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Multicomponent fortified human milk for promoting growth in preterm infants

  1. Carl A Kuschel1,*,
  2. Jane E Harding2

Editorial Group: Cochrane Neonatal Group

Published Online: 26 JAN 2004

Assessed as up-to-date: 28 AUG 2003

DOI: 10.1002/14651858.CD000343.pub2


How to Cite

Kuschel CA, Harding JE. Multicomponent fortified human milk for promoting growth in preterm infants. Cochrane Database of Systematic Reviews 2004, Issue 1. Art. No.: CD000343. DOI: 10.1002/14651858.CD000343.pub2.

Author Information

  1. 1

    The Royal Women's Hospital, Neonatal Services, Carlton, Victoria, Australia

  2. 2

    University of Auckland, Department of Paediatrics, Auckland, New Zealand

*Carl A Kuschel, Neonatal Services, The Royal Women's Hospital, 132 Grattan Street, Carlton, Victoria, 3053, Australia. carl.kuschel@rwh.org.au.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 26 JAN 2004

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Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Declarations of interest
  13. Sources of support
  14. Index terms

Human milk is the recommended nutritional source for full-term infants for at least the first six months of postnatal life (54th WHA). It is known that in this group of infants, breast milk supplies adequate substrate to meet the infant's nutritional demands, as well as supplying the infant with other substances that may afford some physiological advantage (for example, immunoglobulins and gastrointestinal hormones). Breast feeding may also contribute to maternal-infant bonding.

However, the role of human milk in premature infants is less well defined. The nutrient content of premature human milk provides insufficient quantities of protein, sodium, phosphate and calcium to meet the estimated needs of the infant (Schanler 2001). In addition, large fluid volumes may be required to provide sufficient calories to maintain adequate growth.

Observational studies have shown that premature infants fed human milk have lower growth rates than infants fed term or preterm infant formulae (Atkinson 1983; Cooper 1984, Roberts 1987). Serum albumin and blood urea nitrogen concentrations may decline in premature infants as a result of inadequate dietary protein intake. Premature infants are born with low skeletal stores of calcium and phosphate, and have very high requirements for these minerals if they are to attain adequate postnatal skeletal growth. Poor radiological bone mineralisation, rickets, and fractures have been described in premature infants receiving inadequate dietary intakes of calcium and phosphate, as may be supplied by breast milk alone.

Despite these apparent inadequacies of human milk, other studies have demonstrated that feeding human milk to premature infants may lead to benefits in both the short-term (for example, a lower risk of necrotising enterocolitis (Lucas 1990)) and long-term (for example, improved cognitive and neurodevelopmental outcomes (Morley 1998)).

Commercially-produced multicomponent fortifiers are available for the supplementation of breast milk. These fortifiers provide additional nutrients in the form of protein, calcium, phosphate, and carbohydrate, as well as vitamins and trace minerals. However, many of the nutrients contained within commercial preparations have not been studied either individually or in combination. This review includes trials where infants received more than one nutrient supplement (that is, protein and/or fat and/or carbohydrate and/or minerals). This intervention was prespecified prior to the literature search although it is appreciated that this would lead to a range of potential combined interventions. Other reviews have evaluated the effects of individual components given alone - that is, protein (Kuschel 1999a), carbohydrate (Kuschel 1999b), fat (Kuschel 1999c) or minerals (Kuschel 2001).

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Declarations of interest
  13. Sources of support
  14. Index terms

To determine if addition of multicomponent nutritional supplements to human milk leads to improved growth, bone metabolism and neurodevelopmental outcomes without significant adverse effects in premature infants.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Declarations of interest
  13. Sources of support
  14. Index terms
 

Criteria for considering studies for this review

 

Types of studies

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

 

Types of participants

Premature infants receiving care within a nursery setting.

 

Types of interventions

All randomized controlled trials evaluating the supplementation of human milk with multiple nutrients (more than one of the following components: protein, fat, carbohydrate, or minerals [calcium and/or phosphate]), in which treatment was compared with unsupplemented human milk, are included. Supplementation with electrolytes, vitamins, or trace minerals in addition to only one of the above has not been classified as multicomponent fortification for the purposes of this review.

 

Types of outcome measures

1. Primary outcomes
a. Growth to discharge
Weight
Length
Head circumference
b. Size at 12-18 months
Weight
Length
Head circumference
c. Bone metabolism
Serum alkaline phosphatase (ALP)
Bone mineral content (BMC)
d. Neurodevelopmental outcomes
Neurodevelopmental outcomes at 18 months

2. Secondary Outcomes
a. Bone metabolism
Fractures
b. Nitrogen retention studies
c. Adverse effects
Significant hypercalcemia (>2.85mmol/l)
Gastrointestinal disturbance
Feed intolerance
Diarrhoea
Necrotizing enterocolitis (NEC)
Blood pH
Blood urea
Death

 

Search methods for identification of studies

Searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 3003), MEDLINE up to August 29, 2003 (using the search terms infant, premature and milk, human), previous reviews including cross references, abstracts, conferences and symposia proceedings, expert informants, journal handsearching mainly in the English language.

 

Data collection and analysis

The criteria and standard methods of the Cochrane Collaboration and its Neonatal Review Group were used to assess the methodological quality of the included trials.

Additional information was requested from the authors of each trial to clarify methodology and results as necessary.

Each author extracted the data separately, compared data, and resolved differences.

The standard method of the Neonatal Review Group was used to synthesize the data.

 

Results

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Declarations of interest
  13. Sources of support
  14. Index terms
 

Description of studies

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

Details of the included studies are included in the Table 'Characteristics of Included Studies'. Thirteen studies met the inclusion criteria (Modanlou 1986; Carey 1987; Gross 1987 (1); Gross 1987 (2); Greer 1988; Pettifor 1989; Polberger 1989; Kashyap 1990; Zuckerman 1994; Lucas 1996; Wauben 1998; Nicholl 1999 and Faerk 2000).

The types of human milk fortifier (HMF), as defined in this overview, varied from supplementation with a commercial preparation (containing protein, fat, carbohydrate, minerals, electrolytes, and trace minerals) to supplementation with only two individual components. Modanlou 1986 used a fortifier containing protein, carbohydrate, and minerals (Mead Johnson, preparation not specified). Carey 1987 used HMF containing protein and minerals only, but quantities of these were not specified. Gross 1987 (1) and Gross 1987 (2) used Similac Special Care (Ross Laboratories) preterm formula as supplementation, or a powdered HMF. Greer 1988 used a preparation from Ross Laboratories (powdered fortifier, unspecified), as did Pettifor 1989 (Ross Laboratories Human Milk Fortifier) and Kashyap 1990 (preparation not specified). Polberger 1989 supplemented with both protein and fat, and infants in both the control and treatment arms received mineral supplementation. Zuckerman 1994 used an equal mix of maternal milk and a preterm formula (Alprem, Nestle). Lucas 1996 used Enfamil HMF (Mead Johnson). Wauben 1998 used a non-commercial fortifier produced by Wyeth-Ayerst. Nicholl 1999 used Nutriprem human milk fortifier (Cow and Gate Nutricia). Faerk 2000 used a commercial preparation (Milupa Eoprotin).

There was variation between studies in the entry criteria. All studies based entry on birthweight (generally <1850g), although the limits for these were variable. Almost all studies excluded infants with congenital abnormalities or significant illness. Fortification was commenced in most studies once the infant tolerated a prespecified enteral intake. For almost all studies fortification ceased at a specified weight (generally 1800 to 2000g) or at discharge, although, for some studies, the duration of intervention is unclear.

The daily intakes of the various individual components varied between studies, as did enteral intakes. In some studies, there was little or no difference in caloric intakes between the groups (Gross 1987 (1); Gross 1987 (2); Greer 1988; Zuckerman 1994). Details of the individual components are included in the table "Characteristics of Included Studies". In addition, some studies supplemented the control arm with minerals (Polberger 1989; Lucas 1996; Wauben 1998; Faerk 2000)

Excluded studies are listed in the Table "Characteristics of Excluded Studies". Ronnholm 1982 included a treatment group that received both protein and fat supplementation, and was therefore eligible for inclusion. However, it was impossible to extract data from the published reports. Similarly, the data were not presented in an extractable form in Venkataraman 1988. Boehm 1991 compared a commercial preparation (EOPROTIN) with a control group supplemented with albumin, minerals, and sodium, thereby comparing essentially a different form of protein intake. Moyer-Mileur 1992 compared two fortifier preparations but did not have an unsupplemented control group, as also was the case with Metcalf 1994; Schanler 1995; Sankaran 1996; dos Santos 1997; Porcelli 2000 and Reis 2000. Ewer 1996 and McClure 1996 did not report any of the prespecified clinical outcomes, looking only at gastric emptying. Plath 1988 reported in abstract form the results of nitrogen balance studies. Gupta (unpublished) was excluded because of concerns about randomisation and selection criteria. Lucas 1984 was considered for inclusion in this review, particularly as this study was included in a previous systematic review of infant feeding (Sinclair 1992). Although infant nutrition was supplemented, it was by the substitution of maternal milk when insufficient quantities were available. This was not felt to represent "fortification" as such.

 

Risk of bias in included studies

Eight of the thirteen studies report results for fewer than 15 infants in each arm. Only Lucas 1996; Wauben 1998; Nicholl 1999 and Faerk 2000 included sample size estimates as part of the study design.

Pettifor 1989 and Zuckerman 1994 used quasi-random allocation via hospital number. Other studies used sealed envelopes (Modanlou 1986; Gross 1987 (1); Gross 1987 (2); Polberger 1989; Kashyap 1990; Lucas 1996; Nicholl 1999; Faerk 2000) or random number tables (Greer 1988). The method of randomisation is unknown for Carey 1987 and Wauben 1998.

Polberger 1989 conducted a double blind study. The assessment of neurodevelopmental and long term growth outcomes for Lucas 1996 was masked, but short-term outcomes were not. In other studies, there was no masking of the intervention (Modanlou 1986; Greer 1988; Pettifor 1989; Zuckerman 1994; Wauben 1998) or masking was unknown.

Most studies have focussed on relatively well infants. Infants who developed significant illness were frequently not enrolled or not included in results (Modanlou 1986; Carey 1987; Gross 1987 (1); Gross 1987 (2); Greer 1988; Pettifor 1989; Polberger 1989; Zuckerman 1994; Wauben 1998; Nicholl 1999). Polberger 1989 withdrew one control infant for apnoea, and two treatment infants (feed intolerance; apnoea) [additional information provided by author]. Zuckerman 1994 withdrew three infants in the control group because of incorrect feeding. Faerk 2000 withdrew 9 infants randomized (6 in the fortifier group and 3 in the phosphorus group), and a further 18 (9 in each group) because DEXA scans were not technically satisfactory. In only six studies (Modanlou 1986; Pettifor 1989; Kashyap 1990; Lucas 1996; Wauben 1998; Nicholl 1999) are the outcomes reported for all infants enrolled. In other studies, either the number of infants enrolled or the reasons for withdrawal are unknown. Where infants have been withdrawn because of feed intolerance, NEC, or death, results have been included if possible.

Lucas 1996 supplemented the control group with phosphorus and, in both groups, provided premature formula if there was insufficient maternal milk. Similarly, Wauben 1998 supplemented control infants with calcium and phosphate. Polberger 1989, primarily assessing caloric supplementation, provided both treatment and control groups with calcium and phosphate. Faerk 2000 also supplemented the control group with phosphorus. These interventions in the control groups may reduce any differences attributable to treatment. The results of this overview have been subjected to a sensitivity analysis excluding these studies.

 

Effects of interventions

These studies report results for more than 600 infants. There is significant variability between studies in the outcomes of weight gain and linear growth and blood urea levels (all trials included, but not with the sensitivity analysis), head growth, ALP activity, and BMC. This potentially reflects differences in fortifier composition, study design (for example, exclusion criteria, variable enteral and caloric intakes, duration of intervention), and outcome measures (primarily, timing of outcome measurements).

Short-term growth parameters
All studies evaluated short-term growth. The two largest studies (Pettifor 1989; Lucas 1996) did not demonstrate a statistically significant increase in weight gain in the fortification group. Nevertheless, the overall analysis demonstrated greater weight gains in infants receiving fortification (WMD 2.3g/kg/day, 95% CI, 1.7 to 2.9g/kg/day). The difference in daily weight gain remained statistically significant at 3.6g/kg/day (95% CI, 2.7 to 4.6g/kg/day) when the studies where control infants received mineral supplementation are excluded.

For those studies that reported weight gain as g/day, there was a significant increase in the infants receiving fortified feeds (WMD 4.7 g/day, 95%CI 2.8 to 6.7 g/day).

Infants receiving fortifier had greater length gain by 0.12cm/week (95% CI, 0.07 to 0.18cm/week). When the sensitivity analysis was performed, the difference in weekly length gain remained statistically significant at 0.18cm/week (95% CI, 0.08 to 0.28cm/week).

Head growth was also greater in those infants receiving HMF (WMD 0.12cm/week, 95% CI 0.07 to 0.16cm/week). The sensitivity analysis did not significantly alter this finding (WMD 0.14cm/week, 95% CI, 0.09 to 0.20cm/week).

Long-term growth parameters
Two studies (Lucas 1996; Wauben 1998) evaluated long term growth. Wauben 1998 did not demonstrate any differences in weight, length or head circumference at 12 months of corrected age. Similarly, Lucas 1996 did not demonstrate any differences in growth parameters at 18 months corrected age.

Serum alkaline phosphatase
There was no effect on mean ALP activity in the infants studied (WMD 0.2IU/l, 95% CI -34.0 - 34.4IU/l). This result did not change with the sensitivity analysis (WMD -43.2 IU/l, 95% CI -98.3 to 11.8 IU/l).

Bone mineral content
Modanlou 1986; Gross 1987 (1);Gross 1987 (2) found that BMC values were not statistically different between control and treatment groups, although no absolute values are available. BMC has been recorded in two different measurement units. From the two studies where data of radius BMC are available in the format of mg/cm, infants receiving HMF had higher BMC than those receiving unsupplemented milk (WMD 8.3mg/cm, 95% CI 3.8 to 12.8mg/cm). This result is heavily influenced by the study by Pettifor 1989 which contributed 59 of the 79 infants and demonstrated a difference of 12.0 mg/cm (95% CI 6.3 to 17.7mg/cm). The lack of absolute data from those individual trials where there was no difference between groups considerably reduces the confidence of this result. Wauben 1998 and Faerk 2000 - both of whom supplemented their control groups with phosphorus - evaluated whole body BMC and found no difference (WMD 1.7g, 95% CI -1.7 to 5.0g). Wauben 1998 also demonstrated no difference in BMC at 12 months of age.

Neurodevelopmental outcomes
Only Lucas 1996 evaluated developmental performance at 18 months. There was no statistically significant difference between intervention and control groups.

Fractures
No studies addressed this outcome. Zuckerman 1994 evaluated wrist radiographs taken at hospital discharge and at the final follow-up visit, and found no difference between the supplemented and supplemented groups in the frequency of periosteal reaction, osteopenia, or rickets.

Nitrogen retention studies
Two studies (Kashyap 1990 and Wauben 1998) have demonstrated increased nitrogen retention in infants receiving HMF containing protein (WMD 66mg/kg/day, 95% CI 35 to 97mg/kg/day). Sensitivity analysis does not significantly change this result.

Hypercalcemia
Although most studies evaluated serum calcium levels, only Lucas 1996 and Wauben 1998 evaluated absolute hypercalcemia (>2.85mmol/l and >2.7mmol/l, respectively). There was no difference between the treatment and control groups, although both studies supplemented the control groups with minerals.

Feed intolerance
Many studies withdrew infants with feed intolerance and did not report results. Modanlou 1986 and Lucas 1996 both evaluated feed intolerance, finding no difference between the groups, but the outcomes could not be numerically analysed. On the basis of the small number of infants for whom this outcome is reported, there is a non-significant trend towards an increased risk of feed intolerance in treated infants (RR 2.85, 95% CI 0.62 to 13.1).

Diarrhea
No study specifically addressed this outcome. Lucas 1996 found that infants receiving HMF were more likely to have "hard stools" than the control group.

Necrotizing enterocolitis
There is no significantly increased risk of NEC in infants receiving fortified human milk (RR 1.33, 95% CI 0.7 to 2.5). Sensitivity analysis does not significantly alter this result.

Blood pH
Lucas 1996 demonstrated a statistically significant reduction in pH in infants receiving HMF (pH 7.33, vs. pH 7.34 in controls - WMD -0.01, 95%CI -0.02 to 0.00) which is unlikely to have any clinical significance. Wauben 1998 withdrew one control infant because of metabolic acidosis.

Blood urea
Urea levels are significantly increased in infants receiving HMF (WMD 0.27mmol/l, 95% CI 0.14 to 0.40mmol/l). When the studies evaluating mineral supplementation in the control group are excluded, this difference is increased (0.96mmol/l, 95% CI 0.56 to 1.36mmol/l).

Death
Death as a specific outcome is reported by Pettifor 1989 and Lucas 1996. Other studies included only relatively well infants. There does not appear to be any increased risk of death associated with fortification of human milk (RR 1.48, 95% CI 0.66 to 3.34), although all 7 infants who died in one study (Pettifor 1989) were assigned fortifier. Sensitivity analysis, excluding Lucas 1996, results in inclusion of Pettifor's study only with a trend towards increased risk of death (RR 13.3) but with very wide confidence intervals (95% CI, 0.78 to 227).

 

Discussion

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Declarations of interest
  13. Sources of support
  14. Index terms

This overview has demonstrated that fortification of human milk with more than one nutritional supplement (caloric, protein, and/or mineral) results in small but statistically significant increases in weight gain, linear growth, and head growth over the short term study periods evaluated. No long term advantage has been shown in terms of either growth (Lucas 1996, Wauben 1998) or neurodevelopmental outcome (Lucas 1996).

Short-term growth is a difficult outcome to assess - particularly if the first two weeks of life, when weight loss is common, are included in the overall weight gain results. Although the differences for these outcomes are small, the effect of these small increases in growth over the short term may be cumulative. For prolonged hospital stays, a small advantage in weight gain or head or linear growth may have a significant impact on growth parameters at discharge or even age at discharge. However, these outcomes were not evaluated in this review. Two studies reported these outcomes (Modanlou 1986; Wauben 1998) and found no difference between the groups.

Fortification of human milk has no effect on ALP levels. BMC has been variably reported and only one study (Pettifor 1989) has individually shown a difference. The two most recent studies (Wauben 1998 and Faerk 2000) did not demonstrate any differences in whole body BMC, although phosphorus was given to the control groups in both trials. Fractures have not been reported as an outcome in any study. Nitrogen retention has been examined in two studies and is significantly increased in infants receiving fortifier.

Potential adverse effects of fortification do not appear to be significantly increased, although the total number of infants studied and the unavailability of results for some infants randomized and subsequently withdrawn makes it difficult to be confident of this finding. There is no evidence of a significantly increased risk of NEC. Urea levels are higher and pH levels lower in infants receiving fortification, but the clinical significance of this is not clear. The increased urea levels in the fortifier group are not above the accepted range of normal . If anything, excluding Lucas 1996, those in the control group are low and the higher levels in fortified infants may reflect improved dietary protein intake. There are insufficient data to evaluate other potential adverse effects.

 

Authors' conclusions

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Declarations of interest
  13. Sources of support
  14. Index terms

 

Implications for practice

There is sufficient evidence to demonstrate that fortification of human milk with more than one nutritional component is associated with short-term improvements in weight gain, linear and head growth. There is no clear effect on bone mineral content. There is no evidence that these short-term gains in growth lead to any demonstrable long-term benefits in growth, bone mineral content, or neurodevelopmental outcomes, although this may well be related to the absence of follow-up in almost all studies. There does not appear to be any increase in clinically significant adverse effects in supplemented infants, although the total number of infants studied is small and the abstractable data from the published studies is limited.

 
Implications for research

Fortification of human milk has become common practice, based largely on metabolic studies evaluating the composition of human milk and the nutritional requirements of preterm infants. There is an absence of evidence of long-term benefit, and insufficient evidence to be reassured that there are no deleterious effects. Despite this, it is unlikely that further studies evaluating fortification of human milk versus no supplementation will be performed. Indeed, Lucas 1996 felt that it was not ethical to withhold phosphorus supplementation in control infants and other studies since then have also supplemented the control groups (Wauben 1998; Faerk 2000).

Most commercially available fortifiers contain varying amounts of protein, carbohydrate, calcium, phosphate, other minerals (zinc, manganese, magnesium, and copper), vitamins, and electrolytes. The benefits of many of these individual components have not been evaluated in a controlled manner. Further research should be directed toward comparisons between different proprietary preparations and evaluating both short-term and long-term outcomes and adverse effects, in search of the "optimal" composition of fortifiers. This has, in part, been addressed by studies excluded from this overview (Moyer-Mileur 1992; Metcalf 1994; Sankaran 1996; Porcelli 2000; Reis 2000). The number of study subjects required to adequately evaluate these outcomes would be extremely large.

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Declarations of interest
  13. Sources of support
  14. Index terms

The reviewers wish to thank those authors who were able to provide additional information to assist with this review.

 

Data and analyses

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Declarations of interest
  13. Sources of support
  14. Index terms
Download statistical data

 
Comparison 1. Multicomponent fortification vs control (all trials)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Weight gain (g/kg/day)8450Mean Difference (IV, Fixed, 95% CI)2.33 [1.73, 2.93]

 2 Weight gain (g/day)355Mean Difference (IV, Fixed, 95% CI)4.74 [2.78, 6.70]

 3 Length gain (cm/week)8416Mean Difference (IV, Fixed, 95% CI)0.12 [0.07, 0.18]

 4 Head growth (cm/week)9428Mean Difference (IV, Fixed, 95% CI)0.12 [0.07, 0.16]

 5 Weight at 12 months (kg)125Mean Difference (IV, Fixed, 95% CI)Not estimable

 6 Length at 12 months (cm)125Mean Difference (IV, Fixed, 95% CI)-1.0 [-3.50, 1.50]

 7 Head circumference at 12 months (cm)125Mean Difference (IV, Fixed, 95% CI)0.10 [-2.22, 2.42]

 8 Weight at 18 months (kg)1245Mean Difference (IV, Fixed, 95% CI)-0.04 [-0.35, 0.27]

 9 Length at 18 months (cm)1245Mean Difference (IV, Fixed, 95% CI)-0.10 [-0.93, 0.73]

 10 Head circumference at 18 months (cm)1245Mean Difference (IV, Fixed, 95% CI)Not estimable

 11 Serum alkaline phosphatase (IU/l)8469Mean Difference (IV, Fixed, 95% CI)0.22 [-33.99, 34.44]

 12 Bone mineral content (mg/cm)279Mean Difference (IV, Fixed, 95% CI)8.30 [3.84, 12.76]

 13 Whole body bone mineral content (g)2101Mean Difference (IV, Fixed, 95% CI)1.65 [-1.65, 4.95]

 14 Mental development index at 18 months1245Mean Difference (IV, Fixed, 95% CI)2.20 [-3.35, 7.75]

 15 Psychomotor development index at 18 months1245Mean Difference (IV, Fixed, 95% CI)2.40 [-1.90, 6.70]

 16 Nitrogen retention (mg/kg/day)252Mean Difference (IV, Fixed, 95% CI)66.05 [35.28, 96.82]

 17 Hypercalcemia2263Risk Ratio (M-H, Fixed, 95% CI)1.18 [0.76, 1.82]

 18 Feed intolerance367Risk Ratio (M-H, Fixed, 95% CI)2.85 [0.62, 13.08]

 19 Necrotizing enterocolitis7640Risk Ratio (M-H, Fixed, 95% CI)1.33 [0.69, 2.54]

 20 Blood pH1275Mean Difference (IV, Fixed, 95% CI)Not estimable

 21 Blood urea (mmol/l)5350Mean Difference (IV, Fixed, 95% CI)0.27 [0.14, 0.40]

 22 Death8603Risk Ratio (M-H, Fixed, 95% CI)1.48 [0.66, 3.34]

 
Comparison 2. Multicomponent fortification vs control (trials without mineral supplementation of the control group)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Weight gain (g/kg/day)5136Mean Difference (IV, Fixed, 95% CI)3.62 [2.69, 4.55]

 2 Weight gain (g/day)355Mean Difference (IV, Fixed, 95% CI)4.74 [2.78, 6.70]

 3 Length gain (cm/week)5102Mean Difference (IV, Fixed, 95% CI)0.18 [0.08, 0.28]

 4 Head growth (cm/week)6114Mean Difference (IV, Fixed, 95% CI)0.14 [0.09, 0.20]

 5 Serum alkaline phosphatase (IU/l)6169Mean Difference (IV, Fixed, 95% CI)-43.24 [-98.29, 11.81]

 6 Bone mineral content (mg/cm)279Mean Difference (IV, Fixed, 95% CI)8.30 [3.84, 12.76]

 7 Nitrogen retention (mg/kg/day)127Mean Difference (IV, Fixed, 95% CI)82.5 [32.53, 132.47]

 8 Feed intolerance119Risk Ratio (M-H, Fixed, 95% CI)4.55 [0.25, 83.70]

 9 Necrotizing enterocolitis4261Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.44, 2.20]

 10 Blood urea (mmol/l)361Mean Difference (IV, Fixed, 95% CI)0.96 [0.56, 1.36]

 11 Death6297Risk Ratio (M-H, Fixed, 95% CI)13.33 [0.78, 227.34]

 

What's new

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Declarations of interest
  13. Sources of support
  14. Index terms

Last assessed as up-to-date: 28 August 2003.


DateEventDescription

28 October 2008AmendedConverted to new review format.



 

History

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Declarations of interest
  13. Sources of support
  14. Index terms

Protocol first published: Issue 4, 1998
Review first published: Issue 4, 1998


DateEventDescription

29 August 2003New citation required but conclusions have not changedSubstantive amendment

29 August 2003New search has been performedThis review updates the existing review of "Multicomponent fortified human milk for promoting growth in preterm infants" published in The Cochrane Library, Issue 4, 1998.

Location of 6 new studies (included - Zuckerman, Nicholl, Faerk; excluded - Gupta, Porcelli, Reiss) and 1 follow-up report (Wauben).



 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Declarations of interest
  13. Sources of support
  14. Index terms

None known.

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Declarations of interest
  13. Sources of support
  14. Index terms
 

Internal sources

  • National Women's Hospital, Auckland, New Zealand.
  • University of Auckland, Auckland, New Zealand.

 

External sources

  • No sources of support supplied

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. Abstract摘要
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Declarations of interest
  14. Sources of support
  15. Characteristics of studies
  16. References to studies included in this review
  17. References to studies excluded from this review
  18. Additional references
  19. References to other published versions of this review
Carey 1987 {published data only}
  • Carey DE, Rowe JC, Goetz CA, Horak E, Clark RM, Goldberg B. Growth and phosphorus metabolism in premature infants fed human milk, fortified human milk, or special premature formula. Use of serum procollagen as a marker of growth. Am J Dis Child 1987;141:511-15.
Faerk 2000 {published data only}
Greer 1988 {published and unpublished data}
Gross 1987 (1) {published data only}
Gross 1987 (2) {published data only}
Kashyap 1990 {published and unpublished data}
  • Kashyap S, Schulze KF, Forsyth M, Dell RB, Ramakrishnan R, Heird WC. Growth, nutrient retention, and metabolic response of low-birth-weight infants fed supplemented and unsupplemented preterm human milk. Am J Clin Nutr 1990;52:254-62.
  • Kashyap S, Schulze KF, Ramakrishnan R, Dell RB, Forsyth M, Zucker C, Heird WC. Growth, nutrient retention and metabolic response of low birth weight (LBW) infants fed human milk (HM). Pediatr Res 1988;23:486A.
Lucas 1996 {published and unpublished data}
  • Lucas A, Fewtrell MS, Morley R, Lucas PJ, Baker BA, Lister G, Bishop NJ. Randomized outcome trial of human milk fortification and developmental outcome in preterm infants. Am J Clin Nutr 1996;64:142-51.
Modanlou 1986 {published data only}
  • Modanlou HD, Lim MO, Hansen JW, Sickles V. Growth, biochemical status, and mineral metabolism in very-low-birth-weight infants receiving fortified preterm human milk. J Pediatr Gastroenterol Nutr 1986;5:762-67.
Nicholl 1999 {published data only}
Pettifor 1989 {published and unpublished data}
  • Pettifor JM, Rajah R, Venter A, Moodley GP, Opperman L, Cavaleros M, Ross FP. Bone mineralization and mineral homeostasis in very low-birth-weight infants fed either human milk or fortified human milk. J Pediatr Gastroenterol Nutr 1989;8:217-24.
Polberger 1989 {published data only}
  • Polberger SKT, Axelsson IA, Räihä NCE. Growth of very low birth weight infants on varying amounts of human milk protein. Pediatr Res 1989;25:414-19.
  • Polberger SKT, Axelsson IE, Räihä NCR. Amino acid concentrations in plasma and urine in very low birth weight infants fed protein-unenriched or human milk protein-enriched human milk. Pediatrics 1990;86:909-15.
  • Polberger SKT, Fex GA, Axelsson IE, Räihä NCR. Eleven plasma proteins as indicators of protein nutritional status in very low birth weight infants. Pediatrics 1990;86:916-21.
Wauben 1998 {published and unpublished data}
  • Wauben I, Gibson R, Atkinson S. Premature infants fed mothers' milk to 6 months corrected age demonstrate adequate growth and zinc status in the first year. Early Human Dev 1999;54(2):181-94.
  • Wauben IP, Atkinson SA, Grad TL, Shah JK, Paes B. Moderate nutrient supplementation of mother's milk for preterm infants supports adequate bone mass and short-term growth: a randomized, controlled trial. Am J Clin Nutr 1998;67:465-72.
  • Wauben IPM, Atkinson SA, Shah JK, Paes B. Growth and body composition of preterm infants: influence of nutrient fortification of mother's milk in hospital and breastfeeding post-hospital discharge. Acta Paediatr 1998;87(7):780-85.
Zuckerman 1994 {published data only}

References to studies excluded from this review

  1. Top of page
  2. Abstract摘要
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Declarations of interest
  14. Sources of support
  15. Characteristics of studies
  16. References to studies included in this review
  17. References to studies excluded from this review
  18. Additional references
  19. References to other published versions of this review
Boehm 1991 {published data only}
  • Boehm G, Borte M, Müller DM, Senger H, Rademacher C. Nutrition of preterm infants with supplemented human milk: EOPROTIN vs human albumin [Die Ernahrug Fruhgeborener mit angereicherter Frauenmilch: EOPROTIN 60 im Vergleich mit Humanalbumin]. Kinderarztl Praxis 1991;59:S 293-98.
dos Santos 1997 {published data only}
  • dos Santos MM, Martinez FE, Sieber V, Pinhata M, Felin ML. Acceptability and growth of VLBW-infants fed with own mother's milk enriched with a natural or commercial human milk fortifier (HMF). Pediatr Res 1997;41:231A, #1370.
Ewer 1996 {published data only}
Gupta (unpublished) {unpublished data only}
  • Gupta G. Thesis (unpublished).
Lucas 1984 {published data only}
McClure 1996 {published data only}
Metcalf 1994 {published data only}
Moyer-Mileur 1992 {published data only}
  • Moyer-Mileur L, Chan GM, Gill G. Evaluation of liquid or powdered fortification of human milk on growth and bone mineralization status of preterm infants. J Pediatr Gastroenterol Nutr 1992;15:370-74.
Plath 1988 {published data only}
  • Plath Chr, Heine W, Uhlemann M, Wutzke KD, Muller M, Kracht M. 15N-tracer kinetic studies regarding whole body protein metabolism in very small preterm infants for evaluation of human milk fortifier [abstract]. Clin Nutr 1988;7 Spec Suppl:11.
Porcelli 2000 {published data only}
  • Porcelli P, Schanler R, Greer F, Chan G, Gross S, Mehta N, Spear M, Kerner J, Euler AR. Growth in human milk-fed very low birth weight infants receiving a new human milk fortifier. Ann Nutr Metab 2000;44:2-10.
  • Porcelli P, Schanler RJ, Greer F, Chan G, Gross S, Mehta N, Spear M, Kerner J, Flores L, Terry D, Minervini G, Euler A. A new human milk fortifier (HMF): A multicenter report. Pediatr Res 1996;40:548.
Reis 2000 {published data only}
Ronnholm 1982 {published data only}
  • Rönnholm KAR, Perheentupa J, Siimes MA. Supplementation with human milk protein improves growth of small premature infants fed human milk. Pediatrics 1986;77:649-53.
  • Rönnholm KAR, Siimes MA. Haemoglobin concentration depends on protein intake in small preterm infants fed human milk. Arch Dis Child 1985;60:99-104.
  • Rönnholm KAR, Simell O, Siimes MA. Human milk protein and medium-chain triglyceride oil supplementation of human milk: plasma amino acids in very low-birth-weight infants. Pediatrics 1984;74:792-99.
  • Rönnholm KAR, Sipila O, Siimes MA. Human milk protein supplementation for the prevention of hypoproteinemia without metabolic imbalance in breast milk-fed, very low-birth-weight infants. J Pediatr 1982;101:243-47.
Sankaran 1996 {published data only}
  • Sankaran K, Papageorgiou A, Ninan A, Sankaran R. A randomized, controlled evaluation of two commercially available human breast milk fortifiers in healthy preterm neonates. J Am Diet Assoc 1996;96:1145-49.
Schanler 1995 {published data only}
Venkataraman 1988 {published data only}
  • Venkataraman PS, Blick KE. Effect of mineral supplementation of human milk on bone mineral content and trace element metabolism. J Pediatr 1988;113:220-24.

Additional references

  1. Top of page
  2. Abstract摘要
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Declarations of interest
  14. Sources of support
  15. Characteristics of studies
  16. References to studies included in this review
  17. References to studies excluded from this review
  18. Additional references
  19. References to other published versions of this review
54th WHA
  • The World Health Organization. 54th World Health Assemby 2001; Vol. WHA54.2. [: http://www.who.int/gb/EB_WHA/PDF/WHA54/ea54R2.pdf]
Atkinson 1983
Cooper 1984
  • Cooper PA, Rothberg AD, Pettifor JM, Bolton KD, Devenhuis S. Growth and biochemical responses of premature infants fed pooled preterm milk or special formula. J Pediatr Gastroent Nutr 1984;3:749-54.
Kuschel 1999a
Kuschel 1999b
Kuschel 1999c
  • Kuschel CA, Harding JE. Fat supplementation of human milk to promote growth in preterm infants. Cochrane Database of Systematic Reviews 1999, Issue 3. [DOI: 10.1002/14651858.CD000341]
Kuschel 2001
  • Kuschel CA, Harding JE. Calcium and phosphorus supplementation of human milk for preterm infants. Cochrane Database of Systematic Reviews 2001, Issue 4. [DOI: 10.1002/14651858.CD003310]
Lucas 1990
McGuire 2001
  • 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. [DOI: 10.1002/14651858.CD002971]
McGuire 2003
  • McGuire W, Anthony MY. Donor human milk versus formula for prevention of necrotising enterocolitis in preterm infants: systematic review. Arch Dis Child Fetal Neonatal Ed 2003;88:F11-14.
Morley 1998
Roberts 1987
Schanler 2001
Sinclair 1992
  • Sinclair JC, Bracken MB. Effective Care of the Newborn Infant. Oxford: Oxford University Press, 1992.