the analyses. We categorised completeness as:

    1. low risk (< 20% missing data);

    2. high risk (> 20% missing data);

    3. unclear.

Measures of treatment effect

We calculated relative risk (RR) and risk difference (RD) for dichotomous data and weighted mean difference (WMD) for continuous data, with respective 95% confidence intervals (CI). We determined the number needed to treat for benefit (NNTB) or harm (NNTH) for a statistically significant difference in the RD.

Unit of analysis issues

The unit of analysis is the participating infant in individually randomised trials and the neonatal unit for cluster randomised trials.

Assessment of heterogeneity

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

Subgroup analysis and investigation of heterogeneity

We pre-specified the following sub-group analyses:

  1. very preterm (< 32 weeks) or VLBW (< 1500 g) infants;

  2. infants who were small for gestational age (< 10th percentile for weight) at hospital discharge;

  3. infants with chronic lung disease receiving supplemental oxygen therapy at hospital discharge.

Results

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of studies awaiting classification.

Included studies

We identified 15 trials that fulfilled the eligibility criteria (Lucas 1992; Atkinson 1999; Lucas 2001; Cooke 2001; Carver 2001; De Curtis 2002; Agosti 2003; Litmanovitz 2004; Atkinson 2004; Peng 2004; Picaud 2005; Koo 2006; Taroni 2009; Roggero 2011a; Jeon 2011; see Characteristics of included studies).

Participants

The trials were undertaken within the last 20 years by investigators attached to perinatal centres in Europe, North America and the middle-East. In total, 1128 infants have participated in these trials (range 20 to 229).

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

Three trials specified gestational age as an eligibility criterion:

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

Of the other trials, although most reports did not specify intra-uterine or postnatal growth restriction as exclusion criteria, 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 inadequate independent oral feeding or receipt of supplemental oxygen secondary to chronic lung disease, were not eligible to participate.

Interventions

POST-DISCHARGE FORMULA VERSUS STANDARD TERM FORMULA (Comparison 1)
10 trials (N = 762): Lucas 1992; Atkinson 1999; Carver 2001; Lucas 2001; De Curtis 2002; Atkinson 2004; Litmanovitz 2004; Koo 2006;Taroni 2009; Roggero 2011a.

PRETERM FORMULA VERSUS STANDARD TERM FORMULA (Comparison 2)
5 trials (N = 366): Cooke 2001; Agosti 2003; Peng 2004; Picaud 2005; Jeon 2011.

All of the participating infants were fed ad libitum. These feeds 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 occipito-frontal head circumference) assessed up to 12 to 18 months corrected age. Three trials assessed neuro-developmental outcomes at 18 months using Bayley Scales of Infant Development II (Lucas 2001; Cooke 2001; Jeon 2011). One trial assessed Griffiths' Developmental Scales at six, nine and twelve months corrected age(Agosti 2003).

Excluded studies

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

Risk of bias in included studies

The trials were of variable methodological quality (Figure 1).

Figure 1.

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

Allocation

In seven trials, the described method of randomisation was likely to ensure blinding of allocation (Atkinson 1999; Cooke 2001; Lucas 2001; Atkinson 2004; .Picaud 2005; Koo 2006; Cooke 2001). 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 existed, 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 where infants' characteristics were statistically significantly different from other groups at enrolment.

Blinding

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

Most of the trials blinded outcomes assessors and investigators to the type of milk that the infant received but in four of the trials it is unclear if this was satisfactory (Litmanovitz 2004;Taroni 2009; Jeon 2011; Roggero 2011a), and in one trial physicians were unblinded (Peng 2004).

Incomplete outcome data

Ten of the trials achieved complete or near-complete (> 80%) follow-up assessment (Lucas 1992; Lucas 2001; Cooke 2001; De Curtis 2002; Atkinson 2004; Litmanovitz 2004; Peng 2004; Taroni 2009; Roggero 2011a; Jeon 2011). In two of the other trials, 75% of infants underwent outcomes assessments at latest follow-up (Atkinson 1999; Koo 2006). In another two trials, < 50% of infants completed the planned 12 months follow-up assessment (Carver 2001; Agosti 2003). In Picaud 2005, loss to follow-up by 12 months in the control group was substantial (35%) and greater than that in the intervention group (9%).

Effects of interventions

POST-DISCHARGE FORMULA VERSUS STANDARD TERM FORMULA (COMPARISON 1)

Growth (Outcomes 1.1- 1.4)

Lucas 1992 did not detect any statistically significantly differences in weight, length or head circumference at the end of the intervention and follow-up period (nine months corrected age).

Atkinson 1999 reported that infants who received post-discharge formula were statistically significantly heavier at six, nine and twelve months corrected age. There were not any statistically significant differences in length or head circumference.

Carver 2001 did not detect any statistically significant differences in weight, length, or head circumference at six and twelve months corrected age. There was substantial loss to follow-up during the trial and since published report does not state how many infants were assessed at the various time points the data could not be used 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 in infants who received post-discharge formula but that there was not a statistically significant difference in head circumference. At 18 months, there were not any statistically significant differences in weight or head circumference. The group of infants who received post-discharge formula remained statistically significantly longer on average than the control group [mean difference 9.0 (95% CI 0.3 to 17.7) mm].

De Curtis 2002 did not find any statistically significant differences in the rate of gain of weight, length, or head circumference during the two months trial period.

Atkinson 2004 did not find any statistically significant differences in the rate of gain of weight, length, or head circumference up to 12 months corrected age (growth data reported as z scores).

Litmanovitz 2004 did not find any statistically significant differences in the weight, length, or head circumference at six months corrected age.

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

Taroni 2009 did not find any statistically significant differences in weight, length, or head circumference at one month corrected age.

Roggero 2011a did not find any statistically significant differences in weight, length, or head circumference at six months corrected age.

Meta-analyses of growth data

  • Weight (Outcome 1.2; Figure 2): Meta-analyses did not detect any statistically significant differences in weight at three to four and six months corrected age. At nine months, meta-analysis of data from four trials (Lucas 1992; Atkinson 1999; Koo 2006; Lucas 2001) indicated that infants in the post-discharge formula group were heavier [WMD: 244 (95% CI 17 to 471) g]. At follow-up at 12 months, there was not a statistically significant difference.

    Figure 2.

    Forest plot of comparison: 1 POST-DISCHARGE FORMULA VERSUS STANDARD TERM FORMULA, outcome: 1.2 Weight (g).

  • Length (Outcome 1.3; Figure 3): Meta-analyses did not detect any statistically significant differences in weight at three to four and six months corrected age. At nine months, meta-analysis of data from four trials (Lucas 1992; Atkinson 1999; Koo 2006; Lucas 2001) indicated that infants in the post-discharge formula group were longer [WMD: 7.3 (95% CI 1.8 to 12.9) mm]. At follow-up at 12 months, there was not a statistically significant difference.

    Figure 3.

    Forest plot of comparison: 1 POST-DISCHARGE FORMULA VERSUS STANDARD TERM FORMULA, outcome: 1.3 Crown heel length (mm).

  • Head circumference (Outcome 1.4; Figure 4): Meta-analyses did not detect any statistically significant differences at three to four, six, nine or twelve months.

    Figure 4.

    Forest plot of comparison: 1 POST-DISCHARGE FORMULA VERSUS STANDARD TERM FORMULA, outcome: 1.4 Head circumference (mm).

These meta-analyses all contained 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 assessed 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). There was not a 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 mineralization (Outcome 1.6:)
Atkinson 2004 did not find any statistically significant differences in bone mineral content assessed at 12 months corrected age (numerical data not available).

De Curtis 2002 did not find any statistically significant differences in the bone mineral content or the bone area at the end of the two months study period.

Koo 2006 reported that at the end of the 12 months study period the infants who received nutrient-enriched formula had statistically significantly lower bone mass (measured using dual-energy X-ray absorptiometry). The data were presented in graphs and 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. The bone width was not statistically significantly different between the groups. The bone mineral content was statistically significantly higher in the group of infants who received the post-discharge formula: Mean difference 20.6 (95% CI 7.8 to 33.4) mg/cm.

Litmanovitz 2004 did not find any statistically significant differences in bone strength assessed as "bone speed of sound" measured with ultrasound or in serum levels of bone specific alkaline phosphatase at six months corrected age.

None of the trials assessed the effect of the intervention on clinical or radiological evidence of rickets.

Blood pressure on long term follow-up

Not assessed by any of the included trials.

Boby mass index on long term follow-up

Not assessed by any of the included trials.

Sub-group analyses:

  1. VLBW or very preterm infants: Two trials recruited exclusively VLBW infants (Litmanovitz 2004;Taroni 2009). As described above, the investigators did not find any statistically significant difference in the weight, length, or head circumference, or in measures of bone mineralization up to six months corrected age.

  2. Infants who remain small for gestational age at hospital discharge: Three trials recruited growth-restricted at birth infants (Atkinson 2004; Taroni 2009; Roggero 2011a).These trials did not detect any 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 found statistically significant effects on crown heel length (WMD 8.88 [95% CI 0.94 to 16.83] mm) and head circumference (5.36 [95% CI 0.62 to 10.11] mm) (Atkinson 2004; Roggero 2011a).

  3. Infants with chronic lung disease requiring home supplemental oxygen therapy: None of the trials recruited exclusively 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 did not find a statistically significant difference in rate of weight gain during the trial period. These data were presented in graphs only and were not able to be extracted to allow calculation of the mean difference. At 18 months corrected age, the nutrient-enriched formula group was statistically significantly heavier than the control group [mean difference: 500 (95% CI 26 to 974) g], but there were not any statistically significant differences in length or head circumference.

Agosti 2003 did not find any statistically significant differences in mean weight, length, or head circumference at four, six and twelve months after hospital discharge.

Peng 2004 did not find any statistically significant differences in mean weight, length, or head circumference at monthly intervals up to six months corrected age.

Picaud 2005 did not find any statistically significant differences in the rate of gain of weight, length, or head circumference during the initial four months trial period. There were not any statistically significant differences in weight, length or head circumference between the groups at four months. At 12 months post-discharge, infants in the preterm formula group were heavier [mean difference:1007 (95% CI 211 to 1803) g] (Outcome 2.2), longer [mean difference: 27 (95% CI 2 to 52) mm] (Outcome 2.3), and had larger head circumferences [mean difference:12 (95% CI 0.2 to 24) mm] (Outcome 2.4) than control infants. However, loss to follow-up by 12 months in the control group was substantial (35%) and greater than that in the intervention group (9%).

Jeon 2011 did not find any statistically significant differences in mean weight, length, or head circumference at three, twelve and eighteen months after hospital discharge.

Meta-analyses of growth data

  • Weight (Outcome 2.2; Figure 5): Weight (Outcome 2.2; Figure 5): Meta-analysis of data from four trials (Cooke 2001; Agosti 2003; Picaud 2005; Jeon 2011) found a statistically significant 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) found a statistically significant higher weight in the preterm formula group at 18 months [WMD: 491 (95% CI 142 to 839) g] (Outcome 2.2).

    Figure 5.

    Forest plot of comparison: 2 PRETERM FORMULA VERSUS STANDARD TERM FORMULA, outcome: 2.2 Weight (g).

  • Length (Outcome 2.3; Figure 6): Meta-analysis of data from three trials (Agosti 2003; Picaud 2005; Jeon 2011) did not detect a statistically significant difference at 12 months corrected age [WMD: 5.1 (95% CI -4.2 to 14.5) mm]. Meta-analysis of data from two trials (Cooke 2001; Jeon 2011) found a statistically significant higher crown heel length in the preterm formula group at 18 months [WMD:11 (95% CI 2 to 20) mm]

    Figure 6.

    Forest plot of comparison: 2 PRETERM FORMULA VERSUS STANDARD TERM FORMULA, outcome: 2.3 Crown heel length (mm).

  • Head circumference (Outcome 2.4; Figure 7): Meta-analysis of data from three trials (Agosti 2003; Jeon 2011; Picaud 2005) found a statistically significant larger head circumference in the preterm formula group at 12 months corrected age [WMD: 6.1 (95% CI 1.1 to 11.1) mm]. Meta-analysis of data from two trials (Cooke 2001; Jeon 2011) found a statistically significant larger head circumference in the preterm formula group at 18 months [WMD: 5.4 (95% CI 0.7 to 10.1) mm].

    Figure 7.

    Forest plot of comparison: 2 PRETERM FORMULA VERSUS STANDARD TERM FORMULA, outcome: 2.4 Head circumference (mm).

Development (Outcome 2.5)
Neither Cooke 2001 or 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 Psychomotor Development Index [WMD -1.1 (95% CI -4.2 to 1.93)]. Agosti 2003 did not detect any statistically significant differences in the Griffiths' Developmental Scale evaluations at six, nine and twelve months corrected age (numerical data not available from report or trialists).

Feed intolerance

Not assessed by any of the included trials.

Bone mineralization
Cooke 2001 assessed body composition with dual energy x-ray absorptiometry at six and twelve months corrected age. There were not any statistically significant differences in the bone area, bone mineral mass, or bone mineral density measurements between the groups. In the published report, all of these data were presented in graphs and could not be extracted for estimation of mean differences. The investigators also reported that there were not any statistically significant differences in the 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

Not assessed by any of the included trials.

Boby mass index on long term follow-up

Not assessed by any of the included trials.

Sub-group analyses

  1. VLBW or very preterm infants: Two trials recruited exclusively VLBW infants (Agosti 2003; Jeon 2011). See above for details of findings. Subgroup data from the other trials were not available.

  2. Infants who remain small for gestational age (less than 10th percentile for weight) at hospital discharge: Subgroup data were not available.

  3. Infants with chronic lung disease requiring home supplemental oxygen therapy: Subgroup data were not available.

Discussion

Summary of main results

Data from ten randomised controlled trials with a total of 762 participants did not provide consistent evidence that feeding preterm infants after hospital discharge with post-discharge formula (˜74 Kcal/100 ml) versus standard term formula (˜67 Kcal/100 ml) affects growth parameters up to 12 to 18 months corrected age.

The five trials that examined the effect of feeding with preterm formula (˜80 Kcal/100 mL) versus standard term formula provided stronger evidence of an effect on growth parameters. Meta-analyses found a weighted mean difference of about 500 grams for weight, 11 mm for length, and 5 to 6 mm for head circumference at 12 to 18 months corrected age. However, it is not yet known whether any of these differences persist through later childhood.

The evidence of the effect of nutrient-enriched formula on long term development is also unclear. The only trial of post-discharge versus term formula to assess developmental outcomes did not detect a statistically significant difference in the Bayley Scales Mental or Psychomotor Development Index assessed at 18 months corrected age (Lucas 2001). However, the 95% confidence intervals for the estimates of effect are wide and do no exclude modest but potentially important effect sizes. Similarly, meta-analyses of data from two trials (Cooke 2001; Jeon 2011) did not provide evidence that feeding with preterm versus term formula affects neurodevelopmental outcomes at 18 months corrected age. There are not yet any data on longer-term cognitive and educational outcomes.

Overall completeness and applicability of evidence

Although we identified ten eligible trials that compared feeding with post-discharge formula versus term formula, these were generally small and of variable methodological quality. Quantitative synthesis was limited as only six of the trials presented data that could be included in meta-analyses of growth outcomes (Lucas 1992; Atkinson 1999; Lucas 2001; Litmanovitz 2004; Koo 2006; Roggero 2011a). Interpretation of the meta-analyses was further limited by substantial and statistically significant heterogeneity. The source of heterogeneity is not clear as these trials were of similar design (intervention given for 6 to 12 months) and methodological quality (all had satisfactory processes to ensure allocation concealment and all achieved about 70% to 80% follow-up at > 6 months corrected age). The meta-analyses of data from the five trials that compared preterm formula versus term formula were more complete and did not demonstrate statistical heterogeneity.

The explanation for the difference in the measured effect on growth parameters of post-discharge formula and preterm formula may simply be related to total nutrient content and intake. An additional factor is that whereas post-discharge formula contains about 10% more calories and 20% to 25% more protein and bone minerals than term formula, preterm formula is about 20% energy-enriched and contains 40% to 60% more protein and minerals than term formula. Since ad libitum fed infants regulate their volume of milk intake relative to its calorie-density, infants in the comparison groups may have received similar total energy intakes. However, infants fed with post-discharge formula would still have received about 10% more protein and minerals than term formula fed infants, whereas infants fed with preterm formula would have received up to about 25% more protein and minerals than term formula-fed infants. It is possible that the 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 the currently available data is limited by the short duration of follow-up in the trials. None of the trials planned or undertook any assessment of growth or development beyond 12 to 18 months corrected age and some of the trials have only reported growth outcomes up to six months. Similarly, none of the trials have reported data related to possible adverse metabolic consequences of nutrient-supplementation in early infancy or any long term measures of obesity (BMI, fat mass) or cardiovascular disease risk factors (such as elevated blood pressure).

Quality of the evidence

The interpretation of the review findings is limited by the existence in some of the trials of methodological weaknesses associated with potential for bias. The main concern is lack of evidence of use of methods to preserve allocation concealment in many of the trials. However, only one trial had substantial between-group differences in baseline demographics that is likely to be due to allocation bias (Jeon 2011). 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 present in six of the trials was incomplete outcome assessment (loss to follow-up > 20%). In most of these trials, loss to follow-up was < 30% and was distributed evenly between intervention and control groups (Atkinson 1999; Koo 2006; Peng 2004; Picaud 2005). In two trials, loss to follow-up at 12 months assessment was > 50% (Agosti 2003; Carver 2001). However, these trial did not contribute substantially to any of the meta-analyses.

Potential biases in the review process

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

Authors' conclusions

Implications for practice

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

The infants who participated in the trials included in this review were fed ad libitum and the findings may not be applicable to infants who cannot feed ab libitum, 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 later neurodevelopmental outcomes, and on any long term effects on metabolic or cardiovascular outcomes (Euser 2005; Greer 2007). If further large randomised controlled trials to evaluate the effects of feeding preterm infants with nutrient-enriched formulae following hospital discharge are undertaken then it may be appropriate to include in any research efforts those preterm infants who are not able to feed ad libitum following 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 including 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 reviewing systematically trials that could not be included in this review because the nutrient-enriched formula differed only in protein and mineral content (but not energy) from standard term formula.

Acknowledgements

We thank Dr Litmanovitz for clarification of aspects of Litmanovitz 2004. We thank Tom Fahey for contributing to the previous version of this review (McGuire 2005).

Editorial support of the Cochrane Neonatal Review Group has been funded 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.

Data and analyses

Download statistical data

Comparison 1. POST-DISCHARGE FORMULA VERSUS STANDARD TERM FORMULA
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Growth rates during trial period1 Mean Difference (IV, Fixed, 95% CI)Subtotals only
1.1 Weight gain (grams/kilogram/day)133Mean Difference (IV, Fixed, 95% CI)0.0 [-1.37, 1.37]
1.2 Linear growth (millimetres/week)133Mean Difference (IV, Fixed, 95% CI)0.0 [-1.07, 1.07]
1.3 Head circumference (millimetres/week)133Mean Difference (IV, Fixed, 95% CI)0.0 [-0.68, 0.68]
2 Weight (g)6 Mean Difference (IV, Fixed, 95% CI)Subtotals only
2.1 3-4 months post term5408Mean Difference (IV, Fixed, 95% CI)-3.76 [-156.67, 149.15]
2.2 6 months post term6461Mean Difference (IV, Fixed, 95% CI)56.23 [-111.53, 223.98]
2.3 9 months post term4347Mean Difference (IV, Fixed, 95% CI)244.09 [16.95, 471.23]
2.4 12 months post term2120Mean Difference (IV, Fixed, 95% CI)71.53 [-344.06, 487.12]
2.5 18 months post term1192Mean Difference (IV, Fixed, 95% CI)100.0 [-246.90, 446.90]
3 Crown heel length (mm)6 Mean Difference (IV, Fixed, 95% CI)Subtotals only
3.1 3- 4 months post term5408Mean Difference (IV, Fixed, 95% CI)4.18 [-0.77, 9.13]
3.2 6 months post term6461Mean Difference (IV, Fixed, 95% CI)3.46 [-1.21, 8.13]
3.3 9 months post term4347Mean Difference (IV, Fixed, 95% CI)7.33 [1.80, 12.87]
3.4 12 months post term2120Mean Difference (IV, Fixed, 95% CI)-0.83 [-9.00, 9.34]
3.5 18 months post term1192Mean Difference (IV, Fixed, 95% CI)9.0 [0.32, 17.68]
4 Head circumference (mm)6 Mean Difference (IV, Fixed, 95% CI)Subtotals only
4.1 3- 4 months post term5408Mean Difference (IV, Fixed, 95% CI)-0.87 [-3.73, 1.99]
4.2 6 months post term6461Mean Difference (IV, Fixed, 95% CI)0.72 [-2.12, 3.56]
4.3 9 months post-term4347Mean Difference (IV, Fixed, 95% CI)0.16 [-3.21, 3.53]
4.4 12 months post-term2120Mean Difference (IV, Fixed, 95% CI)0.25 [-5.50, 6.01]
4.5 18 months post-term1192Mean Difference (IV, Fixed, 95% CI)-3.0 [-8.24, 2.24]
5 Development1 Mean Difference (IV, Fixed, 95% CI)Subtotals only
5.1 Bayley Scales of Infant Development II: Mental Development Index1184Mean Difference (IV, Fixed, 95% CI)0.90 [-3.24, 5.04]
5.2 Bayley Scales of Infant Development II: Psychomotor Development Index1184Mean Difference (IV, Fixed, 95% CI)2.70 [-1.28, 6.68]
6 Bone mineralization3 Mean Difference (IV, Fixed, 95% CI)Subtotals only
6.1 Bone area at 2 months post-term (cm2)133Mean Difference (IV, Fixed, 95% CI)7.0 [-15.46, 29.46]
6.2 Bone mineral content at 2 months post-term (g)133Mean Difference (IV, Fixed, 95% CI)3.20 [-4.73, 11.13]
6.3 Bone "speed of sound" assessed with ultrasound at 6 months post-term (mm/s)120Mean Difference (IV, Fixed, 95% CI)45.0 [-18.48, 108.48]
6.4 Bone specific serum alkaline phosphatase at 6 months post-term (units/L)120Mean Difference (IV, Fixed, 95% CI)-9.0 [-42.01, 24.01]
6.5 Bone width at 9 months post-term (cm)131Mean Difference (IV, Fixed, 95% CI)0.05 [-0.01, 0.11]
6.6 Bone mineral content at 9 months post-term (mg/cm)131Mean Difference (IV, Fixed, 95% CI)20.60 [7.78, 33.42]
Analysis 1.1.

Comparison 1 POST-DISCHARGE FORMULA VERSUS STANDARD TERM FORMULA, Outcome 1 Growth rates during trial period.

Analysis 1.2.

Comparison 1 POST-DISCHARGE FORMULA VERSUS STANDARD TERM FORMULA, Outcome 2 Weight (g).

Analysis 1.3.

Comparison 1 POST-DISCHARGE FORMULA VERSUS STANDARD TERM FORMULA, Outcome 3 Crown heel length (mm).

Analysis 1.4.

Comparison 1 POST-DISCHARGE FORMULA VERSUS STANDARD TERM FORMULA, Outcome 4 Head circumference (mm).

Analysis 1.5.

Comparison 1 POST-DISCHARGE FORMULA VERSUS STANDARD TERM FORMULA, Outcome 5 Development.

Analysis 1.6.

Comparison 1 POST-DISCHARGE FORMULA VERSUS STANDARD TERM FORMULA, Outcome 6 Bone mineralization.

Comparison 2. PRETERM FORMULA VERSUS STANDARD TERM FORMULA
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Growth rates during trial period1 Mean Difference (IV, Fixed, 95% CI)Subtotals only
1.1 Weight gain (grams/day)142Mean Difference (IV, Fixed, 95% CI)3.70 [-0.16, 7.56]
1.2 Linear growth (millimetres/week)142Mean Difference (IV, Fixed, 95% CI)1.0 [0.09, 1.91]
1.3 Head circumference (millimetres/week)142Mean Difference (IV, Fixed, 95% CI)0.5 [-0.04, 1.04]
2 Weight (g)5 Mean Difference (IV, Fixed, 95% CI)Subtotals only
2.1 3- 4 months post term3130Mean Difference (IV, Fixed, 95% CI)74.41 [-267.10, 415.93]
2.2 6 months post term4273Mean Difference (IV, Fixed, 95% CI)74.60 [-164.73, 313.92]
2.3 9 months post term159Mean Difference (IV, Fixed, 95% CI)112.0 [-482.69, 706.69]
2.4 12 months post term4265Mean Difference (IV, Fixed, 95% CI)539.48 [255.03, 823.92]
2.5 18 months post term2162Mean Difference (IV, Fixed, 95% CI)490.81 [142.19, 839.44]
3 Crown heel length (mm)5 Mean Difference (IV, Fixed, 95% CI)Subtotals only
3.1 3- 4 months post term3130Mean Difference (IV, Fixed, 95% CI)-2.27 [-13.09, 8.56]
3.2 6 months post term3160Mean Difference (IV, Fixed, 95% CI)1.83 [-6.25, 9.92]
3.3 9 months post term159Mean Difference (IV, Fixed, 95% CI)-3.0 [-17.03, 11.03]
3.4 12 months post term3152Mean Difference (IV, Fixed, 95% CI)5.13 [-4.23, 14.49]
3.5 18 months post term2162Mean Difference (IV, Fixed, 95% CI)11.00 [1.89, 20.11]
4 Head circumference (mm)5 Mean Difference (IV, Fixed, 95% CI)Subtotals only
4.1 3- 4 months post term3130Mean Difference (IV, Fixed, 95% CI)3.61 [-2.09, 9.31]
4.2 6 months post term3160Mean Difference (IV, Fixed, 95% CI)5.82 [1.32, 10.32]
4.3 9 months post term159Mean Difference (IV, Fixed, 95% CI)8.0 [0.85, 15.15]
4.4 12 months post term3152Mean Difference (IV, Fixed, 95% CI)6.07 [1.07, 11.06]
4.5 18 months post term2162Mean Difference (IV, Fixed, 95% CI)5.42 [0.69, 10.14]
5 Development2 Mean Difference (IV, Fixed, 95% CI)Subtotals only
5.1 Bayley Scales of Infant Development II: Mental Development Index2143Mean Difference (IV, Fixed, 95% CI)-1.44 [-6.22, 3.35]
5.2 Bayley Scales of Infant Development II: Psychomotor Development Index2143Mean Difference (IV, Fixed, 95% CI)-1.13 [-4.19, 1.93]
Analysis 2.1.

Comparison 2 PRETERM FORMULA VERSUS STANDARD TERM FORMULA, Outcome 1 Growth rates during trial period.

Analysis 2.2.

Comparison 2 PRETERM FORMULA VERSUS STANDARD TERM FORMULA, Outcome 2 Weight (g).

Analysis 2.3.

Comparison 2 PRETERM FORMULA VERSUS STANDARD TERM FORMULA, Outcome 3 Crown heel length (mm).

Analysis 2.4.

Comparison 2 PRETERM FORMULA VERSUS STANDARD TERM FORMULA, Outcome 4 Head circumference (mm).

Analysis 2.5.

Comparison 2 PRETERM FORMULA VERSUS STANDARD TERM FORMULA, Outcome 5 Development.

What's new

DateEventDescription
28 October 2011New search has been performedThis updates the review "Nutrient-enriched formula versus standard term formula for preterm infants following hospital discharge" published in the Cochrane Database of Systematic reviews (McGuire 2007).
28 October 2011New citation required and conclusions have changed

Updated search and availability of new information from trial authors allowed inclusion of eight additional trials.

Revised review structure specified separate comparisons of preterm formula and post-discharge formula versus standard term formula.

Conclusions modified.

New authorship.

History

Protocol first published: Issue 2, 2004
Review first published: Issue 2, 2005

DateEventDescription
28 April 2008AmendedConverted to new review format.
25 June 2007New citation required but conclusions have not changedSubstantive amendment

Contributions of authors

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

Declarations of interest

None.

Sources of support

Internal sources

  • Centre for Reviews and Dissemination, Department of Health Sciences, & Hull York Medical School, University of York, UK.

External sources

  • Tenovus, Scotland, UK.

  • NIHR, UK.

    Lauren Young and Jessie Morgan are NIHR Academic Clinical Fellows.

Differences between protocol and review

We elected to undertake separate comparisons of post-discharge formula and preterm formula versus standard term formula having previously specified a joint comparison with subgroup analysis.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Agosti 2003

MethodsRandomised controlled trial
Participants121 formula milk-fed VLBW (<1500 g) infants
InterventionsPreterm formula (energy content 80 kcal/100 ml, protein content 2.4 g/100ml, and calcium and phosphorus content 100 mg/100ml and 50 mg/100ml respectively) (N=69) or standard term formula (energy content 70 kcal/100ml, protein content 1.7 g/100ml) (N=52). The intention was for the allocated formula to be the only milk source from 40 weeks until 55 weeks postmenstrual age (PMA)
OutcomesGrowth parameters and "Griffiths Developmental Scale" at 40 weeks, 55 weeks PMA, and 6 and 12 months corrected age
Notes

Setting: multicentre trial in Italy (2001)

Research supported by Milupa (formula milk manufacturing company)

Numerical growth data obtained from primary investigators (June 2011)

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskReport simply states that infants were 'randomized' to study groups
Allocation concealment (selection bias)Unclear riskNo mention of randomisation method
Incomplete outcome data (attrition bias)
All outcomes
High riskLoss to follow-up was 34% at 6 months and 66% at 12 months
Blinding of participants and personnel (performance bias)
All outcomes
High riskFamilies and care givers were aware of which formula milk infants received
Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes assessors are unlikely to have been aware of which formula milk infants received

Atkinson 1999

MethodsRandomised controlled trial
Participants70 formula milk-fed preterm infants of birth weight < 1800 g and 'appropriate for gestational age'
InterventionsPost-discharge formula (energy content 74 kcal/100ml, protein content 1.8 g/100ml) (N= 34) versus standard term formula (N=36) for 12 months post-discharge
OutcomesGrowth parameters at 6, 9 and 12 months corrected age
NotesPublished in abstract form only. Additional information and data courtesy of Dr Stephanie Atkinson
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskIndependent generation of random sequence
Allocation concealment (selection bias)Low riskAllocation drawn from sequential sealed opaque envelopes
Incomplete outcome data (attrition bias)
All outcomes
High riskGrowth outcomes data to 12 months were available for 24 (71%) intervention group and 29 (81%) control group infants
Blinding of participants and personnel (performance bias)
All outcomes
Low riskFamilies and care givers were unaware of which formula milk infants received
Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes assessors not aware of which formula milk infants received

Atkinson 2004

MethodsRandomised controlled trial
Participants53 formula milk-fed preterm 'small for gestational age' infants
InterventionsPost-discharge formula (energy content 74 kcal/100ml, protein content 1.8 g/100ml (N=24) versus standard term formula (Ross Similac with Fe) (N=29) for 12 months post-discharge
OutcomesGrowth parameters at 6, 9 and 12 months corrected age
NotesPublished in abstract form only. Additional information and data courtesy of Dr Stephanie Atkinson
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskIndependent generation of random sequence
Allocation concealment (selection bias)Low riskAllocation drawn from sequential sealed opaque envelopes
Incomplete outcome data (attrition bias)
All outcomes
Low riskFollow-up growth parameter outcome assessments were complete
Blinding of participants and personnel (performance bias)
All outcomes
Low riskFamilies and care givers were unaware of which formula milk infants received
Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes assessors not aware of which formula milk infants received

Carver 2001

MethodsRandomised controlled trial
Participants125 preterm infants (birth weight <1800 g or gestation <37 weeks). Infants with severe bronchopulmonary dysplasia, cardiac, respiratory, gastrointestinal or other systemic diseases at time of discharge were not eligible to participate
InterventionsPost-discharge formula (energy content 74 kcal/100ml, protein content 1.9 g/100ml, and calcium and phosphorus content 78 mg/100ml and 46 mg/100ml respectively) (N=67) or standard term formula (energy content 68 kcal/100ml, protein content 1.5 g/100ml) (N=56). The intention was for the allocated formula to be the main milk source from hospital discharge until 12 months corrected age
OutcomesGrowth parameters at intervals until the end of the 12 months study period
NotesSetting: Multi-centre, six perinatal centres in North America
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskNo description of method used to generate random sequence
Allocation concealment (selection bias)Unclear riskNo information on randomisation method
Incomplete outcome data (attrition bias)
All outcomes
High risk

31 of 67 in post-discharge formula group and 26 of 56 in standard term formula group left the study early (plus two other infants who were randomised but did not take part in the study). The total loss of follow-up at growth parameters assessment at 12 months was 60% in the intervention group and 52% in the controls.

Infants exited the study early (and did not have growth parameters measured) for a variety of reasons including study non-compliance (not defined or described), gastro-intestinal upset, and "illness unrelated to the study feedings" (not defined or described)

Blinding of participants and personnel (performance bias)
All outcomes
Low riskFamilies and care givers were unaware of which formula milk infants received
Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes assessors not aware of which formula milk infants received

Cooke 2001

MethodsRandomised controlled trial
Participants103 preterm infants (birth weight < 1750 g or gestation < 35 weeks). Only infants who were "growing normally" (rate of weight gain more than 25 g/kg/day) at time of discharge were eligible to participate
InterventionsPreterm formula (energy content 80 kcal/100ml, protein content 2.2 g/100ml, and calcium and phosphorus content 108 mg/100ml and 54 mg/100ml respectively) (N=49) or a standard term formula (energy content 66 kcal/100ml, protein content 1.4 g/100ml) (N=54) from hospital discharge until six months corrected age
OutcomesAnthropometric and developmental parameters (including Bayley Scales of Infant Development II) and measures of bone mineralization
Notes

Setting: Royal Victoria Hospital, Newcastle upon Tyne, UK

Research supported by Nutricia (formula milk manufacturer)
Article reported growth data for boys and girls separately. We combined the data for inclusion in this review

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom sequence centrally generated
Allocation concealment (selection bias)Low riskSealed opaque envelopes
Incomplete outcome data (attrition bias)
All outcomes
Low riskFollow-up was near complete (> 80%)
Blinding of participants and personnel (performance bias)
All outcomes
Low riskFamilies and care givers were unaware of which formula milk infants received
Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes assessors not aware of which formula milk infants received

De Curtis 2002

MethodsRandomised controlled trial
Participants33 formula milk-fed preterm infants (birth weight < 1750 grams or gestation < 35 weeks)
InterventionsPost-discharge formula (energy content 74 kcal/100ml, protein content 1.8 g/100ml, and calcium and phosphorus content 80 mg/100ml and 40 mg/100ml respectively) (N=16) or standard term formula (energy content 66 kcal/100ml, protein content 1.4 g/100ml) (N=17) from hospital discharge until two months corrected age
OutcomesGrowth parameters and bone mineralization measured using dual energy x-ray absorptiometry at the end of the 2 months study period
NotesSetting: Department of Pediatrics, University of Liege, Belgium
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo description of method used to generate random sequence
Allocation concealment (selection bias)Unclear riskNo information on randomisation method
Incomplete outcome data (attrition bias)
All outcomes
Low riskFollow-up was near complete (> 80%)
Blinding of participants and personnel (performance bias)
All outcomes
Low riskFamilies and care givers were unaware of which formula milk infants received
Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes assessors not aware of which formula milk infants received

Jeon 2011

MethodsRandomised controlled trial
Participants59 preterm very low birth weight infants
InterventionsPreterm formula (energy content 80 kcal/100ml, protein content 2.3 g/100ml, and calcium and phosphorus content 128 mg/100ml and 64 mg/100ml respectively) (N=34) or a standard term formula (energy content 67 kcal/100ml, protein content 1.6 g/100ml) (N=34) from hospital discharge until three months post term then both groups continuing with standard term formula until at least 6 months post term
OutcomesGrowth parameters at 3 monthly intervals until 18 months post term and Bayley Scales of Infant Development II at 18 months corrected age
Notes

Setting: Multicentre trial in four hospitals in South Korea

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

Initially three groups were randomly allocated to receive either (1) standard term formula, (2) preterm formula for 3 months, or (3) preterm formula for 6 months. However, there were substantial and significant between-group differences in the baseline demographic characteristics, especially between group (3) and the other groups. Group (3) infants had statistically significantly lower birth weights and were more likely to be small for gestational age. We therefore chose to discard data from this arm and to restrict comparison of outcomes to group (1) versus group (3)

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo description of method used to generate random sequence
Allocation concealment (selection bias)Unclear riskNo information on randomisation method
Incomplete outcome data (attrition bias)
All outcomes
Low riskGrowth outcomes data to 18 months were available for 30 (88%) intervention group and 29 (85%) control group infants
Blinding of participants and personnel (performance bias)
All outcomes
High riskFamilies and care givers were likely to have been aware of which formula milk infants received
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskOutcomes assessors may have been aware of which formula milk infants received

Koo 2006

MethodsRandomised controlled trial
Participants89 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
InterventionsNutrient-enriched formula (energy content 74 kcal/100ml, protein content 1.9 g/100ml, and calcium and phosphorus content 78 mg/100ml and 46 mg/100ml respectively) (N=44) or standard term formula (energy content 67 kcal/100ml, protein content 1.5 g/100ml) (N=45). The intention was for the allocated formula to be fed ad libitum until 12 months after discharge
OutcomesGrowth parameters and bone mineral content at intervals until the end of the 12 months study period
Notes

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

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

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo description of method used to generate random sequence
Allocation concealment (selection bias)Low riskAllocation drawn from sequential sealed opaque envelopes
Incomplete outcome data (attrition bias)
All outcomes
High riskGrowth outcomes data to 12 months were available for 31 (70%) intervention group and 36 (80%) control group infants
Blinding of participants and personnel (performance bias)
All outcomes
Low riskFamilies and care givers were unaware of which formula milk infants received
Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes assessors not aware of which formula milk infants received

Litmanovitz 2004

MethodsRandomised controlled trial
Participants20 healthy very low birth weight infants at hospital discharge
InterventionsNutrient-enriched formula (energy content 74 kcal/100ml, protein content 1.9 g/100ml (N=10) or a standard term formula (energy content 67 kcal/100ml, protein content 1.5 g/100ml) (N=10) following hospital discharge. The formulas were intended to provide the sole milk intake up to 6 months corrected age
OutcomesWeight, length, head circumference, and measures of bone mineralization at term and at 6 months corrected age
NotesSetting: Meir General Hospital, Kfar-saba, Israel
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo description of method used to generate random sequence
Allocation concealment (selection bias)Unclear riskNo information on randomisation method
Incomplete outcome data (attrition bias)
All outcomes
Low riskFollow-up was near complete (> 80%)
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNo information on whether families and care givers were aware of which formula milk infants received
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information on whether outcomes assessors were aware of which formula milk infants received

Lucas 1992

MethodsRandomised controlled trial
Participants32 exclusively formula milk-fed preterm infants, birth weight < 1850 g, and weight < 3000 g at hospital discharge
InterventionsNutrient-enriched formula (energy content 72 kcal/100ml, protein content 1.8 g/100ml, and calcium and phosphorus content 70 mg/100ml and 35 mg/100ml respectively) (N=16) or standard term formula (energy content 68 kcal/100ml, protein content 1.4 g/100ml) (N=16) following hospital discharge. The formulas were intended to provide the sole milk intake up to 9 months corrected age
OutcomesMeasures of growth (weight, crown-heel length and head circumference), feed tolerance, and bone mineralization during the trial period
Notes

Setting: Department of Paediatrics, Rosie Maternity Hospital, Cambridge

Research supported by Farley Health Products (formula milk company)
One infant who was randomised to the standard term formula group was transferred to another hospital prior to the planned hospital discharge and could not be included in any follow-up assessments

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

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo description of method used to generate random sequence
Allocation concealment (selection bias)Unclear riskNo information on randomisation method
Incomplete outcome data (attrition bias)
All outcomes
Low riskFollow-up was near complete (one infant from the standard term formula group was withdrawn)
Blinding of participants and personnel (performance bias)
All outcomes
Low riskIt is likely that families and care givers were unaware of which formula milk infants received
Blinding of outcome assessment (detection bias)
All outcomes
Low riskIt is likely that outcomes assessors were unaware of which formula milk infants received

Lucas 2001

MethodsRandomised controlled trial
Participants229 formula milk-fed preterm infants, birth weight <1750 g, and weight < 3000 g at hospital discharge
InterventionsNutrient-enriched formula (energy content 72 kcal/100ml, protein content 1.85 g/100ml, and calcium and phosphorus content 70 mg/100ml and 35 mg/100ml respectively) (N=113) or standard term formula (energy content 68 kcal/100ml, protein content 1.5 g/100ml) (N=116) from hospital-discharge until 9 months post-term
OutcomesGrowth parameters up to 18 months post term, and neurodevelopment (Bayley Scales) at 18 months corrected age
Notes

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

Research supported by Farley Health Products (formula milk company)

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskA member of the clinical team not involved in the trial prepared the randomisation assignments
Allocation concealment (selection bias)Low riskAllocation drawn from sequential sealed opaque envelopes
Incomplete outcome data (attrition bias)
All outcomes
Low riskGrowth and developmental outcomes assessed in >80% of participating infants
Blinding of participants and personnel (performance bias)
All outcomes
Low riskFamilies and care givers were unaware of which formula milk infants received
Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes assessors unaware of which formula milk infants received

Peng 2004

MethodsRandomised controlled trial
Participants34 preterm infants with a gestational age of < 35 weeks and birth weight < 1850 g
InterventionsNutrient-enriched formula (energy content 81 kcal/100ml, protein content 2.40 g/100ml, and calcium and phosphorus content 95 mg/100ml and 53 mg/100ml respectively) (N=19) or standard term formula (energy content 67.6 kcal/100ml, protein content 1.4 g/100ml) (N=15) from hospital-discharge until 6 months corrected age
OutcomesMeasures of growth (weight, crown-heel length and head circumference), feed tolerance, and bone mineralization during the trial period
Notes

Setting: Mackay Memorial Hospital, Taipei, Taiwan

Research supported by Mead Johnson (formula milk company)

No differences were found between the two groups in weight, length, or head 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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo description of method used to generate random sequence
Allocation concealment (selection bias)Unclear riskNo information on randomisation method
Incomplete outcome data (attrition bias)
All outcomes
High riskGrowth outcomes data to 6 months were available for 29 of the 40 infants initially enrolled (73%)
Blinding of participants and personnel (performance bias)
All outcomes
High riskFamilies and care givers were likely to have been aware of which formula milk infants received as parents were not blinded to the infants' assignment
Blinding of outcome assessment (detection bias)
All outcomes
High riskOutcomes assessors may have been aware of which formula milk infants received as physicians were not blinded to the infants' assignment

Picaud 2005

MethodsRandomised controlled trial
Participants49 formula milk-fed preterm infants, birth weight <1750 g or gestation at birth <33 weeks
InterventionsPreterm formula (energy content 81 kcal/100ml, protein content 2.3 g/100ml, and calcium and phosphorus content 100 mg/100ml and 53 mg/100ml respectively) (N=23) or a standard term formula (energy content 67 kcal/100ml, protein content 1.7 g/100ml) (N=26) from hospital discharge until 2 months post term
OutcomesGrowth parameters and measures of bone mineralization up to 4 months corrected age
Notes

Setting: two tertiary care neonatal units in France (2001-04)

Research supported by Nestlé France (formula milk manufacturer)

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

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskClinical trials unit generated
Allocation concealment (selection bias)Low riskPharmacy coded
Incomplete outcome data (attrition bias)
All outcomes
High riskLoss to follow-up by 12 months in the control group was substantial (35%) and greater than that in the intervention group (9%)
Blinding of participants and personnel (performance bias)
All outcomes
Low riskFamilies and care givers were unaware of which formula milk infants received
Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes assessors unaware of which formula milk infants received

Roggero 2011a

MethodsRandomised controlled trial
Participants84 formula milk-fed preterm infants born "small for gestational age" (<10th percentile)
InterventionsPost-discharge formula (energy content 75 kcal/100ml, protein content 2.0 g/100ml, and calcium and phosphorus content 100 mg/100ml and 56 mg/100ml respectively) (N=40) or a standard term formula (energy content 67 kcal/100ml, protein content 1.4 g/100ml) (N=44) from hospital discharge until 6 months corrected age
OutcomesGrowth parameters and fat mass up to 6 months corrected age
NotesSetting: Neonatal Intensive Care Unit, Department of Maternal and Paediatric Sciences, Milan, Italy (2008-10).
These trialists also conducted an RCT of nutrient-enriched versus standard formula in appropriate for gestational age infants (N= 123). These data are not yet published or available from the authors (referred to in conference abstract: Roggero 2011b)
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information provided
Allocation concealment (selection bias)Unclear riskNo information provided
Incomplete outcome data (attrition bias)
All outcomes
Low riskFollow-up until 6 months post term was complete
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNo information provided
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information provided

Taroni 2009

MethodsRandomised controlled trial
Participants27 formula milk-fed preterm infants, birth weight <1500 g or gestation at birth <33 weeks, and "small for gestational age" (<10th percentile)
InterventionsPost-discharge formula (energy content 75 kcal/100ml, protein content 2.0 g/100ml, and calcium and phosphorus content 100 mg/100ml and 56 mg/100ml respectively) (N= 14) or a standard term formula (energy content 67 kcal/100ml, protein content 1.4 g/100ml) (N= 13) from hospital discharge until 1 month corrected age
OutcomesGrowth parameters and fat mass up to 1 month corrected age
NotesSetting: Four Italian neonatal units (2008-9)
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskPre-prepared random sequence
Allocation concealment (selection bias)Unclear riskNo information provided
Incomplete outcome data (attrition bias)
All outcomes
Low riskFollow-up until 1 month post term was complete
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNo information provided
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information provided

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Amesz 2010The protein content of both formula milks was <1.7 g/100ml
Bernbaum 1989The energy content of both formula milks was <70 kcal/100ml
Bhatia 1991The protein content of both formula milks was <1.7 g/100ml
Brunton 1998Both of the formula milks were calorie-enriched (90 kcal/100ml)
Chan 1994The energy content of both formula milks was <70 kcal/100ml
Cooper 1985The energy content of both formula milks was <70 kcal/100ml
Friel 1993The energy content of both formula milks was <70 kcal/100ml
Lapillonne 2004Both of the formula milks were calorie-enriched (81kcal/100ml) and protein-enriched (>2.0 grams/100ml
Wheeler 1996The energy content of both formula milks was <70 kcal/100ml

Characteristics of studies awaiting assessment [ordered by study ID]

Roggero 2011b

MethodsRandomised controlled trial
Participants123 formula fed preterm infants who were "appropriate (birth weight) for gestational age"
InterventionsPost-discharge formula (energy content 75 kcal/100ml, protein content 2.0 g/100ml, and calcium and phosphorus content 100 mg/100ml and 56 mg/100ml respectively) (N= 59) or a standard term formula (energy content 67 kcal/100ml, protein content 1.4 g/100ml) (N= 64) from hospital discharge until 6 months corrected age
OutcomesGrowth parameters and fat mass up to (at least) 12 months corrected age
NotesThis has been presented as an abstract at the European Society for Paediatric Research annual scientific meeting in Newcastle (October 2011). When published in full, or if sufficient data are available from the investigators, this trial is likely to be included in this Cochrane review

Ancillary