Description of the condition
Most preterm infants accumulate energy, protein, mineral, and other nutrient deficits by the time of discharge from hospital (Embleton 2001). At this stage, many preterm infants, especially those born with extremely low birth weight, are substantially growth restricted (Lucas 1984; Clark 2003). Following hospital discharge, demand-fed preterm infants consume greater volumes of milk than term infants of the same postmenstrual age in order to attain some "catch up" growth (Lucas 1992). Despite this, growth deficits can persist through infancy and beyond (Morley 2000; Ford 2000; Euser 2008). Slow postnatal growth in preterm infants is associated with neurodevelopmental impairment in later childhood and with poorer cognitive and educational outcomes (Hack 1991; Cooke 2003). Preterm infants who have accumulated deficits in calcium and phosphate by the time of hospital discharge have a higher risk of low bone mineralisation, metabolic bone disease, and slow skeletal growth compared with infants born at term (Rigo 2000). Furthermore, concern exists that nutritional deficiency and growth restriction in utero and during early infancy may have consequences for long-term metabolic and cardiovascular health (Barker 2002; Huxley 2002).
Description of the intervention
Although human milk is the recommended nutritional source for newborn infants for at least the first six months of postnatal life (WHO 2001), unfortified human breast milk may not meet the recommended nutritional needs of growing preterm infants (Tsang 1993; Greer 2007). Feeding preterm infants prior to hospital discharge with expressed human breast milk fortified with energy, protein, and minerals is associated with short-term increases in rates of weight gain and linear and head growth (Kuschel 2004a). Multinutrient breast milk fortifiers contain various amounts of protein, carbohydrate, minerals, and vitamins. These liquid or powder formulations are mixed with expressed breast milk for delivery with the aim of achieving about 5% to 10% nutrient enrichment (Simmer 2000). However, standard clinical practice has been to cease multinutrient fortification during the period prior to hospital discharge when breast feeding is being established since, following hospital discharge, human milk-fed preterm infants usually obtain most of their milk directly from the breast.
It is feasible to continue nutritional supplementation for human milk-fed preterm infants in the post hospital discharge period of early infancy. Multinutrient fortification may be more practical for infants who are fed expressed breast milk (rather than directly from the breast) and may be especially important for infants who receive donated expressed breast milk which may contain lower levels of energy, protein and minerals than maternal expressed breast milk (Gross 1980). Mothers who feed their infants directly from the breast may also express breast milk and give at least some fortified feeds via a bottle, cup, or feeding tube. However, concern exists that this "medicalisation" of infant feeding might alter the maternal perception that breast milk is the preferred nutrition for her infant and interfere with the continuation of exclusive breast milk feeding.
Another putative disadvantage of multinutrient fortification of breast milk is that increasing the nutrient density and osmolarity of breast milk might interfere with gastric emptying and intestinal peristalsis, resulting in feed intolerance, vomiting or diarrhoea. Observational studies have provided conflicting evidence on these potential adverse effects (Ewer 1996; McClure 1996). The Cochrane review of multinutrient fortification of human milk for preterm infants prior to hospital discharge did not find any evidence of a higher incidence of gastrointestinal adverse effects in infants who received fortified milk (Kuschel 2004a). There is also concern that excessive protein supplementation may cause metabolic stresses resulting in acidosis or elevated blood urea levels. However, the Cochrane reviews of multinutrient fortification and of protein supplementation of human milk for preterm infants prior to hospital discharge did not find evidence that blood urea rose to levels outwith normal reference ranges (Kuschel 2004a; Kuschel 2004b). Finally, concern exists that rapid catch-up growth during early infancy may have metabolic programming effects that increase the long-term risk of overweight and obesity, insulin resistance, diabetes, hypertension, and cardiovascular and cerebrovascular disease (Singhal 2003; Singhal 2004; Singhal 2007).
How the intervention might work
In theory, feeding preterm infants following hospital discharge with milk enriched with extra energy, protein, minerals and vitamins may be expected to promote more rapid catch-up growth. Higher levels of nutritional input during this period may be especially important for infants who are not able to consume ad libitum quantities of milk directly from the breast, who have slow growth, or who have on-going additional nutritional and metabolic requirements, for example, due to chronic lung disease (Cooke 2000; Griffin 2002; McLeod 2011). However, if preterm infants are fed in response to hunger and satiation cues (ad libitum or demand), they may adjust their volume of intake depending upon the energy-density of the milk and so consume less nutrient-fortified milk than if fed with unfortified breast milk. Consequently, infants fed ad libitum with nutrient-fortified milk may not receive any more nutrients than infants who receive unfortified breast milk.
Furthermore, concern exists that catch-up growth with accelerated weight gain and crossing of body mass index (BMI) percentiles might be associated with altered fat distribution and related ‘programmed’ metabolic consequences that may increase the risk of insulin resistance and cardiovascular disease (Euser 2005; Euser 2008). However, any effects of nutritional interventions in early infancy on long-term health consequences are likely to be much smaller than those of other environmental or genetic factors (Greer 2007).
Why it is important to do this review
Uncertainty exists about the balance between the putative benefits and harms of multinutrient fortification of breast milk for preterm infants following hospital discharge. Since this intervention has the potential to affect several major outcomes, an attempt to detect, appraise, and synthesise evidence from randomised controlled trials is needed.
To determine the effect of feeding with multinutrient fortified human breast milk versus unfortified breast milk on growth and development in preterm infants following hospital discharge.
Criteria for considering studies for this review
Types of studies
Controlled trials using random or quasi-random patient allocation. Studies published only as abstracts were eligible for inclusion provided assessment of study quality was possible and other criteria for inclusion fulfilled.
Types of participants
Preterm infants (< 37 weeks' gestation at birth) and low birth weight infants (< 2.5 kg) receiving human breast milk following discharge from hospital.
Types of interventions
Supplementation of human breast milk with more than one nutrient (protein, fat, carbohydrate, or minerals [calcium and/or phosphate]), versus feeding with unsupplemented human milk. Supplementation with electrolytes, iron, vitamins, or trace minerals in addition to only one of the above nutrients was not classified as multinutrient fortification for the purposes of this review. Restrictions to the pre-discharge feeding regimens were not prespecified. The intervention could have begun up to one week prior to planned discharge from hospital. Trials that randomly assigned infants to begin the study feed more than one week prior to hospital discharge (and then continued the intervention after hospital discharge) were not included in this review. Eligible studies should have planned to allocate the trial intervention for a sufficient period (at least two weeks) to allow measurable effects on growth. Infants in the comparison groups within each study should have received similar care other than the level of fortification of breast milk. For example, there should not be any within-study differences in the prescription of target levels of volume of intake, or advice or support for demand feeding.
Types of outcome measures
- Growth: Weight, length, head growth, skinfold thickness, BMI and measures of body composition (lean/fat mass) and growth-restriction (proportion of infants who remain < 10th percentile for the index population's distribution of weight, length, or head circumference).
- Development: (a) Neurodevelopmental outcomes assessed using validated tools at >12 months corrected age, and classifications of disability, including non-ambulant cerebral palsy, developmental delay, auditory and visual impairment, (b) Cognitive and educational outcomes at > five years: Intelligence quotient and/or indices of educational achievement measured using a validated tool (including school examination results).
- Feed intolerance defined as vomiting or diarrhoea that results in the infant requiring treatment for dehydration (for example, oral rehydration solution, or hospital admission, or intravenous rehydration).
- Duration of breast milk-feeding (until infant stops receiving any human breast milk) and proportion of infants receiving any breast milk at end of intervention period.
- Measures of bone mineralisation such as serum alkaline phosphatase level, or bone mineral content assessed by dual energy X-ray absorptiometry and clinical or radiological evidence of rickets on long-term follow-up.
- Clinical or radiological evidence of rickets on long-term follow-up.
- Blood pressure on long-term follow-up.
Search methods for identification of studies
We used the standard search strategy of the Cochrane Neonatal Review Group.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, 2012, Issue 3), MEDLINE (1966 to August 2012), EMBASE (1980 to August 2012), and CINAHL (1982 to August 2012) using a combination of the following text words and MeSH terms: [Infant, Newborn OR Infant, Premature OR Infant, Low Birth Weight OR infan* OR neonat*] AND ["Infant-Nutrition"/ all subheadings OR Milk, Human OR milk OR breast OR Infant Formula OR formula OR post-discharge OR fortif* OR supplement*]. The search outputs were limited with the relevant search filters for clinical trials as recommended in the Cochrane Handbook for Systematic Reviews of Interventions . We did not apply any language restrictions.
Searching other resources
We examined the references in studies identified as potentially relevant. We also searched the abstracts from the annual meetings of the Pediatric Academic Societies (1993 to 2012), the European Society for Pediatric Research (1995 to 2011), the UK Royal College of Paediatrics and Child Health (2000 to 2012), and the Perinatal Society of Australia and New Zealand (2000 to 2012). We considered trials reported only as abstracts to be eligible if sufficient information was available from the report, or from contact with the authors, to fulfil the inclusion criteria.
Data collection and analysis
We used the standard search strategy of the Cochrane Neonatal Review Group.
Selection of studies
Two review authors screened the title and abstract of all studies identified by the above search strategy. We reassessed the full text of any potentially eligible reports and excluded those studies that did not meet all of the inclusion criteria. We discussed any disagreements until consensus was achieved.
Data extraction and management
We used a data collection form to aid extraction of relevant information from each included study. Two review authors extracted the data separately. We discussed any disagreements until consensus was achieved. We asked the investigators for further information if data from the trial reports were insufficient.
Assessment of risk of bias in included studies
We used the criteria and standard methods of the Cochrane Neonatal Review Group to assess the methodological quality of any included trials. Additional information from the trial authors was requested to clarify methodology and results as necessary. We evaluated and reported the following issues in the 'Risk of bias' tables:
- 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);
- 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;
- 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;
- 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: < 20% missing data;
- high risk: > 20% missing data;
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). We calculated the number needed to treat for benefit (NNTB) or harm (NNTH) for a statistically significant difference in the RD.
Unit of analysis issues
The unit of analysis is the participating infant in individually-randomised trials and the neonatal unit (or sub-unit) for cluster-randomised trials.
Assessment of heterogeneity
If more than one trial had been included in a meta-analysis, we planned to examine the treatment effects of individual trials and heterogeneity between trial results by inspecting the forest plots. We calculated the I² statistic for each analysis to quantify inconsistency across studies and describe the percentage of variability in effect estimates that may be due to heterogeneity rather than sampling error. If substantial (I² > 50%) heterogeneity was detected, we explored the possible causes (for example, differences in study design, participants, interventions, or completeness of outcome assessments) in sensitivity analyses.
Assessment of reporting biases
If more than five trials had been included in a meta-analysis, we planned to conduct a funnel plot analysis.
Subgroup analysis and investigation of heterogeneity
We pre-specified the following subgroup analyses:
- very preterm (< 32 weeks) or very low birth weight (VLBW) (< 1500 g) infants;
- infants who were small for gestational age (< 10th percentile for the index population's distribution of weight) at hospital discharge;
- infants with chronic lung disease receiving supplemental oxygen therapy at hospital discharge;
- infants who receive donated expressed breast milk.
Description of studies
We identified two eligible trials involving 246 infants (see 'Characteristics of included studies' table).
- O'Connor 2008: The investigators randomly allocated 39 breast milk-fed preterm infants (< 33 weeks' gestation at birth) who were due to be discharged from hospital to receive multinutrient fortifier mixed with expressed breast milk (about half of their estimated total daily milk intake) or to continue with unfortified human milk feeding for 12 weeks post-discharge. The investigators anticipated that, at discharge, infants in the intervention group would receive about 10% more energy and 20% more protein than the controls. Outcomes assessed were growth and bone mineral content and density up to 12 months corrected age, duration of breast feeding, visual acuity and contrast sensitivity at four and six months corrected age, and Bayley II mental development index (MDI) and psychomotor development index (PDI) scores at 18 months corrected age.
- Zachariassen 2011: The investigators randomly allocated 207 breast feeding preterm infants (< 33 weeks' gestation at birth) "shortly before" hospital discharge to receive multinutrient fortifier (total energy content 17.5 kCal, protein 1.375 g) mixed with 20 mL to 50 mL of expressed breast milk once daily or to continue with unfortified human milk feeding until four months post term. This level of supplementation (for an infant weighing 2.2 kg receiving 180 mL/kg/day) equates to about 6.5% more energy and 20% more protein than controls. Outcomes assessed were growth parameters up to 12 months corrected age and duration of breast feeding.
Risk of bias in included studies
In both trials, allocation generation and concealment were adequate. Blinding of the intervention was not attempted but blinding of some assessments (including developmental assessment) was possible. Both trials achieved near complete follow-up assessment at the end of the intervention period and reported intention-to-treat outcome data (see 'Characteristics of included studies' table).
Effects of interventions
Growth (Outcomes 1.1 to 1.3)
Meta-analyses of data from both trials did not find statistically significant differences in growth parameters at three to four months corrected age. Meta-analyses did not find statistically significant differences in weight or head circumference at 12 months corrected age but infants in the intervention group were borderline statistically significantly longer than control infants; MD 0.88 (95% CI 0.01 to 1.74 cm). All of the meta-analyses contained statistically significant heterogeneity, in each case O'Connor 2008 found a larger (and statistically significant) mean difference than Zachariassen 2011 (Figure 1; Figure 2; Figure 3).
|Figure 1. Forest plot of comparison: 1 Multinutrient fortification vs. no fortification of human breast milk, outcome: 1.1 Weight (g).|
|Figure 2. Forest plot of comparison: 1 Multinutrient fortification vs. no fortification of human breast milk, outcome: 1.2 Head circumference (cm).|
|Figure 3. Forest plot of comparison: 1 Multinutrient fortification vs. no fortification of human breast milk, outcome: 1.3 Length (cm).|
Neurodevelopmental outcomes (Outcomes 1.4 to 1.5)
O'Connor 2008 did not detect any statistically significant differences in Bayley II MDI and PDI scores at 18 months corrected age (27 infants assessed).
- MDI: 100 (1st to 3rd centile; 72 to 102.5) versus 91 (1st to 3rd centile; 77 to 107).
- PDI: 94 (1st to 3rd centile; 90 to 99) versus 94 (1st to 3rd centile; 86 to 103).
O'Connor 2008 reported that visual acuity assessed using sweep visual-evoked potential testing at four months and at six months was statistically significantly higher in the intervention group (Figure 4).The same assessments did not detect statistically significant differences in contract sensitivity (Figure 5).
|Figure 4. Forest plot of comparison: 1 Multinutrient fortification vs. no fortification of human breast milk, outcome: 1.4 Visual acuity (cycles/degree).|
|Figure 5. Forest plot of comparison: 1 Multinutrient fortification vs. no fortification of human breast milk, outcome: 1.5 Contrast sensitivity (log).|
Cognitive and educational outcomes:
Not reported by either trial.
Bone mineralisation (Outcomes 1.6)
O'Connor 2008 reported that bone mineral content was statistically significantly higher in the intervention group at four months (mean difference (MD) 20.60 (95% confidence interval (CI) 6.41 to 34.79 g)) and 12 months (MD 29.80 (95% CI 3.63 to 55.97 g)) (Figure 6). Bone mineral density was not statistically significantly different.
|Figure 6. Forest plot of comparison: 1 Multinutrient fortification vs. no fortification of human breast milk, outcome: 1.6 Bone mineral content (g).|
Not reported by either trial.
Breast milk feeding (Outcomes 1.8 to 1.9)
Neither trial found a statistically significant difference in the duration of breast milk feeding. Meta-analysis was not appropriate since O'Connor 2008 reported this outcome as "post natal weeks" and Zachariassen 2011 reported "post term weeks".
Zachariassen 2011 reported that statistically significantly fewer infants in the intervention group remained exclusively fed with human milk (no formula) at four months: risk ratio (RR) 0.48 (95% CI 0.30 to 0.76) ( Analysis 1.9) (proportion still at least partially fed not reported). O'Connor 2008 did not find a statistically significant difference in the proportion of infants receiving any breast milk at the end of the intervention period.
Clinical or radiological evidence of rickets on long-term follow-up
Not reported by either trial.
Blood pressure on long-term follow-up
Not reported by either trial.
Data were not available for any of the prespecified analyses:
- very low birth weight or very preterm infants: In both trials participants were of gestational age < 33 weeks at birth;
- infants with chronic lung disease requiring home supplemental oxygen therapy: None of the participants received home supplemental oxygen therapy;
- infants who received donated expressed breast milk: none of the participants received donated expressed breast milk.
Summary of main results
Two small randomised controlled trials involving 246 infants did not provide consistent evidence that feeding preterm infants with multinutrient fortified versus unfortified human breast milk for three to four months post-discharge affects growth parameters through infancy (O'Connor 2008; Zachariassen 2011). The identified trials reported very limited data on developmental outcomes and have not yet assessed any longer-term growth or health outcomes.
Overall completeness and applicability of evidence
The meta-analyses of growth outcomes contained substantial statistical heterogeneity and need to be interpreted cautiously. In each case O'Connor 2008 found a larger (and statistically significant) mean difference than Zachariassen 2011. The participants in the trials were similar (< 33 weeks gestation at birth, breast-fed at discharge). The overall target level of multinutrient fortification was also similar. Both trials intended to provide extra energy, protein and minerals such that infants received total levels of nutrient input comparable to infants receiving commercially-available "post-discharge formula" (72 kCal to 74 kCal and about 1.6 to 1.8 g of protein/100 mL, plus proportionate supplements of minerals, vitamins, and trace elements). The trials differed slightly in the mechanics of delivering the multinutrient fortifier. In O'Connor 2008, infants received fortifier in about half of their daily intake of breast milk whereas in Zachariassen 2011 the fortifier was given once daily mixed in 20 mL to 50 mL of milk. In both trials the remaining feeds were either taken directly from the breast or as unfortified expressed breast milk ad libitum.
It is unclear whether the slightly different methods of providing fortifier had different impacts on the infants' responses to the energy density of their feeds, in particular whether infants titrated overall volume of intake differently depending on whether they received fortifier in half their feeds or in a once daily feed. Zachariassen 2011 did not report any data on overall levels of nutrient intake in trial participants. However, O'Connor 2008 reported that the estimated total volume of milk consumed differed between the groups. At the end of the 12 weeks intervention period, infants in the intervention group consumed a mean daily volume of 111 mL/kg compared with 134 mL/kg in the control group. Consequently, the intervention group did not receive substantially different amounts of energy (79 versus 87 kCal/kg/day in the control group) or protein (1.9 versus 1.7 g/kg/day). However, infants in the intervention group received statistically significantly more calcium (11.9 versus 4.7 mmol/kg/day) and phosphorous (8.7 versus 3.8 mmol/kg/day) than control infants. Similarly, intake of vitamin D was higher in the intervention group (567 versus 380 IU/kg/day at 12 weeks).
These differences in mineral and vitamin D intake in O'Connor 2008 are possible explanations for the detection of higher whole body bone mineral content in the intervention group maintained until 12 months post term. Bone density and estimated total and percentage fat mass at 12 months were not statistically significantly different suggesting that a higher rate of skeletal growth may be the most important cause of the differences in weight, length and head circumference between the groups. These findings are consistent with data from observational studies that compared preterm infants fed with unfortified breast milk versus formula milk following hospital discharge. These studies found higher levels of bone mineralisation in the formula-fed group suggesting that breast milk mineral or vitamin content may be rate limiting with regard to skeletal growth during early infancy (Chan 1985; Abrams 1988).
Quality of the evidence
Although small, the trials were generally of good methodological quality with adequate measures to conceal random allocation and near-complete follow-up assessment during the intervention period. Blinding of parents and caregivers was not possible given the nature of the intervention. This is not likely to be a source of bias in growth assessments. However, knowledge of the intervention group may have affected caregivers' or mothers' perceptions and views of feeding and may have influenced decisions on whether to give any formula as a supplement to (or instead of) breast feeding. The trials did not find evidence that multinutrient fortification affected the duration of breast feeding. O'Connor 2008 did not find a difference in the proportion of infants receiving any breast milk at the end of the intervention period. In part, this finding may be due to the provision of intensive lactation support from the study co-ordinator for both groups during the trial period. Whether breast feeding rates can be maintained in the absence of intensive support remains to be determined. Zachariassen 2011 did not report he proportion of infants receiving any breast milk at the end of the intervention period. However, this trial did detect a statistically significant reduction in the proportion of intervention group infants receiving exclusive breast milk feeding at four months post term.
Agreements and disagreements with other studies or reviews
The Cochrane review of trials of nutrient-enriched formula versus standard term formula (which contains about the same level of energy, protein and other nutrients as human breast milk) for feeding preterm infants following hospital discharge did not find an effect on growth rates during infancy (Young 2012). This review also found evidence that infants fed ad libitum infants reduce their volume of intake when the energy content of the milk is higher. Consequently, infants fed ad libitum with nutrient-enriched formula milk generally receive similar levels of calories and only slightly more protein and minerals than infants who receive standard term formula. Therefore, the lack of an effect on growth may be due to the differential in bone mineral or vitamin levels of intake being less marked than in the comparison of multinutrient fortified and unfortified breast milk. Given these findings, it is important that future studies attempt to determine whether bone mineral (and/or vitamin D) supplementation has a similar effect on catch-up growth rates as multinutrient fortification (Hall 1993).
Implications for practice
The limited available data do not provide evidence that feeding preterm infants following hospital discharge with multinutrient fortified breast milk compared with unfortified breast milk affects growth rates during infancy. The effect on long-term growth and development has not been assessed.
Implications for research
Given the potential for post-discharge nutrient fortification of breast milk to affect growth and development in preterm infants, this intervention merits further assessment. Further work is also needed to determine which nutrient groups confer the most important benefits to growth and development. Since fortifying breast milk for infants fed directly from the breast is logistically difficult (and has the potential to interfere with breast feeding), it is important to determine if mothers would support a trial of this intervention. It may be that a trial should first focus on infants who are not able to consume ad libitum quantities of milk directly from the breast, who have low rates of in hospital growth, or who have on-going additional metabolic requirements, for example, due to chronic lung disease.
Data and analyses
- Top of page
- Authors' conclusions
- Data and analyses
- What's new
- Contributions of authors
- Declarations of interest
- Sources of support
- Index terms
Last assessed as up-to-date: 10 September 2012.
Protocol first published: Issue 3, 2004
Review first published: Issue 4, 2007
Contributions of authors
Lauren Young, Nick Embleton, Felicia McCormick, William McGuire undertook the electronic search and identified citations for possible inclusion. Lauren Young, Nick Embleton and Felicia McCormick reviewed the citation list (title and abstract) for inclusion and undertook methodological appraisal, data extraction, entry and analysis. William McGuire acted as an arbiter for any disagreements, reviewed data entry and analysis and completed the review.
Declarations of interest
Sources of support
- CRD & Hull York Medical School, University of York, UK.
- NIHR, UK.LY is an NIHR academic clinical fellow.
- Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA.The Cochrane Neonatal Review Group has been funded in part 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. HHSN267200603418C
Medical Subject Headings (MeSH)
MeSH check words
Humans; Infant; Infant, Newborn
* Indicates the major publication for the study