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Formula versus donor breast milk for feeding preterm or low birth weight infants

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Authors

Maria Quigley1, William McGuire2

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


1National Perinatal Epidemiology Unit, University of Oxford, Oxford, UK [top]
2Hull York Medical School & Centre for Reviews and Dissemination, University of York, York, UK [top]

Citation example: Quigley M, McGuire W. Formula versus donor breast milk for feeding preterm or low birth weight infants. Cochrane Database of Systematic Reviews 2014, Issue 4. Art. No.: CD002971. DOI: 10.1002/14651858.CD002971.pub3.

Contact person

Maria Quigley

National Perinatal Epidemiology Unit
University of Oxford
Old Road Campus
Oxford
0X3 7LF
UK

E-mail: Maria.Quigley@npeu.ox.ac.uk

Dates

Assessed as Up-to-date: 31 March 2014
Date of Search: 31 March 2014
Next Stage Expected: 31 March 2016
Protocol First Published: Issue 1, 2001
Review First Published: Issue 4, 2001
Last Citation Issue: Issue 4, 2014

What's new

Date / Event Description
31 March 2014
New citation: conclusions not changed

Conclusions not changed.

31 March 2014
Updated

Search updated March 2013; one new trial included.

History

Date / Event Description
06 June 2008
Amended

Converted to new review format.

18 June 2007
New citation: conclusions changed

Substantive amendment.

Abstract

Background

When sufficient maternal breast milk is not available, alternative sources of enteral nutrition for preterm or low birth weight infants are donor breast milk or artificial formula. Donor breast milk may retain some of the non-nutritive benefits of maternal breast milk for preterm or low birth weight infants. However, feeding with artificial formula may ensure more consistent delivery of optimal levels of nutrients. Uncertainty exists about the balance of risks and benefits of feeding formula versus donor breast milk for preterm or low birth weight infants.

Objectives

To determine the effect of feeding with formula compared with donor breast milk on growth and development in preterm or low birth weight infants.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2014, Issue 3), MEDLINE (1966 to March 2014), EMBASE (1980 to March 2014), CINAHL (1982 to March 2014), conference proceedings and previous reviews.

Selection criteria

Randomised or quasi-randomised controlled trials comparing feeding with formula versus donor breast milk in preterm or low birth weight infants.

Data collection and analysis

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

Results

Nine trials, in which 1070 infants participated, fulfilled the inclusion criteria. Four trials compared standard term formula versus donor breast milk and five compared nutrient-enriched preterm formula versus donor breast milk. Only the two most recent trials used nutrient-fortified donor breast milk. The trials contain various methodological quality weaknesses, specifically uncertainty about adequate allocation concealment methods in three trials and lack of blinding in most of the trials.

Formula-fed infants had higher in hospital rates of increase in weight [mean difference (MD): 2.58 (95% confidence interval (CI) 1.98 to 3.71) g/kg/day], length [MD 1.93 (95% CI 1.23 to 2.62) mm/week] and head circumference [MD 1.59 (95% CI 0.95 to 2.24) mm/week]. We did not find evidence of an effect on post-discharge growth rates or neurodevelopmental outcomes. Formula feeding increased the risk of necrotising enterocolitis: typical risk ratio 2.77 (95% CI 1.40 to 5.46); risk difference 0.04 (95% CI 0.02 to 0.07).

Authors' conclusions

In preterm and low birth weight infants, feeding with formula compared with donor breast milk results in a higher rate of short-term growth but also a higher risk of developing necrotising enterocolitis. Limited data on the comparison of feeding with formula versus nutrient-fortified donor breast milk are available. This limits the applicability of the findings of this review as nutrient fortification of breast milk is now a common practice in neonatal care. Future trials may compare growth, development and adverse outcomes in infants who receive formula milk versus nutrient-fortified donor breast milk given as a supplement to maternal expressed breast milk or as a sole diet.

Plain language summary

Formula milk versus donor breast milk for feeding preterm or low birth weight infants

When a mother's own breast milk is not available for feeding her preterm or low birth weight infant, the alternatives are either formula or expressed breast milk from a donor mother ('donor breast milk'). This review of nine randomised controlled trials suggests that feeding with formula increases short-term growth rates, but is associated with a higher risk of developing the severe gut disorder called 'necrotising enterocolitis'. There is no evidence of an effect on longer-term growth or on development. Further trials that compare these two strategies are needed. These should probably compare formula adapted for preterm infants with donor breast milk supplemented with extra nutrients.

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Background

Maternal breast milk is the recommended form of enteral nutrition for preterm or low birth weight (LBW) infants. Breast milk contains non-nutrient factors including immunoglobulins that may promote intestinal adaptation and maturation, improve enteral feed tolerance, and protect against infective and inflammatory disorders (Agostoni 2010).

When sufficient maternal breast milk is not available, the two common alternatives available for feeding preterm or LBW infants are artificial formula and donor breast milk (donated by other lactating women). These may be given either as the sole form of enteral feeding or as a supplement to maternal breast milk.

Description of the condition

Providing appropriate nutrition for preterm or LBW infants is a critical component of neonatal care. Early enteral nutrition, particularly the use of donor breast milk or formula, may have a substantial impact on clinically important outcomes such as necrotising enterocolitis, invasive infection and short-term growth. These infectious and inflammatory complications may increase the risk of mortality and other morbidities and adversely affect long-term growth and neurodevelopmental outcomes.

Description of the intervention

A variety of artificial formulas (usually adapted from cow's milk) are available. These vary in energy, protein and mineral content but can, broadly, be considered as:

  • standard 'term' formula, designed for term infants based on the composition of mature breast milk: the typical energy content is between about 67 to 70 kcal/100 ml;
  • nutrient-enriched 'preterm' formula, designed to provide nutrient intakes to match intrauterine accretion rates (Tsang 1993): these are energy-enriched (typically up to about 80 kcal/100 ml) and variably protein- and mineral-enriched (Fewtrell 1999).

The comparison arm for the intervention is donor breast milk. Expressed breast milk from donor mothers, usually mothers who have delivered at term, generally has a lower content of energy and protein than term formula milk (Gross 1980; Gross 1981). The nutrient content of donor breast milk may be further compromised by pasteurisation (Wight 2001). Donor human milk also varies with regard to fat, energy and protein content depending upon the stage of lactation at which it is collected. Milk expressed from the donor's lactating breast usually has a higher energy and protein content than that collected from the contralateral breast ('drip' breast milk) (Lucas 1978).

How the intervention might work

There is concern that the nutritional requirements of preterm or LBW infants, who are born with relatively impoverished nutrient reserves and are subject to additional metabolic stresses compared with term infants, may not be fully met by enteral feeding with donor breast milk (Hay 1994; Schanler 1995). These deficiencies may have adverse consequences for growth and development. However, a major putative benefit of donor breast milk is that the delivery of immuno-protective and growth factors to the immature gut mucosa may prevent serious adverse outcomes, including necrotising enterocolitis and invasive infection (Beeby 1992; Lucas 1990).

Why it is important to do this review

Given the potential for the type of enteral nutrition to affect important outcomes for preterm or LBW 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 merited.

Objectives

To determine the effect of feeding with formula compared with donor breast milk on growth and development in preterm or LBW infants.

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Methods

Criteria for considering studies for this review

Types of studies

Controlled trials utilising either random or quasi-random participant allocation.

Types of participants

Preterm (less than 37 weeks' gestation) or low birth weight (less than 2.5 kg) infants.

Types of interventions

Enteral feeding with formula versus donor breast milk. The allocated milk feed may have been a supplement to maternal breast milk or have formed the entire enteral intake (sole diet).

Trials in which parenteral nutritional support was available during the period of advancement of enteral feeds were acceptable provided that the groups received similar treatment other than the type of milk feed.

Types of outcome measures

Primary outcomes
Growth
  1. Time to regain birth weight and subsequent rates of weight gain, linear growth, head growth or skinfold thickness growth up to six months post-term.
  2. Long-term growth: weight, height or head circumference (and/or proportion of infants who remain below the 10th percentile for the index population's distribution) assessed at intervals from six months post-term.
Neurodevelopment
  1. Death or severe neurodevelopmental disability defined as any one or combination of the following: non-ambulant cerebral palsy, developmental delay (developmental quotient less than 70), auditory and visual impairment. We analysed each component indiv idually as well as part of the composite outcome.
  2. Neurodevelopmental scores in survivors aged greater than, or equal to, 12 months of age measured using validated assessment tools.
  3. Cognitive and educational outcomes in survivors aged more than five years old.
Secondary outcomes
  1. All-cause mortality during the neonatal period and prior to hospital discharge.
  2. Necrotising enterocolitis confirmed at surgery or autopsy or diagnosed by at least two of the following clinical features:
    1. abdominal radiograph showing pneumatosis intestinalis or gas in the portal venous system or free air in the abdomen;
    2. abdominal distension with abdominal radiograph with gaseous distension or frothy appearance of bowel lumen (or both);
    3. blood in stool;
    4. lethargy, hypotonia or apnoea (or combination of these).
  3. Days after birth to establish full enteral feeding (independently of parenteral nutrition).
  4. Feeding intolerance defined as a requirement to cease enteral feeds and commence parenteral nutrition.
  5. Incidence of invasive infection as determined by culture of bacteria or fungus from blood, cerebrospinal fluid, urine or from a normally sterile body space.

Search methods for identification of studies

We used the standard search strategy of the Cochrane Neonatal Group (http://neonatal.cochrane.org/).

Electronic searches

We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2014, Issue 3), MEDLINE (1966 to March 2014), EMBASE (1980 to March 2014) and CINAHL (1982 to March 2014) using a combination of the following text words and MeSH terms: [Infant, Newborn OR Infant, Premature OR Infant, Low Birth Weight OR Infant, Very Low Birth Weight/ OR infan* OR neonat* OR preterm OR prem*] AND "Infant-Nutrition"/ all subheadings OR Infant Formula OR milk OR formula]. The search outputs were limited with the filters for clinical trials recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We did not apply any language restrictions.

We searched Clinical Trials for completed or ongoing trials.

Searching other resources

We examined the references in all studies identified as potentially relevant.

We searched the abstracts from the annual meetings of the Pediatric Academic Societies (1993 to 2013), the European Society for Pediatric Research (1995 to 2013), the UK Royal College of Paediatrics and Child Health (2000 to 2014) and the Perinatal Society of Australia and New Zealand (2000 to 2013). Trials reported only as abstracts were 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 Group.

Selection of studies

Two review authors screened the title and abstract of all studies identified by the above search strategy. We assessed 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 contacted 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 Group to assess the methodological quality of any included trials. We requested additional information from the trial authors 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:

  • low risk: any 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; patient case-record number;
  • unclear.

2. 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; unsealed or non-opaque envelopes, alternation; date of birth;
  • unclear.

3. 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;
  • unclear.

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, we re-included missing data in the analyses. We categorised completeness as:

  • low risk: less than 20% missing data;
  • high risk: 20% or more missing data;
  • unclear.

Measures of treatment effect

We calculated risk ratio (RR) and risk difference (RD) for dichotomous data and mean difference (MD) for continuous data, with respective 95% confidence intervals (CI). When it was deemed appropriate to combine two or more study arms, we obtained the treatment effects from the combined data using the methods described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We determined the number needed to treat to benefit (NNTB) or harm (NNTH) for a statistically significant difference in the RD.

Unit of analysis issues

The unit of analysis was the participating infant in indiv idually randomised trials and the neonatal unit for cluster-randomised trials.

Dealing with missing data

We requested missing data from trial investigators where possible.

Assessment of heterogeneity

If more than one trial was included in a meta-analysis, we examined the treatment effects of indiv idual 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 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 quality, participants, intervention regimens or outcome assessments) in sensitivity and subgroup analyses.

Assessment of reporting biases

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

Data synthesis

We used fixed-effect models for meta-analysis.

Subgroup analysis and investigation of heterogeneity

We planned the following subgroup analyses of trials to compare:

  1. formula versus donor breast milk given as (i) a sole diet or (ii) a supplement to maternal expressed breast milk;
  2. formula versus donor breast milk that is (i) unfortified or (ii) nutrient-fortified (defined as supplementation with more than one of the following components: protein, fat, carbohydrate or minerals).

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Results

Description of studies

Results of the search

We identified 16 reports of studies for full-text screening. We included nine trials and excluded seven studies.

We found three on-going trials (Characteristics of ongoing studies).

Included studies

Nine trials fulfilled the review eligibility criteria (Raiha 1976; Davies 1977; Schultz 1980; Gross 1983; Tyson 1983; Lucas 1984a; Lucas 1984b; Schanler 2005; Cristofalo 2013). Most of these trials were undertaken during the late 1970s and early 1980s by investigators attached to neonatal units in Europe and North America. Two trials have been undertaken since the year 2000 (Schanler 2005; Cristofalo 2013). For further details see Characteristics of included studies.

Participants

In total, 1070 infants participated in the included trials. Most participants were clinically stable preterm infants of gestational age less than 32 weeks or birth weight less than 1800 g. Most of the trials specifically excluded infants who were small for gestational age at birth and infants with congenital anomalies, or gastrointestinal or neurological problems.

Interventions

The trials varied according to type of formula, whether donor breast milk feeds were fortified and whether the intervention was a sole diet or a supplement to mother's own milk:

Five trials used donor breast milk collected from mothers who had delivered an infant at term (Davies 1977; Lucas 1984a; Lucas 1984b; Raiha 1976; Schultz 1980). Two of these trials used 'drip' breast milk (Lucas 1984a; Lucas 1984b). One trial used preterm donor breast milk (Schanler 2005), one trial used both term and preterm milk (Gross 1983) and two trials did not specify the type of donor breast milk (Tyson 1983; Cristofalo 2013). In all trials except Tyson 1983, the donor breast milk was pasteurised.

Only the two more recent trials used nutrient-fortified donor breast milk (Schanler 2005;Cristofalo 2013).

In general, feeds were allocated for several weeks, or until participating infants reached a specified weight (generally over 2 kg).

Outcomes

The most commonly reported outcomes were growth parameters during the study period or until hospital discharge. Most reports also gave information on adverse outcomes, including feeding intolerance and the incidence of necrotising enterocolitis. Only two trials reported long-term growth and neurodevelopmental outcomes for surviving infants (Lucas 1984a; Lucas 1984b).

Excluded studies

We excluded seven studies (Cooper 1984; Jarvenpaa 1983; Narayanan 1982; O'Connor 2003; Putet 1984; Sullivan 2010; Svenningsen 1982). The reasons for exclusion are described in the table Characteristics of excluded studies.

Risk of bias in included studies

Quality assessments are detailed in the table Characteristics of included studies ans summarised in Figure 1.

Allocation (selection bias)

Three trials reported adequate allocation concealment methods (sealed, numbered envelopes; central randomisation in blocks) (Lucas 1984a; Lucas 1984b; Tyson 1983). Five trials did not report details of allocation concealment. One trial randomly allocated participants to one of the four formula arms, but allocated every fifth infant to the donor breast milk arm (Raiha 1976).

Blinding (performance bias and detection bias)

Two trials blinded the staff or caregivers to the feeding arms (Schanler 2005; Cristofalo 2013). Three trials did not blind the staff (Lucas 1984a; Lucas 1984b; Tyson 1983). Four trials did not report whether staff were blinded.

Most of the trials did not specify whether the outcome assessors were blind to the feeding arms. In two trials staff were blind to the post-discharge outcomes (Lucas 1984a; Lucas 1984b).

Incomplete outcome data (attrition bias)

Six trials reported 100% follow-up for the short-term outcomes. In the other three trials infants who developed complications (5% to 10% of the total enrolled) were withdrawn from the study and therefore the short-term growth data for these infants were not presented (Gross 1983; Raiha 1976; Tyson 1983). In the two trials which assessed long-term outcomes more than 80% of participants were assessed (Lucas 1984a; Lucas 1984b).

Selective reporting (reporting bias)

Some of the outcomes in this review were reported as adverse outcomes in some of the studies rather than as a predefined outcome, but there is no evidence of selective reporting.

Effects of interventions

Growth

See Analysis 1.1 to Analysis 1.15.

Time to regain birth weight

Meta-analysis of data from Gross 1983 and Raiha 1976 found that the formula-fed group regained birth weight more quickly: mean difference (MD) -4.0 days (95% confidence interval (CI) -5.8 to -2.2) (Analysis 1.1; Figure 2).

Schultz 1980 did not detect a statistically significant difference, but standard deviations were not reported and the data could not be included in the meta-analysis.

Lucas 1984a reported the median time to regain birth weight as statistically significantly lower in the formula-fed infants (10 versus 16 days). Lucas 1984b did not find a statistically significant difference (13 versus 15 days). Standard deviations were not reported and these data were not included in a meta-analysis.

Weight gain

Formula-fed infants had a statistically significant higher rate of weight gain but with substantial heterogeneity in the size of this effect [MD 2.58 (95% CI 1.98 to 3.17) g/kg/day, I² = 91%, 8 trials, 702 participants (Analysis 1.2; Figure 3)]. This effect existed in separate comparisons of feeding with term formula versus donor breast milk [MD 1.74 (95% CI 0.96 to 2.53) g/kg/day] and preterm formula versus donor breast milk [MD 3.71 (95% CI 2.79 to 4.63) g/kg/day].

Linear growth

Formula-fed infants had a statistically significant higher rate of increase in crown-heel length but with substantial heterogeneity in the size of this effect [MD 1.36 (95% CI 0.87 to 1.85) mm/week, I² = 70%, 7 trials, 492 participants (Analysis 1.3; Figure 4)]. This effect existed in separate comparisons of feeding with term formula versus donor breast milk [MD 0.80 (95% CI 0.10 to 1.50) mm/week] and preterm formula versus donor breast milk [MD 1.93 (95% CI 1.23 to 2.62) mm/week].

Head growth

Formula-fed infants had a statistically significant higher rate of increase in occipito-frontal head circumference but with substantial heterogeneity in the size of this effect [MD 1.21 (95% CI 0.75 to 1.67) mm/week, I² = 69%, 7 trials, 568 participants (Analysis 1.6; Figure 5)]. This effect existed in separate comparisons of feeding with term formula versus donor breast milk [MD 0.81 (95% CI 0.15 to 1.47) mm/week] and preterm formula versus donor breast milk [MD 1.59 (95% CI 0.95 to 2.24) mm/week ].

Long-term growth

Post-hospital discharge growth was reported by Lucas 1984a and Lucas 1984b. Neither indiv idual study, nor meta-analyses of data from both studies, found any statistically significant differences in the weight, length or head circumference at nine months, 18 months or 7.5 to eight years post-term.

Neurodevelopment

See Analysis 1.16 to Analysis 1.18.

Neurodevelopmental outcomes were reported by two trials. Neither Lucas 1984a nor Lucas 1984b, nor a meta-analysis of data from both, found statistically significant differences in Bayley Psychomotor and Mental Development Indices at 18 months corrected age:

  • Bayley Mental Development Index: MD 1.24 (95% CI -2.6 to 5.1).
  • Bayley Psychomotor Development Index: MD -0.3 (95% CI -3.8 to 3.9).

Gross 1983 stated that there was "no difference" in Bayley Mental or Psychomotor Developmental Indices at 15 months post-term (study published as abstract only).

Severe neurodevelopmental disability (Amiel-Tison 1986 classification) was assessed in two trials. Neither Lucas 1984a nor Lucas 1984b, nor a meta-analysis of data from both trials, demonstrated a statistically significant difference in the incidence of neurological impairment at 18 months post-term: typical RR 1.2 (95% CI 0.6 to 2.3); RD -0.02 (95% CI -0.04 to 0.17).

Lucas 1984a and Lucas 1984b assessed cognitive outcomes (verbal and performance intelligence quotient) in about 20% of participants at ages eight and 16 years. However, numerical data were not reported for the indiv idual trials but rather were combined with data from another trial undertaken by the same investigators that compared feeding preterm infants with nutrient-enriched versus standard formula (Isaacs 2009).

Secondary outcomes

All-cause mortality

See Analysis 1.19.

Data were available from four trials. Two trials reported mortality until nine months post-term (Lucas 1984a; Lucas 1984b). Two trials reported mortality until hospital discharge (Schanler 2005; Cristofalo 2013). None of the trials found a statistically significant difference in mortality between the feeding groups. Since it is likely that most infant mortality in this population occurred before hospital discharge, we combined the data from the trials in a meta-analysis. This analysis did not demonstrate a statistically significant difference: typical RR 1.33 (95% CI 0.79 to 2.25); RD 0.02 (95% CI -0.02 to 0.06). There was no evidence of statistical heterogeneity (I² = 0%).

Necrotising enterocolitis

See Analysis 1.20.

Meta-analysis of data from six trials (including both term and preterm formula) found a statistically significant higher incidence of necrotising enterocolitis in the formula-fed group: typical RR 2.77 (95% CI 1.40 to 5.46); RD 0.04 (95% CI 0.02 to 0.07); number needed to treat to benefit (NNTB) 25 (95% CI 14 to 50). There was no statistically significant heterogeneity (I² = 0%) (Figure 6).

Days after birth to establish full enteral feeding

See Analysis 1.21

This was reported by only one of the included trials. Cristofalo 2013 did not detect a statistically significant difference: MD 4.70 (95% CI -2.56 to 11.96).

Feeding intolerance

See Analysis 1.22.

Meta-analysis of data from Gross 1983 and Tyson 1983 found a statistically significant higher incidence of feeding intolerance in the formula-fed group: typical RR 4.92 (95% CI 1.17 to 20.70); RD 0.10 (95% CI 0.01, 0.19); NNTH 10 (95% CI 5 to 100).

Lucas 1984a reported that significantly more infants in the formula-fed group failed to tolerate full enteral feeds by two weeks after birth (25/76 versus 9/83 in the donor breast milk group) and by three weeks after birth (13/76 versus 4/83).

Incidence of invasive infection

Meta-analysis of data from Schanler 2005 and Cristofalo 2013 did not find a statistically significant difference: RR 1.12 (95% CI 0.84 to 1.49).

Subgroup analysis: formula versus donor breast milk as (i) sole diet or (ii) supplement to maternal expressed breast milk

Seven trials compared feeding with preterm formula versus donor breast milk as a sole diet (Raiha 1976; Davies 1977; Schultz 1980; Gross 1983; Tyson 1983; Lucas 1984a; Cristofalo 2013).

Two trials compared feeding with preterm formula versus donor breast milk as a supplement to maternal expressed breast milk (Lucas 1984b; Schanler 2005).

Growth

Analysis 2.1 to Analysis 2.12.

Time to regain birth weight
Sole diet

Meta-analysis of data from Gross 1983 and Raiha 1976 found that the formula-fed group regained birth weight more quickly: mean difference (MD) -4.0 days (95% confidence interval (CI) -5.8 to -2.2) (Analysis 1.1; Figure 2).

Schultz 1980 did not detect a statistically significant difference, but standard deviations were not reported and the data could not be included in the meta-analysis.

Lucas 1984a reported the median time to regain birth weight as statistically significantly lower in the formula-fed infants (10 versus 16 days). Standard deviations were not reported.

Supplement to maternal expressed breast milk

Lucas 1984b did not find a statistically significant difference (13 versus 15 days). Standard deviations were not reported.

Weight gain
Sole diet

Meta-analysis demonstrated a statistically significant higher rate of weight gain in the formula-fed group: MD 2.65 (95% CI 1.94 to 3.36) g/kg/day (Analysis 2.1).

Supplement to maternal expressed breast milk

Meta-analysis demonstrated a statistically significant higher rate of weight gain in the formula-fed group: MD 2.39 (95% CI 1.28 to 3.50) g/kg/day (Analysis 2.1).

Linear growth
Sole diet

Meta-analysis demonstrated a statistically significant higher rate of increase in crown-heel length: MD 1.54 (95% CI 0.98 to 2.11) mm/week (Analysis 2.2).

Supplement to maternal expressed breast milk

Meta-analysis did not detect a statistically significant difference: MD 0.75 (95% CI -0.28 to 1.78) mm/week (Analysis 2.2).

Head growth
Sole diet

Meta-analysis demonstrated a statistically significant higher rate of increase in occipito-frontal head circumference: MD 1.36 (95% CI 0.85 to 1.88) mm/week (Analysis 2.3).

Supplement to maternal expressed breast milk

Meta-analysis did not detect a statistically significant difference: MD 0.59 (95% CI -0.44 to 1.62) mm/week (Analysis 2.3).

Long-term growth

See Analysis 2.4 to Analysis 2.12.

Sole diet

Lucas 1984a did not find any statistically significant differences in the weight, length or head circumference at nine months, 18 months or 7.5 to eight years post-term.

Supplement to maternal expressed breast milk

Lucas 1984b did not find any statistically significant differences in the weight, length or head circumference at nine months, 18 months or 7.5 to eight years post-term.

Neurodevelopment

See Analysis 2.13 to Analysis 2.15.

Sole diet

Lucas 1984a did not find statistically significant differences in Bayley Psychomotor and Mental Development Indices or in the incidence of neurological impairment at 18 months post-term. Numerical data for cognitive and educational outcomes were not reported.

Supplement to maternal expressed breast milk

Lucas 1984b did not find statistically significant differences in Bayley Psychomotor and Mental Development Indices or in the incidence of neurological impairment at 18 months post-term. Numerical data for cognitive and educational outcomes were not reported.

Secondary outcomes

All-cause mortality

See Analysis 2.16.

Sole diet

Meta-analysis did not find a statistically significant difference [MD: 1.70 (95% CI 0.71 to 4.07)]

Supplement to maternal expressed breast milk

Meta-analysis did not detect a statistically significant difference [MD: 1.16 (95% CI 0.60 to 2.24)].

Necrotising enterocolitis

See Analysis 2.17.

Sole diet

Meta-analysis demonstrated a statistically significant higher incidence of necrotising enterocolitis in the formula-fed group: typical RR 4.62, 95% CI 1.47 to 14.56 (Analysis 2.17).

Supplement to maternal expressed breast milk

Meta-analysis did not detect a statistically significant difference (typical RR 1.96, 95% CI 0.82 to 4.67) (Analysis 2.17).

Feeding intolerance

See Analysis 2.18.

Sole diet

Meta-analysis demonstrated a statistically significant higher incidence of feeding intolerance in the formula-fed group: typical RR 4.92, 95% CI 1.17 to 20.70 (Analysis 2.18).

Supplement to maternal expressed breast milk

Feeding intolerance was not reported by Lucas 1984b or Schanler 2005.

Incidence of invasive infection

See Analysis 2.19.

Sole diet

Cristofalo 2013 did not detect a statistically significant difference: RR 3.09 (95% CI 0.90 to 10.53).

Supplement to maternal expressed breast milk

Schanler 2005 did not detect a statistically significant difference: RR 0.97 (95% CI 0.66 to 1.44).

Subgroup analysis: formula versus donor breast milk that is (i) unfortified or (ii) fortified

Seven trials compared feeding with preterm formula versus unfortified donor breast milk (Raiha 1976; Davies 1977; Schultz 1980; Gross 1983; Tyson 1983; Lucas 1984a; Lucas 1984b).

Two trials compared feeding with preterm formula versus donor breast milk with multi-nutrient fortifier (Schanler 2005; Cristofalo 2013).

Growth

See Analysis 3.1 to Analysis 3.12.

Time to regain birth weight
Unfortified donor breast milk

Meta-analysis of data from Gross 1983 and Raiha 1976 found that the formula-fed group regained birth weight more quickly: mean difference (MD) -4.0 days (95% confidence interval (CI) -5.8 to -2.2) (Analysis 1.1; Figure 2).

Schultz 1980 did not detect a statistically significant difference, but standard deviations were not reported and the data could not be included in the meta-analysis.

Lucas 1984a reported the median time to regain birth weight as statistically significantly lower in the formula-fed infants (10 versus 16 days). Lucas 1984b did not find a statistically significant difference (13 versus 15 days). Standard deviations were not reported.

Fortified donor breast milk

Time to regain birth weight was not reported by Schanler 2005 or Cristofalo 2013.

Weight gain
Unfortified donor breast milk

Meta-analysis demonstrated a statistically significant higher rate of weight gain in the formula-fed group: MD 2.54 (95% CI 1.89 to 3.19) g/kg/day. There was statistically significant heterogeneity in this meta-analysis (I² = 94%) (Analysis 3.1).

Fortified donor breast milk

Meta-analysis of data from Schanler 2005 and Cristofalo 2013 found a statistically significant higher rate of weight gain in the formula-fed group: MD 2.80 (95% CI 1.20 to 4.39) g/kg/day (Analysis 3.1).

Linear growth
Unfortified donor breast milk

Meta-analysis demonstrated a statistically significant higher rate of increase in crown-heel length: MD 1.26 (95% CI 0.72 to 1.80) mm/week. There was statistically significant heterogeneity in this meta-analysis (I² = 60%) (Analysis 3.2).

Fortified donor breast milk

Meta-analysis of data from Schanler 2005 and Cristofalo 2013 found a statistically significant higher rate of linear growth in the formula-fed group:: MD 1.86 (95% CI 0.64 to 3.07) mm/week (Analysis 3.2).

Head growth
Unfortified donor breast milk

Meta-analysis demonstrated a statistically significant higher rate of increase in occipitofrontal head circumference: MD 1.29 (95% CI 0.79 to 1.80) mm/week. There was statistically significant heterogeneity in this meta-analysis (I² = 78%) (Analysis 3.3).

Fortified donor breast milk

Meta-analysis did not detect a statistically significant difference: MD 0.83 (95% CI -0.25 to 1.91) mm/week (Analysis 3.3).

Long-term growth

See Analysis 3.4 to Analysis 3.12.

Unfortified donor breast milk

Post-hospital discharge growth was reported by Lucas 1984a and Lucas 1984b. Neither indiv idual study, nor meta-analyses of data from both studies, found any statistically significant differences in the weight, length or head circumference at nine months, 18 months or 7.5 to eight years post-term.

Fortified donor breast milk

Long-term growth was not reported by Schanler 2005 or Cristofalo 2013.

Neurodevelopment

See Analysis 3.13 to Analysis 3.15.

Unfortified donor breast milk

Neither Lucas 1984a nor Lucas 1984b, nor a meta-analysis of data from both, found statistically significant differences in Bayley Psychomotor and Mental Development Indices at 18 months corrected age. Numerical data for cognitive and educational outcomes were not reported.

Supplement to maternal expressed breast milk

Neurodevelopmental outcomes were not reported by Schanler 2005 or Cristofalo 2013.

Secondary outcomes

All-cause mortality

See Analysis 3.16.

Unfortified donor breast milk

Meta-analysis did not detect a statistically significant difference in mortality (typical RR 1.29, 95% CI 0.73 to 2.29) (Analysis 3.16).

Fortified donor breast milk

Meta-analysis did not detect a statistically significant difference (RR 1.53, 95% CI 0.42 to 5.51) (Analysis 3.16).

Necrotising enterocolitis

See Analysis 3.17.

Unfortified donor breast milk

Meta-analysis demonstrated a statistically significant difference (typical RR 3.30, 95% CI 1.16 to 9.41) (Analysis 3.17).

Fortified donor breast milk

Meta-analysis of data from Schanler 2005 and Cristofalo 2013 did not detect a statistically significant difference (typical RR 2.40, 95% CI 0.98 to 5.87) (Analysis 3.17).

Feeding intolerance

See Analysis 3.18.

Unfortified donor breast milk

Meta-analysis detected a statistically significant higher rate in the formula-fed group (RR 4.92, 95% CI 1.17 to 20.70) (Analysis 3.18).

Fortified donor breast milk

Feeding intolerance was not reported by either trial.

Incidence of invasive infection

See Analysis 3.19.

Unfortified donor breast milk

Incidence of invasive infection was not reported by any of the trials.

Fortified donor breast milk

Meta-analysis of data from Schanler 2005 and Cristofalo 2013 did not detect a statistically significant difference (RR 1.12, 95% CI 0.84 to 1.49) (Analysis 3.19).

Discussion

Summary of main results

We found nine randomised controlled trials in which 1070 preterm or low birth weight infants participated. Preterm or low birth weight infants who receive formula regain birth weight earlier and have higher short-term rates of weight gain, linear growth and head growth than infants who receive donor breast milk. These effects on growth parameters are greater in trials that compare feeding with nutrient-enriched preterm formula compared to standard term formula versus donor breast milk. Follow-up of the infants who participated in two of the largest trials did not find any statistically significant effects on long-term growth parameters or neurodevelopmental outcomes (Lucas 1984a; Lucas 1984b).

Meta-analysis of data from six trials suggests that feeding with formula significantly increases the risk of feeding intolerance and necrotising enterocolitis in preterm and low birth weight infants. The pooled estimate suggests that one extra case of necrotising enterocolitis will occur in every 25 infants who receive formula.

Overall completeness and applicability of evidence

These findings should be interpreted with caution. Substantial heterogeneity in the meta-analyses of the effect on growth parameters limits the validity of the pooled estimates of effect size. Most of these trials were undertaken more than 20 years ago and the trials used different inclusion criteria and varied with respect to the type of formula and donor breast milk used. Only two trials were undertaken in the past 15 years and only these trials compared feeding with formula versus donor breast milk with added multi-nutrient fortifier (Schanler 2005; Cristofalo 2013). This limits the applicability of the findings to current practice, where nutrient fortification of breast milk is commonly undertaken (Klingenberg 2012).

Meta-analysis of data from six trials suggests that feeding with formula more than doubles the risk of necrotising enterocolitis. The observed effect sizes were similar across the trials and there was no statistical evidence of heterogeneity. The pooled estimate suggests that one extra case of necrotising enterocolitis will occur in every 25 infants who receive formula. This beneficial effect of donor breast milk exists even when donor breast milk is given as a supplement to maternal breast milk rather than as a sole diet and also when the donor breast milk is fortified. However, only one of the trials was able to blind caregivers and assessors to the intervention. This methodological weakness may have resulted in surveillance and ascertainment biases that contributed to the higher rate of detection of necrotising enterocolitis in formula-fed infants. Finally, caution should be exercised in applying these data to growth-restricted preterm infants or sick infants, since these infants, although at high risk of developing necrotising enterocolitis, were generally excluded from the included trials.

The data in this review are from trials undertaken in high-income countries. In low- or middle-incomes countries, the anti-infective properties of breast milk may confer advantages that outweigh the lower rate of short-term growth. In India, a randomised trial in low birth weight infants "at risk of infection" found that serious infections (diarrhoea, pneumonia, septicaemia) were statistically significantly less common in infants allocated to received "expressed human milk" versus formula milk (Narayanan 1982). "Expressed human milk" in this study referred to a mixture of maternal and donor breast milk. As these could not be separated into subgroups, the data were not included in the review.

Quality of the evidence

The trials contain various methodological quality weaknesses, specifically uncertainty about adequate allocation concealment methods in three trials and lack of blinding in most of the trials. Parents, caregivers, clinicians and investigators were likely to have been aware of the treatment group to which infants had been allocated and this knowledge may have affected some care practices or investigation strategies including thresholds for screening or diagnosing for necrotising enterocolitis, which may have affected the outcomes assessed.

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 from trials that reported statistically significant or clinically important effects. We attempted to minimise this threat by screening the reference lists of included trials and related reviews and 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 whether 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

Feeding with formula compared with donor breast milk may increase rates of short-term growth in preterm or low birth weight infants but is associated with a doubling of the risk of developing necrotising enterocolitis. There are only limited data from randomised trials on the comparison of feeding with formula milk versus nutrient-fortified human milk. This limits the implications for practice from this review as nutrient fortification of human milk is now a common practice in neonatal care.

Implications for research

Further randomised controlled trials are needed to assess the effect of feeding preterm or low birth weight infants with formula versus donor breast milk in situations where the expressed breast milk of the infant's mother is not consistently available. Future studies should probably compare enteral feeding with formula milk versus nutrient-fortified donor breast milk in a population of infants at increased risk of necrotising enterocolitis. Separate comparisons of formula versus donor breast milk as supplements to maternal expressed breast milk and as sole diets are warranted since their effects may vary. Trials should attempt to ensure that caregivers and assessors are blind to the intervention. Although more easily achievable for the longer-term assessments, this is also important with regard to ascertainment of adverse events, such as feeding intolerance and necrotising enterocolitis, where the threshold for investigation or diagnosis may be affected by knowledge of the intervention.

Acknowledgements

We thanks Mary Anthony and Ginny Henderson for contributing to previous versions of this review.

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 authors and not necessarily those of the NHS, the NIHR, or the UK Department of Health.

Contributions of authors

William McGuire (WM) and Mary Anthony developed the protocol and undertook the original review in 2000. Ginny Henderson and WM updated the review in 2003. Maria Quigley and WM revised the protocol and updated the review in 2007 and in 2014.

Declarations of interest

William McGuire and Maria Quigley do not have any declarations of interest.

Differences between protocol and review

We revised the structure of the review in 2007. We now include:
1. Trials that compared feeding with formula milk with either term or preterm donor breast milk (inception protocol and review restricted to term breast milk).
2. Trials that compared feeding with formula versus donor breast milk as a sole diet or as a supplement to maternal expressed breast milk (inception protocol and review restricted to sole diet).

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Characteristics of studies

Characteristics of included studies

Cristofalo 2013

Methods

Randomised controlled trial

Participants

53 newborn infants: birth weight 500 - 1250 g
Exclusions: major congenital abnormalities, high likelihood of transfer to a non-study site after 48 hours
Seven neonatal intensive care units: six in US, one in Austria

(Probably) 2010-12

Interventions

Preterm formula milk (N = 24) versus fortified (with human milk-based fortifier), pasteurised donor breast milk (N = 29). Assigned until 91 days after birth, or discharge, or oral feeding at least 50% of feeds.

Outcomes

Duration of parenteral nutrition, growth, respiratory support, and NEC

Notes

Additional information on methods courtesy of Dr Cristafalo (April 2014)

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

Random sequence generated centrally in permuted blocks stratified by investigational site

Allocation concealment (selection bias) Low risk

Allocation outcome provided to an indiv idual at each site who was not connected with the evaluation of outcomes for participants

Blinding (performance bias and detection bias) Low risk

Investigators, caregivers, and families were blinded

Incomplete outcome data (attrition bias) Low risk

100% follow-up

Davies 1977

Methods

Randomised controlled trial

Participants

68 preterm infants: 28 to 36 weeks in 2 strata
Exclusions: multiple births, congenital abnormalities and chromosomal disorders, congenital infection. Growth-restricted infants (< 5th percentile) may also have been excluded
Department of Child Health, University Hospital of Wales, Cardiff
1972-1973

Interventions

Term formula milk (N = 34) versus unfortified, pasteurised donor breast milk (N = 34). Assigned from birth for 2 months

Outcomes

Rates of weight gain, increase in head circumference and length from birth until 1 month and from 1 month until 2 months

Notes

Infants of mothers who wished to breast-feed were initially given expressed breast milk if unable to feed naturally. There were only 2 such infants, their feeding group was not specified and the results for these infants are not presented separately in the paper. Given that this applies to only 2 out of 68 infants, we have included this study in the review

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

Method not stated

Allocation concealment (selection bias) Unclear risk

Method not stated

Blinding (performance bias and detection bias) Unclear risk

No information given

Incomplete outcome data (attrition bias) Low risk

100% follow-up

Gross 1983

Methods

Randomised controlled trial

Participants

67 preterm infants (27 to 33 weeks)
Birth weight < 1600 g. Excluded if "congenital anomaly or major disease"
Department of Pediatrics, Duke University, USA
1980-1982

Interventions

Term formula milk (N = 26) versus unfortified, pasteurised donor breast milk (N = 41). Feeds were assigned until the infant reached a weight of 1800 g or until withdrawn from the study because of feeding intolerance or NEC

Outcomes

Time to regain birth weight
Mean daily gain in weight, length and head circumference, from regaining birth weight until reaching 1800 g
Data on adverse events can be determined although these were not primary endpoints of the study

Notes

Although the report gave information on adverse outcomes, the 7 affected infants were withdrawn from the study and not included in the analyses of growth rates. Therefore, growth data are reported for 20 infants in each arm of the trial

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

Random number table

Allocation concealment (selection bias) Unclear risk

Method not stated

"Any infant withdrawn from the study was replaced by the next one enrolled": implies lack of allocation concealment for these infants

Blinding (performance bias and detection bias) Unclear risk

No information given

Incomplete outcome data (attrition bias) Unclear risk

7 out of 67 (10%) with adverse outcomes (NEC, mortality) were not assessed for growth outcomes. This included 6/26 (23%) in the formula group and 1/41 (2.4%) in the donor breast milk group, so potential bias

100% follow-up and low risk of bias for mortality and NEC

Lucas 1984a

Methods

Randomised controlled trial

Participants

159 infants of birth weight < 1850 g. Stratified by birth weight < 1200 g and 1201 g to 1850 g

Infants with congenital abnormalities excluded. Infants with intrauterine growth restriction not excluded
Study undertaken in the early 1980s in neonatal units in the Anglia region of the UK

Interventions

Preterm formula milk (N = 76) versus donor (mainly "drip") breast milk (N = 83)

The formula was intended to be delivered at 180 ml/kg/day versus the breast milk at 200 ml/kg/day

Feeds were assigned until the infant reached a weight of 2000 g or until discharge from the neonatal unit

Outcomes

Short term outcomes:
Time to regain birth weight (62 infants). Rates of change in weight (58 infants), crown-heel length (26 infants) and head circumference (48 infants) from the point of regained birth weight until discharge from the neonatal unit or reaching a weight of 2000 g
Incidence of NEC - suspected and confirmed reported on complete cohort of 159 infants

Longer-term outcomes:
Validated neurological assessment at 18 months in 122 (85%) of surviving infants
Bayley Mental Development Index and Psychomotor Development Index at 18 months post-term, in 114 (94%) of surviving infants suitable for the assessment
Growth performance in surviving infants (weight, length and head circumference) at 9 months (110 infants), 18 months (136 infants) and 7.5 to 8 years (130 infants) post-term

Notes

The first "interim" report provided data on short-term growth outcomes in a predefined subset of the total cohort recruited.
Follow-up at 18 months was achieved for more than 80% of surviving infants. Developmental assessments (Bayley Psychomotor and Mental Development Indices) at 18 months post-term were reported for 114 of the 159 children originally enrolled in the study. 16 children had died and 7 had been lost to follow-up. 12 surviving children had cerebral palsy affecting fine motor skills and these children were not assessed. A further 10 children were not assessed due to severe visual or hearing impairment or because follow-up data were obtained by telephone for geographical reasons

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

Balanced randomisation sequence was prepared for each centre, within strata defined by birth weight (method of sequence generation not stated explicitly)

Allocation concealment (selection bias) Low risk

Sealed, numbered envelopes

Blinding (performance bias and detection bias) Unclear risk

No information given

Incomplete outcome data (attrition bias) Low risk

100% assessment of in-hospital outcomes and > 80% follow-up for long-term outcomes (except for cognitive outcomes (verbal and performance intelligence quotient), which were assessed in about 20% of participants at ages 8 and 16 years)

Lucas 1984b

Methods

Randomised controlled trial

Participants

343 infants of birth weight < 1850 g. Stratified by birth weight < 1200g and 1201 to 1850 g. Infants with congenital abnormalities excluded. Infants with intrauterine growth restriction not excluded
Study undertaken in the early 1980s in neonatal units in the Anglia region of the UK

Interventions

Preterm formula milk (N = 173) versus banked donor breast milk (N = 170) as a supplement to the mother's own breast milk

Outcomes

Short-term outcomes: time to regain birth weight (132 infants). Rates of change in weight (115 infants), crown-heel length (45 infants) and head circumference (97 infants) from the point of regained birth weight until discharge from the neonatal unit or reaching a weight of 2000 g
Incidence of NEC - suspected and confirmed reported on complete cohort of 343 infants
Longer-term outcomes:
Validated neurological assessment, at 18 months, in 278 (88%) of surviving infants
Bayley Mental Development Index and Psychomotor Development Index at 18 months, corrected for preterm gestation, in 273 (96%) of surviving infants suitable for the assessment
Growth performance in surviving infants (weight, length and head circumference) at 9 months (259 infants), 18 months (302 infants) and 7.5 to 8 years (290 infants) post-term

Notes

The first "interim" report provided data on short-term growth outcomes in a predefined subset of the total cohort recruited.
Developmental assessments (Bayley Psychomotor and Mental Development Indices) at 18 months post-term were reported for 273 of 343 children originally enrolled in the study. 29 children had died and 12 had been lost to follow-up. 24 surviving children had cerebral palsy affecting fine motor skills and these children were not assessed. A further 5 children were not assessed due to severe visual or hearing impairment or because follow-up data were obtained by telephone for geographical reasons

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

Not stated

Allocation concealment (selection bias) Low risk

Sealed, numbered envelopes

Blinding (performance bias and detection bias) Unclear risk

No information given

Incomplete outcome data (attrition bias) Low risk

100% assessment of in-hospital outcomes and > 80% follow-up for long-term outcomes (except for cognitive outcomes (verbal and performance intelligence quotient), which were assessed in about 20% of participants at ages 8 and 16 years)

Raiha 1976

Methods

Randomised controlled trial

Participants

106 preterm infants of birth weight < 2100 g, but between 10th and 90th centiles for birth weight. Infants excluded if evidence of "physical abnormality or obvious disease"

Premature Unit, Helsinki University Children's Hospital, 1972 to 1975

Interventions

Term formula milk (N = 84) versus unfortified donor breast milk (N = 22)

Feeds continued until a weight of 2.4 kg was attained or until infants were withdrawn from the study because of a "medical complication"

Outcomes

Time, from birth, to regain birth weight. Rate of weight change from birth and from point of regained birth weight

Notes

Donor breast milk was given at a 170 ml/kg/day, compared with formula at 150 ml/kg/day, "in order to achieve equivalent calorie inputs". Donor breast milk-fed infants were also given supplemental vitamins

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

Randomly selected permutations of 1, 2, 3, 4 were prepared in advance, which were used to allocate to the 4 formula arms. Every 5th infant was assigned to pooled breast milk. Hence, it was not strictly random. Also, no details of how the permutations were generated

Allocation concealment (selection bias) High risk

Every 5th infant was assigned to pooled breast milk so allocation concealment may have been sub-optimal

Blinding (performance bias and detection bias) Unclear risk

No information given

Incomplete outcome data (attrition bias) Low risk

95% follow-up (5/106 infants who were enrolled were dropped from the study for medical reasons)

Schanler 2005

Methods

Randomised controlled trial

Participants

173 infants of gestational age < 30 weeks, whose mothers intended to breast-feed but whose own milk became insufficient from birth until 90 days of age or hospital discharge
North Shore University Hospital, New York, USA, 2000 to 2003

Interventions

Preterm formula (N = 81) versus unfortified donor breast milk (N = 92) given as a supplement to maternal breast milk

Outcomes

Incidence of late-onset invasive infection and NEC, duration of hospitalisation and growth during the study period (weight gain, head circumference increment and length increment)

Notes

Participating infants received small quantities (20 ml/kg/day) of their own mother's milk during the first week after birth and continued for 3 to 5 days before the volume was advanced. Milk intake was increased by 20 to 100 ml/kg/day at which time human milk fortifier was added. Subsequently the volume of fortified human milk was advanced by 20 ml/kg/day until 160 ml/kg/day was achieved. If no mother's milk was available and the baby was assigned to donor breast milk then a similar advancement and fortification protocol was followed. For all infants, adjustments in milk intake between 160 and 200 ml/kg/day were recommended to ensure an average weekly weight gain of at least 15 g/kg per day
17 enrolled infants were switched from donor breast milk to preterm formula because of poor weight gain but all of these analyses were by intention-to-treat. However, 7 infants who were never fed (3 in the donor milk group, 4 in the formula group) were excluded from the analyses

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

Method not stated explicitly but very likely to be computer-generated since the random sequence was "an unbalanced blocked design, according to the stratification variables of gestational age and receipt of prenatal steroids"

Allocation concealment (selection bias) Low risk

Allocation was "performed by the research nurse coordinator with sealed opaque envelopes"

Blinding (performance bias and detection bias) High risk

Unblinded

Incomplete outcome data (attrition bias) Low risk

Complete follow-up

Schultz 1980

Methods

Randomised controlled trial

Participants

20 preterm or LBW infants; all infants were "physically normal with no further signs of disease"
Department of Paediatrics, University Medical School, Pecs, Hungary, prior to 1980

Interventions

Term formula milk (N = 10) versus donor breast milk (N = 10) for at least 4 weeks from birth

Outcomes

Time, from birth, to regain birth weight (mean but no SD reported)
Mean weight change from birth and from regaining birth weight calculable from graph but no SD

Notes

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

Method not stated

Allocation concealment (selection bias) Unclear risk

No information given

Blinding (performance bias and detection bias) Unclear risk

No information given

Incomplete outcome data (attrition bias) Low risk

100% follow-up

Tyson 1983

Methods

Randomised controlled trial

Participants

81 VLBW infants, excluding infants with "any significant illness" or those who required ventilatory support at day 10
Parklands Memorial Hospital, Dallas, USA, early 1980s

Interventions

Preterm formula milk (N = 44) versus donor breast milk (N = 37). The donor breast milk was not pasteurised. Feeds were allocated on the 10th day of life, and continued until the infant reached a weight of 2000 g or until withdrawn from the study because of "any illness requiring intravenous infusion of fat or protein"

Outcomes

Mean daily rates of change in weight, crown-heel length and head circumference from the 10th until the 30th day of life were reported

Notes

The feeds were not allocated until the 10th day after birth in order to avoid the use of protein-enriched formula "when active growth was unlikely". In the first 9 days of life the infants received a term formula or maternal expressed breast milk (if available). Although the report gave information on adverse outcomes, including NEC, the 5 affected infants were withdrawn from the study and not included in the analyses of growth rates

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

Infants were stratified by birth weight and randomised, but how the sequence was generated is not stated

Allocation concealment (selection bias) Low risk

Concealed envelope opened only after informed parental consent obtained

Blinding (performance bias and detection bias) Unclear risk

No information given

Incomplete outcome data (attrition bias) Low risk

5 infants with adverse outcomes did not have growth data

Footnotes

LBW: low birth weight
NEC: necrotising enterocolitis
SD: standard deviation
VLBW: very low birth weight

Characteristics of excluded studies

Cooper 1984

Reason for exclusion

Cooper 1984 measured growth and adverse events in preterm infants fed preterm formula or donor breast milk, but for most participants the feeding group was not allocated randomly

Jarvenpaa 1983

Reason for exclusion

Jarvenpaa 1983 compared growth in low birth weight infants fed formula versus breast milk. However, the allocation was not random since those infants whose mothers chose to provide their own milk were selectively assigned to the human milk group

Narayanan 1982

Reason for exclusion

Narayanan 1982 reported a block randomised trial in low birth weight infants of feeding with formula milk versus "expressed human milk", the latter being a mixture of preterm and term human milk. The randomised blocked design was followed strictly at first, but in the second year, many of the low birth weight infants were allocated to one of the human milk groups (rather than the formula group). Hence, the data for year 1 are completely random (all 4 groups can be compared and be included in our review), but the data for year 2 (and beyond) were not completely random (and should not be included). The authors reported that the results in the random and "non-random" phases were similar and therefore presented the combined results. The authors have been contacted to see if the results for year 1 are available separately

O'Connor 2003

Reason for exclusion

O'Connor 2003 compared growth, feeding tolerance, morbidity and development in 463 low birth weight infants fed human milk or formula. However, the feeding groups were not randomly allocated

Putet 1984

Reason for exclusion

Although not clearly stated in the title or abstract, feeds do not appear to have been randomly assigned

Sullivan 2010

Reason for exclusion

Randomised controlled trial

207 infants with birth weight 500 g to 1250 g, with intention to receive mother's milk, and ability to adhere to feeding protocol (based on use of mother's own milk, initiation of enteral feeding before 21 days after birth, and initiation of parenteral nutrition within 48 hours of birth)
Recruited from 12 neonatal intensive care units (11 in the US and 1 in Austria)

All infants received their mother's own milk and 1 of 3 fortifiers, which was supplemented, if necessary, with either formula or donor breast milk as follows:

1. Human milk-based fortifier (HMF) started when enteral intake was 40 ml/kg/day and donor breast milk as a supplement to mother's own milk

2. Human milk-based fortifier (HMF) started when enteral intake was 100 ml/kg/day and donor breast milk as a supplement to mother's own milk

3. Bovine milk-based fortifier (BMF) started when enteral intake was 100 ml/kg/day and preterm formula as a supplement to mother's own milk

Svenningsen 1982

Reason for exclusion

Svenningsen 1982 randomly assigned 48 low birth weight infants to formula milk versus breast milk. However, most infants in the breast milk group received their own mother's expressed milk rather than donor breast milk

Characteristics of ongoing studies

NCT01390753

Study name

'Role of Human Milk Bank in the Protection of Severe Respiratory Disease in Very Low Birth Weight Premature Infants'

Methods

Randomised controlled trial

Participants

Very low birth weight infants (sample size not stated)

Interventions

Donor breast milk and preterm formula versus preterm formula alone

Outcomes

Incidence of respiratory infections in infancy

Starting date

2011

Contact information

Fernando Pedro Polack: malinez@infant.org.ar

Notes

NCT01534481

Study name

'Donor Milk vs. Formula in Extremely Low Birth Weight (ELBW) Infants (The MILK trial)'

Methods

Randomised controlled trial

Participants

670 ELBW infants

Interventions

Donor breast milk (provided by the Human Milk Banking Association of North America) versus preterm formula

Outcomes

Primary: Bayley Scales of Infant Development III (BSID III) at 22 to 26 months post-term

Starting date

2012 (estimated completion 2018)

Contact information

Tarah Colaizy: tarah-colaizy@uiowa.edu

Notes

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) - sponsored in 17 centres, USA

NCT01686477

Study name

'PREterM FOrmula Or Donor Breast Milk for Premature Babies (PREMFOOD)'

Methods

Randomised controlled trial (3 arms)

Participants

66 very preterm infants

Interventions

Donor breast milk or donor breast milk with fortifier or preterm formula

Outcomes

Primary: total body adiposity measured by MRI at "term equivalent"

Starting date

2012

Contact information

Luke Mills: l.mills@imperial.ac.uk

Notes it really

Footnotes

ELBW: extremely low birth weight

Additional tables

  • None noted

References to studies

Included studies

Cristofalo 2013

Cristofalo EA, Schanler RJ, Blanco CL, Sullivan S, Trawoeger R, Kiechl-Kohlendorfer U, et al. Randomized trial of exclusive human milk versus preterm formula diets in extremely premature infants. The Journal of Pediatrics 2013;163:1592-1595.e1. [PubMed: 23968744]

Davies 1977

Davies DP. Adequacy of expressed breast milk for early growth of preterm infants. Archives of Disease in Childhood 1977;52(4):296-301.

Gross 1983

Gross SJ. Growth and biochemical response of preterm infants fed human milk or modified infant formula. New England Journal of Medicine 1983;308(5):237-41.

Lucas 1984a

Lucas A, Cole TJ. Breast milk and neonatal necrotising enterocolitis. Lancet 1990;336(8730):1519-23.

* 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(8):722-30.

Lucas A, Morley R, Cole TJ, Gore SM, Davis JA, Bamford MF, et al. Early diet in preterm babies and developmental status in infancy. Archives of Disease in Childhood 1989;64(11):1570-8.

Lucas A, Morley R, Cole TJ, Gore SM. A randomised multicentre study of human milk versus formula and later development in preterm infants. Archives of Disease in Childhood. Fetal and Neonatal Edition 1994;70(2):F141-6.

Morley R, Lucas A. Randomized diet in the neonatal period and growth performance until 7.5-8 y of age in preterm children. American Journal of Clinical Nutrition 2000;71(3):822-8.

Lucas 1984b

Lucas A, Cole TJ. Breast milk and neonatal necrotising enterocolitis. Lancet 1990;336(8730):1519-23.

* 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 A, Morley R, Cole TJ, Gore SM, Davis JA, Bamford MF, et al. Early diet in preterm babies and developmental status in infancy. Archives of Disease in Childhood 1989;64:1570-8.

Lucas A, Morley R, Cole TJ, Gore SM. A randomised multicentre study of human milk versus formula and later development in preterm infants. Archives of Disease in Childhood 1994;70:F141-6.

Morley R, Lucas A. Randomized diet in the neonatal period and growth performance until 7.5-8 y of age in preterm children. American Journal of Clinical Nutrition 2000;71:822-8.

Raiha 1976

Gaull GE, Rassin DK, Raiha NC, Heinonen K. Milk protein quantity and quality in low-birth-weight infants. III. Effects on sulfur amino acids in plasma and urine. Journal of Pediatrics 1977;90(3):348-55.

* Raiha NC, Heinonen K, Rassin DK, Gaull GE. Milk protein quantity and quality in low-birthweight infants: I. Metabolic responses and effects on growth. Pediatrics 1976;57(5):659-84.

Rassin DK, Gaull GE, Heinonen K, Raiha NC. Milk protein quantity and quality in low-birth-weight infants: II. Effects on selected aliphatic amino acids in plasma and urine. Pediatrics 1977;59(3):407-22.

Rassin DK, Gaull GE, Raiha NC, Heinonen K. Milk protein quantity and quality in low-birth-weight infants. IV. Effects on tyrosine and phenylalanine in plasma and urine. Journal of Pediatrics 1977;90(3):356-60.

Schanler 2005

Schanler RJ, Lau C, Hurst NM, Smith EO. Randomized trial of donor human milk versus preterm formula as substitutes for mothers' own milk in the feeding of extremely premature infants. Pediatrics 2005;116(2):400-6.

Schultz 1980

Schultz K, Soltesz G, Mestyan J. The metabolic consequences of human milk and formula feeding in premature infants. Acta Paediatrica Scandinavica 1980;69(5):647-52.

Tyson 1983

Tyson JE, Lasky RE, Mize CE, Richards CJ, Blair-Smith N, Whyte R, et al. Growth, metabolic response, and development in very-low-birth-weight infants fed banked human milk or enriched formula. I. Neonatal findings. Journal of Pediatrics 1983;103(1):95-104.

Excluded studies

Cooper 1984

Cooper PA, Rothberg AD, Pettifor JM, Bolton KD, Devenhuis S. Growth and biochemical response of premature infants fed pooled preterm milk or special formula. Journal of Pediatric Gastroenterology and Nutrition 1984;3(5):749-54.

Jarvenpaa 1983

Jarvenpaa AL, Raiha NC, Rassin DK, Gaull GE. Feeding the low-birth-weight infant: I. Taurine and cholesterol supplementation of formula does not affect growth and metabolism. Pediatrics 1983;71(2):171-8.

Narayanan 1982

Narayanan I, Prakash K, Gujral VV. The value of human milk in the prevention of infection in the high-risk low-birth-weight infant. Journal of Pediatrics 1981;99(3):496-8.

* Narayanan I, Prakash K, Prabhakar AK, Gujral VV. A planned prospective evaluation of the anti-infective property of varying quantities of expressed human milk. Acta Paediatrica Scandinavica 1982;71(3):441-5.

O'Connor 2003

O'Connor DL, Jacobs J, Hall R, Adamkin D, Auestad N, Castillo M, et al. Growth and development of premature infants fed predominantly human milk, predominantly premature infant formula, or a combination of human milk and premature formula. Journal of Pediatric Gastroenterology and Nutrition 2003;37(4):437-46.

Putet 1984

Putet G, Senterre J, Rigo J, Salle B. Nutrient balance, energy utilization, and composition of weight gain in very-low-birth-weight infants fed pooled human milk or a preterm formula. Journal of Pediatrics 1984;105(1):79-85.

Sullivan 2010

* Sullivan S, Schanler RJ, Kim JH, Patel AL, Trawoger R, Kiechl-Kohlendorfer U, et al. An exclusively human milk-based diet is associated with a lower rate of necrotizing enterocolitis than a diet of human milk and bovine milk-based products. Journal of Pediatrics 2010;156(4):562-7.

Svenningsen 1982

Svenningsen NW, Lindroth M, Lindquist B. Growth in relation to protein intake of low birth weight infants. Early Human Development 1982;6(1):47-58.

Studies awaiting classification

  • None noted

Ongoing studies

NCT01390753

[ClinicalTrials.gov: Role of Human Milk Bank in the Protection of Severe Respiratory Disease in Very Low Birth Weight Premature Infants]

NCT01534481

[ClinicalTrials.gov: Donor Milk vs. Formula in Extremely Low Birth Weight (ELBW) Infants]

NCT01686477

[ClinicalTrials.gov: PREterM FOrmula Or Donor Breast Milk for Premature Babies]

Other references

Additional references

Agostoni 2010

Agostoni C, Buonocore G, Carnielli VP, De Curtis M, Darmaun D, Decsi T et al. Enteral nutrient supply for preterm infants: commentary from the European Society of Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition. Journal of Pediatric Gastroenterology and Nutrition 2010;50(1):85-91. [PubMed: 19881390]

Amiel-Tison 1986

Amiel-Tison C, Grenier A. Neurological Assessment During the First Year of Life. Oxford: Oxford University Press, 1986.

Beeby 1992

Beeby PJ, Jeffrey H. Risk factors for necrotising enterocolitis: the influence of gestational age. Archives of Disease in Childhood 1992;67(4 Spec No):432-5.

Fewtrell 1999

Fewtrell M, Lucas A. Nutritional physiology: dietary requirements of term and preterm infants. In: Rennie JM, Roberton NRC, editor(s). Textbook of Neonatology. 3rd edition. Edinburgh: Churchill Livingstone, 1999:305-25.

Gross 1980

Gross SJ, David RJ, Bauman L, Tomarelli RM. Nutritional composition of milk produced by mothers delivering preterm. Journal of Pediatrics 1980;96:641-4.

Gross 1981

Gross SJ, Buckley RH, Wakil SS, McAllister DC, David RJ, Faix RG. Elevated IgA concentration in milk produced by mothers delivered of preterm infants. Journal of Pediatrics 1981;99(3):389-93.

Hay 1994

Hay WW Jr. Nutritional requirements of extremely low birthweight infants. Acta Paediatrica. Supplement 1994;402:94-9.

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. Available from www.cochrane-handbook.org.

Isaacs 2009

Isaacs EB, Morley R, Lucas A. Early diet and general cognitive outcome at adolescence in children born at or below 30 weeks gestation. Journal of Pediatrics 2009;155(2):229-34. [PubMed: 19446846]

Klingenberg 2012

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 2012;97(1):F56-61. [PubMed: 21856644]

Lucas 1978

Lucas A, Gibbs JA, Baum JD. The biology of drip breast milk. Early Human Development 1978;2(4):351-61.

Lucas 1990

Lucas A, Cole TJ. Breast milk and neonatal necrotising enterocolitis. Lancet 1990;336(8730):1519-23.

Schanler 1995

Schanler RJ. Suitability of human milk for the low-birthweight infant. Clinics in Perinatology 1995;22(1):207-22.

Tsang 1993

Tsang RC, Lucas A, Uauy R, Zlotkin S. Nutritional Needs of the Newborn Infant: Scientific Basis and Practical Guidelines. Pawling, New York: Caduceus Medical Publishers, 1993.

Wight 2001

Wight NE. Donor human milk for preterm infants. Journal of Perinatology 2001;21(4):249-54.

Other published versions of this review

Henderson 2004

Henderson G, Anthony MY, McGuire W. Formula milk versus term human milk for feeding preterm or low birth weight infants. Cochrane Database of Systematic Reviews 2004, Issue 1. Art. No.: CD002971. DOI: 10.1002/14651858.CD002971.

McGuire 2001a

McGuire W, Anthony MY. Formula milk versus term human milk for feeding preterm or low birth weight infants. Cochrane Database of Systematic Reviews 2001, Issue 4. Art. No.: CD002971. DOI: 10.1002/14651858.CD002971.

Quigley 2007

Quigley MA, Henderson G, Anthony MY, McGuire W. Formula milk versus donor breast milk for feeding preterm or low birth weight infants. Cochrane Database of Systematic Reviews 2007, Issue 4. Art. No.: CD002971. DOI: 10.1002/14651858.CD002971.

Classification pending references

  • None noted

[top]

Data and analyses

1 Formula (term or preterm) versus donor breast milk

For graphical representations of the data/results in this table, please use link under "Outcome or Subgroup."

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
1.1 Time to regain birth weight (days from birth) 2 166 Mean Difference (IV, Fixed, 95% CI) -4.00 [-5.81, -2.18]
1.2 Short term weight change (g/kg/day) 8 702 Mean Difference (IV, Fixed, 95% CI) 2.58 [1.98, 3.17]
  1.2.1 Term formula 3 234 Mean Difference (IV, Fixed, 95% CI) 1.74 [0.96, 2.53]
  1.2.2 Preterm formula 5 468 Mean Difference (IV, Fixed, 95% CI) 3.71 [2.79, 4.63]
1.3 Short-term change in crown-heel length (mm/week) 7 494 Mean Difference (IV, Fixed, 95% CI) 1.36 [0.87, 1.85]
  1.3.1 Term formula 2 128 Mean Difference (IV, Fixed, 95% CI) 0.80 [0.10, 1.50]
  1.3.2 Preterm formula 5 366 Mean Difference (IV, Fixed, 95% CI) 1.93 [1.23, 2.62]
1.4 Short-term change in crown-rump length (mm/week) 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
1.5 Short-term change in femoral length (mm/week) 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
1.6 Short-term change in head circumference (mm/week) 7 568 Mean Difference (IV, Fixed, 95% CI) 1.21 [0.75, 1.67]
  1.6.1 Term formula 2 128 Mean Difference (IV, Fixed, 95% CI) 0.81 [0.15, 1.47]
  1.6.2 Preterm formula 5 440 Mean Difference (IV, Fixed, 95% CI) 1.59 [0.95, 2.24]
1.7 Weight (kg) at 9 months post-term 2 369 Mean Difference (IV, Fixed, 95% CI) -0.03 [-0.26, 0.21]
1.8 Length (cm) at 9 months post-term 2 369 Mean Difference (IV, Fixed, 95% CI) 0.03 [-0.64, 0.70]
1.9 Head circumference (cm) at 9 months post-term 2 369 Mean Difference (IV, Fixed, 95% CI) 0.20 [-0.13, 0.53]
1.10 Weight (kg) at 18 months post-term 2 438 Mean Difference (IV, Fixed, 95% CI) 0.10 [-0.15, 0.35]
1.11 Length (cm) at 18 months post-term 2 438 Mean Difference (IV, Fixed, 95% CI) 0.53 [-0.15, 1.20]
1.12 Head circumference (cm) at 18 months post-term 2 438 Mean Difference (IV, Fixed, 95% CI) 0.10 [-0.19, 0.39]
1.13 Weight (kg) at 7.5 to 8 years of age 2 420 Mean Difference (IV, Fixed, 95% CI) -0.56 [-1.42, 0.29]
1.14 Length (cm) at 7.5 to 8 years of age 2 420 Mean Difference (IV, Fixed, 95% CI) 0.05 [-1.12, 1.23]
1.15 Head circumference (cm) at 7.5 to 8 years of age 2 420 Mean Difference (IV, Fixed, 95% CI) -0.19 [-0.54, 0.16]
1.16 Bayley Mental Development Index at 18 months 2 387 Mean Difference (IV, Fixed, 95% CI) 1.24 [-2.62, 5.09]
1.17 Bayley Psychomotor Development Index at 18 months 2 387 Mean Difference (IV, Fixed, 95% CI) -0.32 [-3.43, 2.79]
1.18 Neurological impairment at 18 months 2 400 Risk Ratio (M-H, Fixed, 95% CI) 1.21 [0.62, 2.35]
1.19 All-cause mortality 4 721 Risk Ratio (M-H, Fixed, 95% CI) 1.33 [0.79, 2.25]
1.20 Necrotising enterocolitis 6 869 Risk Ratio (M-H, Fixed, 95% CI) 2.77 [1.40, 5.46]
  1.20.1 Term formula 1 67 Risk Ratio (M-H, Fixed, 95% CI) 4.73 [0.52, 43.09]
  1.20.2 Preterm formula 5 802 Risk Ratio (M-H, Fixed, 95% CI) 2.61 [1.27, 5.35]
1.21 Days after birth to establish full enteral feeding 1 53 Mean Difference (IV, Fixed, 95% CI) 4.70 [-2.56, 11.96]
1.22 Feeding intolerance or diarrhoea 2 148 Risk Difference (M-H, Fixed, 95% CI) 0.10 [0.01, 0.19]
  1.22.1 Term formula 1 67 Risk Difference (M-H, Fixed, 95% CI) 0.21 [0.04, 0.38]
  1.22.2 Preterm formula 1 81 Risk Difference (M-H, Fixed, 95% CI) 0.02 [-0.06, 0.10]
1.23 Incidence of invasive infection 2 219 Risk Ratio (M-H, Fixed, 95% CI) 1.12 [0.84, 1.49]

2 Subgroup analysis: Formula (preterm) versus donor breast milk given as (i) sole diet or (ii) a supplement to maternal expressed breast milk

For graphical representations of the data/results in this table, please use link under "Outcome or Subgroup."

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
2.1 Short-term weight change (g/kg/day) 8 Mean Difference (IV, Fixed, 95% CI) Subtotals only
  2.1.1 Sole diet 6 421 Mean Difference (IV, Fixed, 95% CI) 2.65 [1.94, 3.36]
  2.1.2 Supplement 2 281 Mean Difference (IV, Fixed, 95% CI) 2.39 [1.28, 3.50]
2.2 Short-term change in crown-heel length (mm/week) 7 Mean Difference (IV, Fixed, 95% CI) Subtotals only
  2.2.1 Sole diet 5 283 Mean Difference (IV, Fixed, 95% CI) 1.54 [0.98, 2.11]
  2.2.2 Supplement 2 211 Mean Difference (IV, Fixed, 95% CI) 0.75 [-0.28, 1.78]
2.3 Short-term change in head circumference (mm/week) 7 Mean Difference (IV, Fixed, 95% CI) Subtotals only
  2.3.1 Sole diet 5 305 Mean Difference (IV, Fixed, 95% CI) 1.36 [0.85, 1.88]
  2.3.2 Supplement 2 263 Mean Difference (IV, Fixed, 95% CI) 0.59 [-0.44, 1.62]
2.4 Weight (kg) at 9 months post-term 2 Mean Difference (IV, Fixed, 95% CI) Subtotals only
  2.4.1 Sole diet 1 110 Mean Difference (IV, Fixed, 95% CI) 0.20 [-0.27, 0.67]
  2.4.2 Supplement 1 259 Mean Difference (IV, Fixed, 95% CI) -0.10 [-0.37, 0.17]
2.5 Length (cm) at 9 months post-term 2 Mean Difference (IV, Fixed, 95% CI) Subtotals only
  2.5.1 Sole diet 1 110 Mean Difference (IV, Fixed, 95% CI) 0.40 [-0.93, 1.73]
  2.5.2 Supplement 1 259 Mean Difference (IV, Fixed, 95% CI) -0.10 [-0.88, 0.68]
2.6 Head circumference (cm) at 9 months post-term 2 Mean Difference (IV, Fixed, 95% CI) Subtotals only
  2.6.1 Sole diet 1 110 Mean Difference (IV, Fixed, 95% CI) 0.20 [-0.45, 0.85]
  2.6.2 Supplement 1 259 Mean Difference (IV, Fixed, 95% CI) 0.20 [-0.18, 0.58]
2.7 Weight (kg) at 18 months post-term 2 Mean Difference (IV, Fixed, 95% CI) Subtotals only
  2.7.1 Sole diet 1 136 Mean Difference (IV, Fixed, 95% CI) 0.10 [-0.37, 0.57]
  2.7.2 Supplement 1 302 Mean Difference (IV, Fixed, 95% CI) 0.10 [-0.19, 0.39]
2.8 Length (cm) at 18 months post-term 2 Mean Difference (IV, Fixed, 95% CI) Subtotals only
  2.8.1 Sole diet 1 136 Mean Difference (IV, Fixed, 95% CI) 0.60 [-0.68, 1.88]
  2.8.2 Supplement 1 302 Mean Difference (IV, Fixed, 95% CI) 0.50 [-0.29, 1.29]
2.9 Head circumference (cm) at 18 months post-term 2 Mean Difference (IV, Fixed, 95% CI) Subtotals only
  2.9.1 Sole diet 1 136 Mean Difference (IV, Fixed, 95% CI) 0.10 [-0.44, 0.64]
  2.9.2 Supplement 1 302 Mean Difference (IV, Fixed, 95% CI) 0.10 [-0.25, 0.45]
2.10 Weight (kg) at 7.5 to 8 years of age 2 Mean Difference (IV, Fixed, 95% CI) Subtotals only
  2.10.1 Sole diet 1 130 Mean Difference (IV, Fixed, 95% CI) 0.50 [-1.24, 2.24]
  2.10.2 Supplement 1 290 Mean Difference (IV, Fixed, 95% CI) -0.90 [-1.88, 0.08]
2.11 Length (cm) at 7.5 to 8 years of age 2 420 Mean Difference (IV, Fixed, 95% CI) 0.05 [-1.12, 1.23]
  2.11.1 Sole diet 1 130 Mean Difference (IV, Fixed, 95% CI) 1.00 [-1.26, 3.26]
  2.11.2 Supplement 1 290 Mean Difference (IV, Fixed, 95% CI) -0.30 [-1.68, 1.08]
2.12 Head circumference (cm) at 7.5 to 8 years of age 2 420 Mean Difference (IV, Fixed, 95% CI) -0.19 [-0.54, 0.16]
  2.12.1 Sole diet 1 130 Mean Difference (IV, Fixed, 95% CI) 0.10 [-0.56, 0.76]
  2.12.2 Supplement 1 290 Mean Difference (IV, Fixed, 95% CI) -0.30 [-0.71, 0.11]
2.13 Bayley Mental Development Index at 18 months 2 Mean Difference (IV, Fixed, 95% CI) Subtotals only
  2.13.1 Sole diet 1 114 Mean Difference (IV, Fixed, 95% CI) 0.50 [-6.21, 7.21]
  2.13.2 Supplement 1 273 Mean Difference (IV, Fixed, 95% CI) 1.60 [-3.11, 6.31]
2.14 Bayley Psychomotor Development Index at 18 months 2 Mean Difference (IV, Fixed, 95% CI) Subtotals only
  2.14.1 Sole diet 1 114 Mean Difference (IV, Fixed, 95% CI) 1.20 [-4.38, 6.78]
  2.14.2 Supplement 1 273 Mean Difference (IV, Fixed, 95% CI) -1.00 [-4.74, 2.74]
2.15 Neurological impairment at 18 months 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
  2.15.1 Sole diet 1 122 Risk Ratio (M-H, Fixed, 95% CI) 2.06 [0.64, 6.68]
  2.15.2 Supplement 1 278 Risk Ratio (M-H, Fixed, 95% CI) 0.92 [0.40, 2.10]
2.16 All-cause mortality 4 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
  2.16.1 Sole diet 2 212 Risk Ratio (M-H, Fixed, 95% CI) 1.70 [0.71, 4.07]
  2.16.2 Supplement 2 509 Risk Ratio (M-H, Fixed, 95% CI) 1.16 [0.60, 2.24]
2.17 Necrotising enterocolitis 6 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
  2.17.1 Sole diet 4 360 Risk Ratio (M-H, Fixed, 95% CI) 4.62 [1.47, 14.56]
  2.17.2 Supplement 2 509 Risk Ratio (M-H, Fixed, 95% CI) 1.96 [0.82, 4.67]
2.18 Feeding intolerance or diarrhoea 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
  2.18.1 Sole diet 2 148 Risk Ratio (M-H, Fixed, 95% CI) 4.92 [1.17, 20.70]
2.19 Incidence of invasive infection 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
  2.19.1 Sole diet 1 53 Risk Ratio (M-H, Fixed, 95% CI) 1.43 [0.97, 2.11]
  2.19.2 Supplement 1 166 Risk Ratio (M-H, Fixed, 95% CI) 0.97 [0.66, 1.44]

3 Subgroup analysis: Formula (preterm) versus donor breast milk given (i) unfortified or (ii) fortified

For graphical representations of the data/results in this table, please use link under "Outcome or Subgroup."

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
3.1 Short-term weight change (g/kg/day) 8 Mean Difference (IV, Fixed, 95% CI) Subtotals only
  3.1.1 Unfortified donor breast milk 6 483 Mean Difference (IV, Fixed, 95% CI) 2.54 [1.89, 3.19]
  3.1.2 Fortified donor breast milk 2 219 Mean Difference (IV, Fixed, 95% CI) 2.80 [1.20, 4.39]
3.2 Short-term change in crown-heel length (mm/week) 7 Mean Difference (IV, Fixed, 95% CI) Subtotals only
  3.2.1 Unfortified donor breast milk 5 275 Mean Difference (IV, Fixed, 95% CI) 1.26 [0.72, 1.80]
  3.2.2 Fortified donor breast milk 2 219 Mean Difference (IV, Fixed, 95% CI) 1.86 [0.64, 3.07]
3.3 Short-term change in head circumference (mm/week) 7 Mean Difference (IV, Fixed, 95% CI) Subtotals only
  3.3.1 Unfortified donor breast milk 5 349 Mean Difference (IV, Fixed, 95% CI) 1.29 [0.79, 1.80]
  3.3.2 Fortified donor breast milk 2 219 Mean Difference (IV, Fixed, 95% CI) 0.83 [-0.25, 1.91]
3.4 Weight (kg) at 9 months post-term 2 Mean Difference (IV, Fixed, 95% CI) Subtotals only
  3.4.1 Unfortified donor breast milk 2 369 Mean Difference (IV, Fixed, 95% CI) -0.03 [-0.26, 0.21]
3.5 Length (cm) at 9 months post-term 2 Mean Difference (IV, Fixed, 95% CI) Subtotals only
  3.5.1 Unfortified donor breast milk 2 369 Mean Difference (IV, Fixed, 95% CI) 0.03 [-0.64, 0.70]
3.6 Head circumference (cm) at 9 months post-term 2 Mean Difference (IV, Fixed, 95% CI) Subtotals only
  3.6.1 Unfortified donor breast milk 2 369 Mean Difference (IV, Fixed, 95% CI) 0.20 [-0.13, 0.53]
3.7 Weight (kg) at 18 months post-term 2 Mean Difference (IV, Fixed, 95% CI) Subtotals only
  3.7.1 Unfortified donor breast milk 2 438 Mean Difference (IV, Fixed, 95% CI) 0.10 [-0.15, 0.35]
3.8 Length (cm) at 18 months post-term 2 Mean Difference (IV, Fixed, 95% CI) Subtotals only
  3.8.1 Unfortified donor breast milk 2 438 Mean Difference (IV, Fixed, 95% CI) 0.53 [-0.15, 1.20]
3.9 Head circumference (cm) at 18 months post-term 2 Mean Difference (IV, Fixed, 95% CI) Subtotals only
  3.9.1 Unfortified donor breast milk 2 438 Mean Difference (IV, Fixed, 95% CI) 0.10 [-0.19, 0.39]
3.10 Weight (kg) at 7.5 to 8 years of age 2 Mean Difference (IV, Fixed, 95% CI) Subtotals only
  3.10.1 Unfortified donor breast milk 2 420 Mean Difference (IV, Fixed, 95% CI) -0.56 [-1.42, 0.29]
3.11 Length (cm) at 7.5 to 8 years of age 2 Mean Difference (IV, Fixed, 95% CI) Subtotals only
  3.11.1 Unfortified donor breast milk 2 420 Mean Difference (IV, Fixed, 95% CI) 0.05 [-1.12, 1.23]
3.12 Head circumference (cm) at 7.5 to 8 years of age 2 Mean Difference (IV, Fixed, 95% CI) Subtotals only
  3.12.1 Unfortified donor breast milk 2 420 Mean Difference (IV, Fixed, 95% CI) -0.19 [-0.54, 0.16]
3.13 Bayley Mental Development Index at 18 months 2 Mean Difference (IV, Fixed, 95% CI) Subtotals only
  3.13.1 Unfortified donor breast milk 2 387 Mean Difference (IV, Fixed, 95% CI) 1.24 [-2.62, 5.09]
3.14 Bayley Psychomotor Development Index at 18 months 2 Mean Difference (IV, Fixed, 95% CI) Subtotals only
  3.14.1 Unfortified donor breast milk 2 387 Mean Difference (IV, Fixed, 95% CI) -0.32 [-3.43, 2.79]
3.15 Neurological impairment at 18 months 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
  3.15.1 Unfortified donor breast milk 2 400 Risk Ratio (M-H, Fixed, 95% CI) 1.21 [0.62, 2.35]
3.16 All-cause mortality 4 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
  3.16.1 Unfortified donor breast milk 2 502 Risk Ratio (M-H, Fixed, 95% CI) 1.29 [0.73, 2.29]
  3.16.2 Fortified donor breast milk 2 219 Risk Ratio (M-H, Fixed, 95% CI) 1.53 [0.42, 5.51]
3.17 Necrotising enterocolitis 6 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
  3.17.1 Unfortified donor breast milk 4 650 Risk Ratio (M-H, Fixed, 95% CI) 3.30 [1.16, 9.41]
  3.17.2 Fortified donor breast milk 2 219 Risk Ratio (M-H, Fixed, 95% CI) 2.40 [0.98, 5.87]
3.18 Feeding intolerance or diarrhoea 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
  3.18.1 Unfortified donor breast milk 2 148 Risk Ratio (M-H, Fixed, 95% CI) 4.92 [1.17, 20.70]
3.19 Incidence of invasive infection 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
  3.19.1 Fortified donor breast milk 2 219 Risk Ratio (M-H, Fixed, 95% CI) 1.12 [0.84, 1.49]

Figures

Figure 1

Refer to figure 1 caption below.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies (Figure 1 description).

Figure 2 (Analysis 1.1)

Refer to figure 2 caption below.

Forest plot of comparison: 1 Formula (term or preterm) versus donor breast milk, outcome: 1.1 Time to regain birth weight (days from birth) (Figure 2 description)..

Figure 3 (Analysis 1.2)

Refer to figure 3 caption below.

Forest plot of comparison: 1 Formula (term or preterm) versus donor breast milk, outcome: 1.2 Short-term weight change (g/kg/day) (Figure 3 description)..

Figure 4 (Analysis 1.3)

Refer to figure 4 caption below.

Forest plot of comparison: 1 Formula (term or preterm) versus donor breast milk, outcome: 1.3 Short-term change in crown-heel length (mm/week) (Figure 4 description)..

Figure 5 (Analysis 1.6)

Refer to figure 5 caption below.

Forest plot of comparison: 1 Formula (term or preterm) versus donor breast milk, outcome: 1.6 Short-term change in head circumference (mm/week) (Figure 5 description)..

Figure 6 (Analysis 1.20)

Refer to figure 6 caption below.

Forest plot of comparison: 1 Formula (term or preterm) versus donor breast milk, outcome: 1.20 Necrotising enterocolitis (Figure 6 description)..

Sources of support

Internal sources

  • National Perinatal Epidemiology Unit, UK
  • Centre for Reviews and Dissemination, University of York, UK

External sources

  • National Institute for Health Research, UK
  • Tenovus, Scotland, UK
  • 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 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.
  • Department of Health, UK

This review is published as a Cochrane review in The Cochrane Library, Issue 4, 2014 (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 version of the review.