Assessed as Up-to-date:	14 May 2010
Date of Search:	30 April 2010
Next Stage Expected:	14 May 2012
Protocol First Published:	Issue 3, 2004
Review First Published:	Issue 4, 2007
Last Citation Issue:	Issue 7, 2010

Date / Event	Description
14 May 2010 Updated	The review title and description of intervention have been amended at this update to "Multinutrient fortification of human breast milk for preterm infants following hospital discharge". This review was previously titled 'Multicomponent fortification of human breast milk for preterm infants following hospital discharge" (Henderson 2007). New author Felicia M McCormick has been added.
14 May 2010 New citation: conclusions changed	Updated search in April 2010 found one new trial for inclusion in this update (O'Connor 2008). The available data suggest that feeding preterm infants following hospital discharge with multinutrient fortified breast milk compared with unfortified breast milk increases growth rates during infancy. The importance of these effects on long term growth and development is unclear and deserves further assessment in randomised controlled trials.

Date / Event	Description
22 August 2008 Amended	Converted to new review format.

Abstract

Background

Preterm infants are usually growth restricted at hospital discharge. Feeding preterm infants after hospital discharge with multinutrient fortified breast milk rather than unfortified breast milk may facilitate more rapid catch-up growth and improve neurodevelopmental outcomes.

Objectives

To determine the effect of feeding with multinutrient fortified human breast milk versus unfortified breast milk on growth and development in preterm or low birth weight infants following hospital discharge.

Search methods

The standard search strategy of the Cochrane Neonatal Review Group was used. This included searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 4, 2010), MEDLINE (1966 to April 2010), EMBASE (1980 to April 2010), CINAHL (1982 to April 2010), conference proceedings, and previous reviews.

Selection criteria

Randomised or quasi-randomised controlled trials that compared feeding preterm infants following hospital discharge with multinutrient fortified breast milk compared with unfortified human breast milk.

Data collection and analysis

The standard methods of the Cochrane Neonatal Review Group were used, with separate evaluation of trial quality and data extraction by two review authors.

Results

One small trial (N = 39) was identified. Multinutrient fortification of breast milk for 12 weeks after hospital discharge resulted in higher rates of growth during infancy. At 12 months corrected age, weight (mean difference 1187g, 95% confidence interval (CI) 259, 2115 g), length (3.8 cm, 95%CI 1.2, 6.4 cm) and head circumference (1.0 cm, 95%CI 0.1, 1.9 cm) were statistically significantly greater in the intervention group. No evidence of an effect on neurodevelopmental assessments at 18 months corrected age was found.

Authors' conclusions

The limited available data suggest that feeding preterm infants following hospital discharge with multinutrient fortified breast milk compared with unfortified breast milk increases growth rates during infancy. The importance of these effects on long-term growth and development is unclear and deserves further assessment in randomised controlled trials. 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 further trials of this intervention.

Plain language summary

Multicomponent fortification of human breast milk for preterm infants following hospital discharge

Preterm infants are often much smaller than term infants by the time that they are discharged home from hospital. This review attempted to identify trials that evaluated whether feeding these infants with breast milk fortified with added nutrients rather than unfortified breast milk would increase growth rates and benefit development. Only one small trial (in which 39 infants participated) of this intervention was found. This trial did provide some evidence that multinutrient fortification increases growth rates during infancy. Further trials are needed to confirm this finding and to determine long term effects on growth and development .

Background

Description of the condition

Most preterm infants accumulate significant energy, protein, mineral, and other nutrient deficits by the time of discharge from hospital (Embleton 2001). At this stage, many preterm infants are significantly growth restricted, the risk increasing with lower birth weight and gestational age (Lucas 1984; Clark 2003). Following hospital discharge, demand fed preterm infants may 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 (Cooke 2003; Hack 1991). 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 to infants born at term (Rigo 2000). There is also some concern that nutritional deficiency and growth restriction both in utero and in the early postnatal period 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 weight gain, linear and head growth (Kuschel 2004a). There is an opportunity for continued nutritional supplementation for preterm infants in the post hospital discharge period of early infancy. 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 poor growth or nutritional status, or who have on-going additional metabolic requirements, for example, due to chronic lung disease (Cooke 2000; Griffin 2002).

The available multinutrient breast milk fortifiers contain varying amounts of protein, carbohydrate, minerals, and vitamins. These liquid and powder formulations are mixed with expressed breast milk for delivery with the aim of achieving approximately 5% to 10% nutrient enrichment (Simmer 2000). Following hospital discharge, human milk-fed preterm infants usually obtain most of their milk directly from their mother's breast. Consequently, standard clinical practice has been to cease multinutrient fortification during the period prior to hospital discharge when breast feeding is being established.

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). Although 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, this medialization 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 outside with 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).

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.

Objectives

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.

Methods

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

Multinutrient fortification:
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, 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 may 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

Primary:

Growth and development

Growth during the trial period: Weight, linear growth, head growth, skinfold thickness.
Long-term growth and growth-restriction (proportion of infants who remain below the tenth percentile for the index population's distribution of weight, height, or head circumference).
Neurodevelopmental outcomes assessed at > 12 months of age (corrected for preterm birth) measured using validated assessment tools, and classifications of disability, including auditory and visual disability. Severe neurodevelopmental disability was defined as any one or combination of the following: non-ambulant cerebral palsy, developmental delay (developmental quotient less than 70), auditory and visual impairment.
Cognitive and educational outcomes at > 5 years old: Intelligence quotient and/or indices of educational achievement measured using a validated assessment tool (including school examination results).

Secondary

Measures of bone mineralization: serum alkaline phosphatase level, bone mineral content or density.
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).
Clinical or radiological evidence of rickets on long-term follow-up.
Blood pressure on long-term follow-up.
Body mass index or waist circumference on long-term follow-up.

Search methods for identification of studies

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

Electronic searches

This consisted of searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 4, 2010), MEDLINE (1966 to April 2010), and EMBASE (1980 to April 2010), and CINAHL (1982 to April 2010). The electronic search used 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 fortif* OR supplement*]. The search outputs were limited with the relevant search filters for clinical trials. No language restriction was applied.

The following web sites were searched for completed or ongoing trials:

ClinicalTrials.gov

Current Controlled Trials

Searching other resources

The references in studies identified as potentially relevant were examined.

The abstracts from the meetings of the Pediatric Academic Societies (1993 to 2009), the European Society for Pediatric Research (1995 to 2009), the Royal College of Paediatrics and Child Health (2000 to 2010), the North American Society of Pediatric Gastroenterology and Nutrition, and the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (1990 to 2009) were searched.

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

The standard methods of the Cochrane Neonatal Review Group were used.

Selection of studies

The title and abstract of all studies identified by the above search strategy were screened and the full articles for all potentially relevant trials obtained. The full text of any potentially eligible reports was reassessed and those studies that did not meet all of the inclusion criteria were excluded. Any disagreements were discussed until consensus was achieved.

Data extraction and management

A data collection form was used to aid extraction of relevant information from each included study. Each review author extracted the data separately. Any disagreements were discussed until consensus was achieved. If data from the trial reports were insufficient, the investigators were contacted for further information.

Assessment of risk of bias in included studies

The criteria and standard methods of the Cochrane Neonatal Review Group were used to assess the methodological quality of any included trials in terms of allocation concealment, blinding of parents or caregivers and assessors to the intervention and completeness of assessment in all randomised individuals. Additional information from the trial authors was requested to clarify methodology and results as necessary. This information was added to the table 'Characteristics of Included Studies'. In addition, the following issues were evaluated and entered into the Risk of Bias table:

Sequence generation: Was the allocation sequence adequately generated?
Allocation concealment: Was allocation adequately concealed?
Blinding of participants, personnel and outcome assessors: Was knowledge of the allocated intervention adequately prevented during the study? At study entry? At the time of outcome assessment?
Incomplete outcome data: Were incomplete outcome data adequately addressed?
Selective outcome reporting: Are reports of the study free of suggestion of selective outcome reporting?
Other sources of bias: Was the study apparently free of other problems that could put it at a high risk of bias?

Measures of treatment effect

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

Unit of analysis issues

The unit on 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 was included in a meta-analysis, the treatment effects of individual trials and heterogeneity between trial results were to be examined by inspecting the forest plots. The I² statistic was to be calculated 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, the possible causes (for example, differences in study design, participants, interventions, or completeness of outcome assessments) were to be explored in sensitivity analyses.

Assessment of reporting biases

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

Subgroup analysis and investigation of heterogeneity

The following subgroup analyses were prespecified:

Very low birth weight (< 1.5 kg) or very preterm (< 32 weeks') 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 requiring home supplemental oxygen therapy;
Infants who receive donated expressed breast milk.

Results

Description of studies

One eligible trial was identified (O'Connor 2008; see Characteristics of included studies for details). 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 either multinutrient fortification to half of their total daily milk intake or to continue with unfortified human milk feeding for 12 weeks post-discharge. Outcomes assessed were growth and bone mineral content and density up to 12 months corrected age, and Bayley II mental and psychomotor index scores at 18 months corrected age.

One trial was excluded as the intervention group received only mineral fortification (Hall 1993). See Characteristics of excluded studies for details.

Risk of bias in included studies

Quality assessments are described in Characteristics of included studies.

O'Connor 2008: Allocation generation and concealment was adequate. Blinding of intervention was not attempted but blinding of some assessment (including developmental assessment) was possible. Of the 39 randomised infants, follow up assessment was achieved for 34 infants at 12 weeks post-discharge, 30 infants at 12 months (growth and bone mineralization) and 29 children at 18 months.

Effects of interventions

PRIMARY OUTCOMES

Growth during the trial period (Outcomes 1.01 - 1.03):
O'Connor 2008 reported that, at the completion of the 12 weeks intervention period, weight was not statistically significantly different between the groups (MD 493.00 g, 95% CI -93.42, 1079.42 g) (Figure 1). Length (MD 2.30 cm, 95% CI 0.38, 4.22 cm) (Figure 2) and head circumference (MD1.20 cm, 95% CI 0.34, 2.06 cm Figure 3) were statistically significantly higher in the intervention group.

Long term growth (Outcomes 1.04 - 1.06):
O'Connor 2008 reported that, at 12 months corrected age, weight (MD 1187.00 g, 95% CI 259.31, 2114.69 g) (Figure 4), length (MD 3.80 cm, 95% CI 1.24, 6.36 cm) (Figure 5) and head circumference (MD 1.00 cm, 95% CI 0.10, 1.90 cm) (Figure 6) were statistically significantly higher in the intervention group (data available for 30 out of 39 randomised infants).

Neurodevelopmental outcomes:
O'Connor 2008 did not detect any statistically significant differences in Bayley II mental and psychomotor development index (MDI and PDI) scores at 18 months corrected age .

MDI: 100 (1st - 3rd centile; 72 - 102.5) versus 91 (1st - 3rd centile; 77 - 107)
PDI: 94 (1st - 3rd centile; 90 - 99) versus 94 (1st - 3rd centile; 86 - 103)

Cognitive and educational outcomes:
Not reported.

SECONDARY OUTCOMES

Bone mineralization (Outcomes 1.07 - 1.10):
O'Connor 2008 reported that bone mineral content was statistically significant higher in the intervention group at four months (MD 20.60 g, 95% CI 6.41, 34.79 g) (Figure 7) and 12 months (MD 29.80 g, 95% CI 3.63, 55.97 g) (Figure 8) corrected age. Bone mineral density at four months and 12 months corrected age were not statistically significantly different (Figure 9; Figure 10).

Feed intolerance:
Not reported.

Duration of breast milk feeding (Outcome 1.11):
O'Connor 2008 did not detect a statistically significant difference (WMD -8.20 [-19.48, 3.08] postnatal weeks) (Figure 11).

Clinical or radiological evidence of rickets on long-term follow-up:
Not reported.

Blood pressure on long-term follow-up:
Not reported.

Body mass index on long-term follow-up:
Not reported.

Subgroup analyses: Data were not available for any of the prespecified analyses:

Very low birth weight (< 1.5 kg) or very preterm (< 32 weeks') infants: The O'Connor 2008 population was infants with birth weight < 1.8 kg or gestational age at birth < 33 weeks.
Infants who were small for gestational age (< 10th percentile for the index population's distribution of weight) at hospital discharge: In O'Connor 2008, three of 39 participants were small for gestational age.
Infants with chronic lung disease requiring home supplemental oxygen therapy: None of the participants received home supplemental oxygen therapy.
Infants who receive donated expressed breast milk: None of the participants received donated expressed breast milk.

Discussion

Only one randomised controlled trial of multinutrient fortification of breast milk for preterm infants following hospital discharge was identified (O'Connor 2008). Although small, this trial was generally of good methodological quality. However, loss to follow up of nine of the 39 participants (23%) by 12 months may limit the validity of the longer term growth and development data.

The main finding is that multinutrient fortification of human breast milk for preterm infants for 12 weeks post-discharge is feasible and results in higher rates of growth during infancy. At the end of the 12 weeks intervention period, infants in the two groups were of similar weight, but infants who received multinutrient fortification were 2.3 cm longer and had 1.2 cm larger head circumferences than control infants. Follow up assessment at 12 months suggested that this trajectory was maintained during infancy. Infants in the intervention group were 1.2 kg heavier, 3.8 cm longer and had 1.0 cm larger head circumferences than control infants. With regard to development, O'Connor 2008 did not detect any statistically significant differences in the Bayley II MDI and PDI scores at 18 months corrected age. Currently there are no data available regarding longer term growth rates and developmental outcomes.

Infants in the intervention group of O'Connor 2008 received about 75 ml/kg/day as expressed breast milk fortified with a commercially-available multinutrient fortifier. The remaining feeds were either taken directly from the breast or as unfortified expressed breast milk ad libitum. The aim of this strategy was to deliver approximately the same total amount of nutrients as contained in commercially-available "post-discharge formula" milk (72- 74 kCal and about 1.8 grams of protein/100ml, plus variable supplements of minerals, vitamins, and trace elements). Infants in the control group were fed unfortified breast milk ad libitum.

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 volume of 111 ml/kg/day compared with 134 ml/kg/day in the control group. Consequently, the intervention group did not receive more calories (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 are likely explanations for the detection of higher whole body bone mineral content in the intervention group maintained until 12 months corrected age. 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 mineralization 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).

In contrast to the finding that breast milk fed infants who received multinutrient fortification had higher rates of growth during infancy, a 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 (McGuire 2007). This review also found evidence that ad libitum fed 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 (and/or vitamin D) 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).

It is reassuring that the included trial did not detect an adverse effect of multinutrient fortification on continuation of exclusive breast feeding. The proportion of total feeds consumed as breast milk did not differ between the groups throughout the trial period and there was not a statistically significant difference in the duration of exclusive breast milk feeding. However, this may in part be related 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.

The data identified in this review are insufficient to address concerns regarding the possible competing effects of increasing catch up growth rates during infancy on developmental versus long term metabolic and cardiovascular outcomes. However, evidence exists that 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 (Euser 2005; Greer 2007).

Authors' conclusions

Implications for practice

The limited available data suggest that feeding preterm infants following hospital discharge with multinutrient fortified breast milk compared with unfortified breast milk increases growth rates during infancy. The effect on long term growth and development is unclear. The relative contributions of different nutrient groups is uncertain but some evidence exists that mineral and vitamin supplementation for skeletal growth is key.

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 poor growth or nutritional status, or who have on-going additional metabolic requirements, for example due to chronic lung disease.

Acknowledgements

We thanks Dr Deborah O'Connor for providing further information regarding O'Connor 2008.

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.

Contributions of authors

William McGuire and Tom Fahey developed the protocol.
Felicia McCormick, Ginny Henderson and William McGuire undertook the electronic and hand searches, screened the title and abstract of all studies identified, and the full text of potentially relevant reports.
Each review author independently assessed the methodological quality of the trials, extracted the relevant information and data, and completed the final review.

Methods	Randomised controlled trial Blinding of randomisation: yes Blinding of intervention: no Complete follow-up: no Blinding of outcome measurement: unclear
Participants	39 preterm infants born < 33 weeks' gestation with birthweight 750-1800 g. Enrolled when receiving 80% of enteral feedings orally as human milk (fortified or unfortified) 3 days before planned hospital discharge. Exclusion criteria: Infants with serious anomalies affecting growth; grade 3 or 4 periventricular haemorrhage; receipt of oral steroids within 14 days of randomisation; Apgar score < 5 at 5 minutes; known maternal alcohol or drug abuse; family habitat outside study area; mother unable to communicate verbally in English; infant needed nutrient enrichment incompatible with the intervention.
Interventions	Intervention (N=19): Feeding after hospital discharge with human milk, half of which to be fortified with 3.6 g commercially-available powdered multinutrient human milk fortifier per 100 ml fresh or thawed human milk for 12 weeks following discharge. Control (N=20): "standard care" - feeding after hospital discharge with unfortified human milk. Both groups received standard vitamin/iron supplements post-discharge. Both groups had access to intensive lactation support from the study co-ordinator, a certified lactation consultant, who also performed the study measures during home visits.
Outcomes	1. Growth: weight , length and head circumference up to completion of intervention period (12 weeks post-discharge) and up to 12 months corrected age. 2. Bayley II mental and psychomotor development index scores at 18 months corrected age. 3. Bone mineral content and density at 4 months and 12 months corrected age. 4. Nutrient intake up to completion of intervention period. 5. Duration of breast milk feeding (at least one human milk feed per day) and proportion of daily feeds provided as human milk up to 12 weeks.
Notes	Aim with fortification of half of the daily human milk intake was to provide milk with an overall average calorie content of 74 kcal/100 ml and protein content of 1.8 g/100ml; that is, about the same nutrient density as commercially-available "post-discharge" formula milk. Infants in the intervention group did receive about 50% fortified feeds as planned. Infants in the control group received about 8% fortified feeds at each data collection point. The investigators estimated that "energy intakes did not differ between the groups, suggesting human milk fed infants are able to compensate to some degree for the energy and/or nutrient density of their feeding."

Item	Judgement	Description
Adequate sequence generation?	Yes	Computer generated
Allocation concealment?	Yes	Sequence stored in sealed envelopes.
Blinding?	No	Parents or other caregivers were not blind to intervention. Unclear whether assessors (e.g. developmental assessment) were aware of intervention group.
Incomplete outcome data addressed?	No	Outcome data not reported for five infants withdrawn post-randomisation (from total N= 39).
Free of selective reporting?	Yes
Free of other bias?	Yes

Reason for exclusion	The intervention group received only mineral supplements. The trial did not report growth as an outcome. ABSTRACT:This study evaluated whether calcium and phosphorus supplementation after initial hospital discharge was advisable in infants of < 1800 g birth weight who were being breast fed. Twenty-seven infants (15 without any illness affecting nutritional intake and 12 with medical illness) received breast milk plus a liquid human milk fortifier mixed 1:1 and 400 IU vitamin D daily during initial hospitalisation. At discharge, 12 infants (6 without and 6 with previous illness) were randomly assigned to receive calcium and phosphorus supplementation, and 15 infants (9 without illness and 6 with previous illness) received no mineral supplementation. A third group of seven healthy infants received a formula for premature infants during initial hospitalisation and a standard cow's milk formula (20 calories per ounce) after discharge. The mean plasma calcium, phosphorus, and alkaline phosphatase levels did not differ among the three groups at study entry. Eight weeks after discharge, eight infants (four without illness and four with illness) had hypophosphataemia < 4.5 mg/dl. All were breast fed, and seven of eight had not received posthospitalisation calcium and phosphorus supplementation. The incidence of hypophosphataemia in infants with or without illness was significantly greater in infants who did not receive supplementation (p = 0.038). These data indicate that calcium, phosphorus, and vitamin D supplementation may be necessary in approximately 50% of breast-fed infants of < 1800 gm birth weight after hospital discharge. It is recommended that serum calcium, phosphorus, and alkaline phosphatase be measured 4 to 8 weeks after discharge to identify those infants who require supplementation.

References to studies

Included studies

O'Connor 2008

Aimone A, Rovet J, Ward W, Jefferies A, Campbell DM, Asztalos E, et al. Growth and body composition of human milk-fed premature infants provided with extra energy and nutrients early after hospital discharge: 1-year follow-up. Journal of Pediatric Gastroenterology and Nutrition 2009;49:456-66.

O'Connor DL, Khan S, Weishuhn K, Vaughan J, Jefferies A, Campbell DM, et al. Growth and nutrient intakes of human milk-fed premature infants provided with extra energy and nutrients after hospital discharge. In: E-PAS:60:7720.6. Pediatric Academic Societies's Annual Meeting, 2007.

* O'Connor DL, Khan S, Weishuhn K, Vaughan J, Jefferies A, Campbell DM, et al. Growth and nutrient intakes of human milk-fed preterm infants provided with extra energy and nutrients after hospital discharge. Pediatrics 2008;121:766-76.

Excluded studies

Hall 1993

Hall RT, Wheeler RE, Rippetoe LE. Calcium and phosphorus supplementation after initial hospital discharge in breast-fed infants of less than 1800 grams birth weight. Journal of Perinatology 1993;13:272-8.

Other references

Additional references

Abrams 1988

Abrams SA, Schanler RJ, Garza C. Bone mineralization in former very low birth weight infants fed either human milk or commercial formula. The Journal of Pediatrics 1988;112:956-60.

Barker 2002

Barker DJ. Fetal programming of coronary heart disease. Trends in Endocrinology and Metabolism 2002;13:364-8.

Chan 1985

Chan GM, Mileur LJ. Posthospitalization growth and bone mineral status of normal preterm infants. Feeding with mother's milk or standard formula. American Journal of Diseases of Children 1985;139:896-8.

Clark 2003

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

Cooke 2000

Cooke RJ, Embleton ND. Feeding issues in preterm infants. Archives of Disease in Childhood 2000;83:F215-8.

Cooke 2003

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

Embleton 2001

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

Euser 2005

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

Euser 2008

Euser AM, de Wit CC, Finken MJ, Rijken M, Wit JM. Growth of preterm born children. Hormone Research 2008;70:319-28.

Ewer 1996

Ewer AK, Yu VY. Gastric emptying in pre-term infants: the effect of breast milk fortifier. Acta Paediatrica 1996;85:1112-5.

Ford 2000

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

Greer 2007

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

Griffin 2002

Griffin IJ. Post discharge nutrition for high risk neonates. Clinics in Perinatology 2002;29:327-44.

Gross 1980

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Other published versions of this review

Henderson 2007

Henderson G, Fahey T, McGuire W. Multicomponent fortification of human breast milk for preterm infants following hospital discharge. Cochrane Database of Systematic Reviews 2007, Issue 4. Art. No.: CD004866. DOI: 10.1002/14651858.CD004866.pub2 .

Multinutrient fortification of human breast milk for preterm infants following hospital discharge

Authors

Contact person

William McGuire

Dates

What's new

History

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Results

Authors' conclusions

Plain language summary

Multicomponent fortification of human breast milk for preterm infants following hospital discharge

Background

Description of the condition

Description of the intervention

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary:

Growth and development

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Assessment of heterogeneity

Assessment of reporting biases

Subgroup analysis and investigation of heterogeneity

Results

Description of studies

Risk of bias in included studies

Effects of interventions

Discussion

Authors' conclusions

Implications for practice

Implications for research

Acknowledgements

Contributions of authors

Characteristics of studies

Characteristics of included studies

O'Connor 2008

Risk of bias table

Characteristics of excluded studies

Hall 1993

References to studies

Included studies

O'Connor 2008

Excluded studies

Hall 1993

Other references

Additional references

Abrams 1988

Barker 2002

Chan 1985

Clark 2003

Cooke 2000

Cooke 2003

Embleton 2001

Euser 2005

Euser 2008

Ewer 1996

Ford 2000

Greer 2007

Griffin 2002

Gross 1980

Hack 1991