Location of 6 new studies (included - Zuckerman, Nicholl, Faerk; excluded - Gupta, Porcelli, Reiss) and 1 follow-up report (Wauben).
Multicomponent fortified breast milk for promoting growth in preterm infants
Babies born at full term (40 weeks) get all their nutritional needs from breast milk. Babies born early (preterm) have different needs and grow very rapidly. Those fed breast milk may need extra supplements. The review of trials found evidence that adding nutritional supplements to breast milk leads to short term improved growth and possibly also bone formation. The review found no evidence of long-term benefits or adverse effects.
For term infants, human milk provides adequate nutrition to facilitate growth, as well as potential beneficial effects on immunity and the maternal-infant emotional state. However, the role of human milk in premature infants is less well defined as it contains insufficient quantities of some nutrients to meet the estimated needs of the infant. Observational studies have suggested that infants fed formula have a higher rate of growth than infants who are breast fed. However, there are potential short term and long term benefits from human milk. Commercially-produced multicomponent fortifiers provide additional nutrients to supplement human milk (in the form of protein, calcium, phosphate, and carbohydrate, as well as vitamins and trace minerals).
The main objective was 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.
Searches were made of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 3003), MEDLINE (searched August 29, 2003), previous reviews including cross references, abstracts, conferences and symposia proceedings, expert informants, journal handsearching mainly in the English language.
All trials utilising random or quasi-random allocation to supplementation of human milk with multiple nutrients or no supplementation in premature infants within a nursery setting were eligible.
Data were extracted using the standard methods of the Cochrane Collaboration and its Neonatal Review Group, with separate evaluation of trial quality and data extraction by each author and synthesis of data using relative risk and weighted mean difference.
Supplementation of human milk with multicomponent fortifiers is associated with short term increases in weight gain, linear and head growth. There is no effect on serum alkaline phosphatase levels; it is not clear if there is an effect on bone mineral content. Nitrogen retention and blood urea levels appear to be increased.
There are insufficient data to evaluate long term neurodevelopmental and growth outcomes, although there appears to be no effect on growth beyond one year of life.
Use of multicomponent fortifiers does not appear to be associated with adverse effects, although the total number of infants studied and the large amount of missing data reduces confidence in this conclusion. Blood urea levels are increased and blood pH levels minimally decreased, but the clinical significance of this is uncertain.
Multicomponent fortification of human milk is associated with short-term improvements in weight gain, linear and head growth. Despite the absence of evidence of long-term benefit and insufficient evidence to be reassured that there are no deleterious effects, it is unlikely that further studies evaluating fortification of human milk versus no supplementation will be performed. Further research should be directed toward comparisons between different proprietary preparations and evaluating both short-term and long-term outcomes in search of the "optimal" composition of fortifiers.
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).
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.
Controlled trials utilising either random or quasi-random patient allocation.
Premature infants receiving care within a nursery setting.
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.
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
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.
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.
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.
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.
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).
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.
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.
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.
The reviewers wish to thank those authors who were able to provide additional information to assist with this review.
None known.
| Study | Methods | Participants | Interventions | Outcomes | Notes | Allocation concealment |
| Carey 1987 | Randomized study, single centre Sample size estimate: No Randomization method: Not stated Blinding of randomization: Can't tell Complete follow-up: No Blinding of outcome measure: Can't tell |
Birthweight <1500g Exclusions: significant illness and congenital malformation Enteral feeds of 150ml/kg/day for 48 hours Number of Treatment Infants Randomized: Unknown Number of Control Infants Randomized: Unknown |
Maternal milk supplemented with Protein, Calcium, and Phosphate
(exact quantities not specified) vs. unsupplemented maternal milk. Intervention ceased at approximately 4.5 weeks. No information about supplemental vitamins. |
Short term growth Biochemical indices of bone metabolism Serum protein levels |
Some results expressed as means for the number of observations,
rather than individuals. Some infants excluded from results because of missing data. |
B |
| Faerk 2000 | Randomized study, two centres Sample size estimate: Yes, based on BMC (at term corrected) Method of randomization: Block randomization by sealed envelopes, stratified by birthweight Blinding of randomization: Adequate Blinding of intervention: Yes Complete follow-up: No Blinding of outcome measurement: Yes |
Gestational age <32 weeks Exclusions: major congenital abnormalities |
Maternal or donor milk supplemented with Eoprotin (0.4g Protein,
35mg Calcium, and 17mg Phosphorus) per 100ml vs. maternal or donor milk supplemented
with 10mg Phosphorus per 100ml Target intake of 200ml/kg/day All infants received Vitamin D 800iU per day Intervention ceased when breast fed or 36 weeks corrected GA |
BMC (whole body) Growth at term |
103 infants randomized to fortifier or phosphorus. 9 infants were withdrawn (6 fortifier) and DEXA scans were not considered technically suitable for a further 18 infants (9 fortifier). Only extractable data were BMC and rates of NEC. Further information about other outcomes requested from the authors. | A |
| Greer 1988 | Randomized study, single centre Sample size estimate: No Method of randomization: Random number table Blinding of randomization: Can't tell Blinding of intervention: No Complete follow-up: No Blinding of outcome measurements: Can't tell |
Infants <32 weeks GA or <1600g Exclusions: major congenital abnormalities, congenital intrauterine infection, significant gastrointestinal disease, or seizures requiring anticonvulsant therapy. Study commenced once infants tolerating full oral feeds. Number of Treatment Infants Randomized: Unknown Number of Control Infants Randomized: Unknown |
Maternal milk supplemented with 0.85g Protein, 90mg Calcium, and
45mg Phosphorus per 100ml (Ross Laboratories) vs. unsupplemented maternal
milk Enteral intake >120ml/kg/day and <200ml/kg/day - varied according to weight gain, appetite, and tolerance. All infants received Vitamin D 400IU/day. |
Short term growth BMC Biochemical indices of bone metabolism Urea Total protein |
The fortified group received significantly less milk (152 vs.
180 ml/kg/day) than the unsupplemented group. There was no significant difference
in caloric intake. Of 176 eligible infants, only 10 in the HMF arm and 10 in the unsupplemented arm completed the study. |
B |
| Gross 1987 (1) | Randomized study, single centre. Sample size estimate: No Randomization method: Sealed envelopes Blinding of randomization: Can't tell Complete follow-up: No Blinding of outcome measures: Can't tell Two phase trial, referred to as Gross 1987 (1) and Gross 1987 (2) |
Birthweight <1600g, AGA Free from congenital anomalies and major disease, no supplemental oxygen, enteral feeds begun within one week of birth. Number of Treatment Infants Randomized to Phase 1: 10 Number of Control Infants Randomized to Phase 1: 10 Number of Treatment Infants Randomized to Phase 2: 10 Number of Control Infants Randomized to Phase 2: 9 |
Phase 1: Maternal or donor milk mixed ml-for-ml with Similac Special
Care (Ross Laboratories) vs. unsupplemented human milk. Phase 2: Maternal or donor milk with powdered HMF (Ross Laboratories) providing 0.9g protein, 87mg Calcium, and 50mg Phosphorus and electrolytes per 100ml vs. unsupplemented human milk. Enteral intake 180ml/kg/day, adjusted according to weight gains. Intervention ceased at a weight of 1800-2000g. All infants received supplemental vitamins (including Vitamin D 400IU/day). |
Short term growth Growth at 44 weeks postconceptional age BMC Biochemical indices of bone metabolism |
Phase 2 compared HMF to unsupplemented human milk, as well as
a group who received preterm formula as in Phase 1. Only the control group
and the group receiving powdered fortifier have been included in this review. Results of short-term weight gain could not be included as they were expressed in g/day. Information has been requested from the author. 4 infants in the phase 2 study were withdrawn post-randomization because of feed intolerance (2 each from the HMF and formula supplementation arms). |
B |
| Gross 1987 (2) | See Gross (1) | See Gross (1) | See Gross (1) | See Gross (1) | See Gross (1) | B |
| Kashyap 1990 | Randomized study, single centre Sample size estimate: No Randomization Method: Sealed envelope Blinding of randomization: Adequate Blinding of intervention: Can't tell Complete follow-up: No Blinding of outcome measurement: Can't tell |
Birthweight 900-1750g Number of Treatment Infants Randomized: 30 Number of Control Infants Randomized: 36 |
Intervention commenced once infants enterally feeding. Maternal milk supplemented with (per kg/day) with 1.1g Protein, 3.7mmol Calcium, 2.11mmol Phosphate, and Sodium (Ross Laboratories) vs. unsupplemented maternal milk. Feeds maintained at 180ml/kg/day Outcomes assessed at 2200g. All infants received supplemental Vitamin D (400 iU/day) |
Short term growth Biochemical indices of bone metabolism Nitrogen retention Urea |
High attrition from both unsupplemented (22 of 36) and fortified
(17 of 30) groups. Reasons included NEC, PDA, and insufficient maternal milk. Some of these infants were placed into a third, non-random arm of the study in which they received supplemented term human milk. This arm has not been included in this review. Other outcomes included plasma amino acid levels and skinfold thickness. |
A |
| Lucas 1996 | Randomized trial, two centres Sample size estimate: Yes - neurodevelopmental outcome Method of randomization: Sealed opaque envelope, stratified by birthweight (<1200 and >1200g) Blinding of randomization: Yes Blinding of intervention: No Complete follow-up: Yes Blinding of outcome measurement: Yes (neurodevelopmental outcome) |
<37 weeks and <1850g Survival to 48-72 hours Exclusions: major congenital abnormalities affecting neurodevelopmental outcomes, non-resident in UK Number of Treatment Infants Randomized: 137 Number of Control Infants Randomized: 138 |
Maternal milk supplemented with (per 100ml) 0.7g Protein (bovine),
2.73g Carbohydrate, 0.05g Fat, 90mg Calcium, and 45mg Phosphate, and electrolytes
(Enfamil, Mead Johnson), vs. maternal milk supplemented with 15mg/100ml Phosphate. Enteral intake 180ml/kg/day. Intervention ceased at discharge or 2000g. All infants received vitamins (including Vitamin D 260 IU/100ml). Infants whose mothers could not provide sufficient milk were supplemented with a premature formula and not excluded from the analysis. |
Neurodevelopmental outcome at 9 and 18 months. Short term growth. Growth to 9 and 18 months. Serum indices of bone metabolism Urea |
The authors felt it was not ethical to provide totally unsupplemented
human milk so added 15mg Phosphate/100ml in control infants. A large proportion of infants in both groups were supplemented with a premature formula when there was insufficient maternal milk. Linear and head growth have been converted from mm/day to cm/week. |
A |
| Modanlou 1986 | Randomized study, single centre Sample size estimate: No Randomization Method: Sealed envelopes Blinding of randomization: Adequate Blinding of intervention: No Complete follow-up: Yes Blinding of outcome measurement: No |
1000-1500g AGA infants. Exclusions: Ventilatory assistance >1 week, oxygen >10 days, diuretic therapy >3 days, not enterally fed by 14 days Number of Treatment Infants Randomized: 20 Number of Control Infants Randomized: 19 |
Maternal milk supplemented with (per 100ml) 0.7g Protein, 2.7g
Carbohydrate, "trace" Fat, 60mg Calcium, and 33mg Phosphate, trace minerals,
and electrolytes (preparation not specified), vs. unsupplemented maternal
milk. Enteral intake approximately 135-140ml/kg/day. Intervention ceased at discharge or 1800g. Vitamin D supplementation unknown. |
Short term growth Indices of bone metabolism BMC Urea Serum proteins |
A third arm of the study evaluated infants receiving a premature
formula (not analysed in this review). 9 infants in the control arm and 10 in the HMF arm were withdrawn for insufficient maternal milk. 2 infants in the HMF arm were withdrawn for suspected NEC. Infants whose mothers could not provide sufficient milk were supplemented with a term infant formula and not excluded from the analysis unless formula intake was >10% of weekly total. |
A |
| Nicholl 1999 | Randomized study, single centre Sample size estimate: Yes, based on leg length by knemometry Method of randomization: Sealed envelopes Blinding of randomization: Yes Blinding of intervention: No Complete follow-up: Yes Blinding of outcome: No |
<1500g Enteral feeds at least 150ml/kg/day Exclusions: Fluid restriction, diuretics, postnatal systemic steroid use, significant congenital abnormality |
Maternal (or pasteurised pooled donor milk) supplemented with
(per 100ml) 0.7g Protein, 2.0g Carbohydrate, 30mg Calcium, 40mg Phosphorus,
trace minerals and vitamins vs. unsupplemented maternal or donor milk Intervention ceased when infants no longer required nasogastric feeds |
Short term growth (including knemometry) Indices of bone metabolism (ALP) |
One infant whose mother declined fortifier was included in the results of the non-fortified infants. A third group of infants received a preterm formula. | A |
| Pettifor 1989 | Quasi-randomized trial, single centre. Sample size estimate: No Method of randomization: Allocation by maternal hospital number Blinding of randomization: No Blinding of intervention: Can't tell Complete follow-up: No Blinding of outcome measurement: Can't tell |
1000-1500g birthweight No major congenital abnormalities, no ventilator requirement, no serious infection, no major metabolic disturbance, and enteral intake at least 45ml/kg/day on Day 4 Number of Treatment Infants Randomized: 53 Number of Control Infants Randomized: 47 |
Maternal milk supplemented with (per 100ml) 0.05g Protein, 1.1g
Carbohydrate, 0.26g Fat, 72.3mg Calcium, and 34mg Phosphate, and electrolytes
and vitamins (HMF, Ross Laboratories) vs. unsupplemented maternal milk. Maximal enteral intake 200ml/kg/day Intervention ceased at approximately 1800g. All infants received additional Vitamin D 750IU/day. |
Short term growth BMC Serum indices of bone metabolism Serum albumin |
41 of 100 infants enrolled were withdrawn - 13 for insufficient maternal milk, 16 for significant illness [2 NEC, 11 respiratory causes, and 3 others], and 7 died. 5 others were excluded for incomplete data. | C |
| Polberger 1989 | Randomized trial. Single centre Method of randomization: Sealed envelopes Blinding of randomization: Adequate Blinding of intervention: Adequate Complete follow-up: No |
AGA preterm infants <1500g Enteral intake 170ml/kg/day Exclusions: major illness, requirement for supplemental oxygen Number of Treatment Infants Randomized: 9 Number of Control Infants Randomized: 8 |
Maternal or donor milk supplemented with (per 100ml) 1.0g human
milk protein and 1.0g human milk fat vs. unsupplemented human milk. Intervention ceased at 2200g or when breast fed. All infants were supplemented with vitamin E, folic acid, multivitamins, and extra Vitamin D (to a total of 1200 IU/day). All infants received Calcium (30mg/kg/day) and Phosphate (20mg/kg/day) from day 5. 2mg elemental iron per kg per day given from 4 weeks. |
Short term growth Plasma protein levels |
This study is included in the multicomponent review because of
the two nutritional supplements. This study had four arms - unsupplemented,
vs. supplemented with protein, vs. supplemented with fat, vs. supplemented
with fat and protein. Supplementation with fat alone and protein alone is
discussed in separate reviews. 34 infants were enrolled in all four study
groups, but six infants were excluded following randomization (reasons discussed
in separate reviews). Results were reported for only 7 infants in each group. Ultrafiltration of human milk to obtain protein may result in additional calcium being provided to the fortifier group. There were large fluctuations in the energy intake for all four groups across the study. Other outcomes, not included in the review, included plasma and urine amino acid levels. |
A |
| Wauben 1998 | Randomized trial. Single centre Method of randomization: Block randomization, random number tables Blinding of randomization: Yes Blinding of intervention: No Complete follow-up: No Sample size estimate: Yes (BMC at term corrected) |
AGA preterm infants <1800g, greater than 1 week old Enteral intake 160ml/kg/day Exclusions: Gastrointestinal disease, major congenital anomalies Number of Treatment Infants Randomized: 15 Number of Control Infants Randomized: 16 |
Commenced when maternal milk providing >80% of enteral intake Maternal supplemented with (per 100ml) 0.37g human milk protein, 3.47g carbohydrate, 61mg Calcium, 44mg Phosphorus, as well as electrolytes, other minerals, and vitamins (including Vit D 472IU/day) (Wyeth-Ayerst, Toronto) vs. unsupplemented human milk. Mean fluid intakes significantly greater in the control group (177 vs. 164ml/kg/day). Intervention ceased at discharge or 38 weeks corrected GA, whichever occurred later. Control infants supplemented with vitamin D (600IU/day) whilst receiving supplements. All infants received "standard" vitamin supplementation following discharge. |
Short term growth Biochemical indices of bone metabolism BMC (whole body) Nitrogen retention |
6 infants (3 in each group) were withdrawn - 2 in the HMF group
for feed intolerance (defined as abdominal distension - personal communication,
Dr S Atkinson), and 1 for insufficient maternal milk. 2 infants in the control
group developed chronic lung disease, and 1 developed a metabolic acidosis.
These infants' results are not included in the paper. A third arm of the study (not analysed in this review) evaluated infants who received a preterm formula. Infants in the control arm were significantly lighter at birth, and significantly lighter and shorter at study entry and exit than the group receiving HMF. Nutrient intakes were also measured. |
A |
| Zuckerman 1994 | Quasi-randomized trial. Single Centre Method of randomization: by hospital number (even/odd) Blinding of randomization: No Blinding of intervention: No Complete follow-up: No Blinding of outcome measure: Can't tell Sample size estimate: No |
Infants <1200g, greater than 2 weeks old Enteral intake maximum 200ml/kg/day Exclusions: congenital abnormalities, infections, any diseases causing bone disease |
Maternal milk mixed in equal proportions with premature infant
formula (Alprem, Nestle) to give supplements (per 100ml) of calcium 14.5mg,
phosphorus 7mg, and protein 0.6g vs. unsupplemented human milk. Intervention ceased at 1800g. All infants received 800iU/day Vitamin D |
Short term growth Serum indices of bone metabolism Radiographic changes of metabolic bone disease Serum vitamin D levels |
Mainly SGA infants in each group. 3 infants in the control group were excluded because of incorrect feeding. 16 of 27 control infants completed follow-up. All 29 infants in the supplemented group completed the hospital study but only 14 completed post-discharge follow-up. Energy intakes were similar between both groups, despite the increased caloric density in the supplemented group. |
C |
| Study | Reason for exclusion |
| Boehm 1991 | No unsupplemented control group. The interventions contrasted were multicomponent fortifier (EOPROTIN) versus supplementation with human albumin, minerals, and sodium. |
| dos Santos 1997 | Comparison of multicomponent fortifiers. |
| Ewer 1996 | Did not include any prespecified outcomes of this review. |
| Gupta (unpublished) | Randomized study (method not stated) comparing a commercial multicomponent fortifer vs. individualised supplements (fat, minerals, vitamins) vs. low-birth-weight formula +/- human milk. Concerns about randomization method and imbalance in characteristics of the study groups. |
| Lucas 1984 | Infants received a preterm formula or donor term human milk as a substitute for maternal milk. The supplements were given in varying amounts, with the median intake 42%. Over a third of mothers provided less than 20% of their infant's intake. |
| McClure 1996 | Did not include any prespecified outcomes of this review. |
| Metcalf 1994 | Comparison of multicomponent fortifiers. |
| Moyer-Mileur 1992 | Comparison of multicomponent fortifiers. |
| Plath 1988 | Did not include any prespecified outcomes. |
| Porcelli 2000 | Comparison of multicomponent fortifiers. |
| Reis 2000 | Comparison of multicomponent fortifiers. |
| Ronnholm 1982 | Unable to abstract data for those infants supplemented with fat and protein together vs. those who were unsupplemented. |
| Sankaran 1996 | Comparison of multicomponent fortifiers. |
| Schanler 1995 | Comparision of two multicomponent fortifiers in two cohorts over two separate time periods. |
| Venkataraman 1988 | Unable to abstract data from published report. |
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}
Faerk J, Peitersen B, Petersen S, Michaelsen KF. Bone mineralisation in preterm infants cannot be predicted from serum alkaline phosphatase or serum phosphate. Arch Dis Child Fetal Neonatal Ed 2002;87:F133-36.
* Faerk J, Petersen S, Peitersen B, Michaelsen KF. Diet and bone mineral content at term in premature infants. Pediatr Res 2000;47(1):148-56.
Faerk J, Petersen S, Peitersen B, Michaelsen KF. Diet, growth, and bone mineralisation in premature infants. Adv Exp Med Biol 2001;501:479-83.
Greer 1988 {published and unpublished data}
Greer FR, McCormick A. Improved bone mineralization and growth in premature infants fed fortified own mother's milk. J Pediatr 1988;112:961-69.
Gross 1987 (1) {published data only}
Gross SJ. Bone mineralization in preterm infants fed human milk with and without mineral supplementation. J Pediatr 1987;111:450-58.
Gross 1987 (2) {published data only}
Gross SJ. Bone mineralization in preterm infants fed human milk with and without mineral supplementation. J Pediatr 1987;111:450-58.
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}
Nicholl RM, Gamsu HR. Changes in growth and metabolism in very low birthweight infants fed with fortified breast milk. Acta Paediatr 1999;88:1056-61.
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}
Zuckerman M, Pettifor JM. Rickets in very-low-birth-weight infants born at Baragwanath Hospital. S Afr Med J 1994;84:216-20.
Boehm G, Borte M, Müller DM, Senger H, Rademacher C. Die Ernahrug Fruhgeborener mit angereicherter Frauenmilch: EOPROTIN 60 im Vergleich mit Humanalbumin [Nutrition of preterm infants with supplemented human milk: EOPROTIN vs human albumin]. 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}
Ewer AK, Yu VYH. Gastric emptying in pre-term infants: the effect of breast milk fortifier. Acta Paediatr 1996;85:1112-15.
Gupta (unpublished) {unpublished data only}
Gupta G. Thesis (unpublished).
Lucas 1984 {published data only}
Bishop NJ, Dahlenburg SL, Fewtrell MS, Morley R, Lucas A. Early diet of preterm infants and bone mineralization at age five years. Acta Paediatr 1996;85:230-36.
Lucas A, Baker BA. Breast milk jaundice in premature infants. Arch Dis Child 1986;61:1063-67.
Lucas A, Brooke OG, Morley R, Cole TJ, Bamford MF. Early diet of preterm infants and development of allergic or atopic disease: randomised prospective study. BMJ 1990;300:837-40.
Lucas A, Cole TJ. Breast milk and neonatal necrotising enterocolitis. Lancet 1990;336:1519-23.
* Lucas A, Gore SM, Cole TJ, et al. Multicentre trial on feeding low birthweight infants: effects of diet on early growth. Arch Dis Child 1984;59:722-30.
Lucas A, Morley R, Cole TJ, et al. Early diet in preterm infants and developmental status in infancy. Arch Dis Child 1989;64:1570-78.
Lucas A, Morley R, Cole TJ, et al. Early diet in preterm babies and developmental status at 18 months. Lancet 1990;335:1477-81.
Lucas A, Morley R, Cole TJ, Gore SM. A randomised multicentre study of human milk versus formula and later development in preterm infants. Arch Dis Child 1994;70:F141-F146.
Lucas A, Morley R. Does early nutrition in infants born before term programme later blood pressure? BMJ 1994;309:304-8.
Morley R, Lucas A. Randomized diet in the neonatal period and growth performance until 7.5-8 y of age in preterm children. Am J Clin Nutr 2000;71(3):822-28.
McClure 1996 {published data only}
McClure RJ, Newell RJ. Effect of fortifying breast milk on gastric emptying. Arch Dis Child 1996;74:F60-F62.
Metcalf 1994 {published data only}
Metcalf R, Dilena B, Gibson R, Marshall P, Simmer K. How appropriate are commercially available human milk fortifiers? J Paediatr Child Health 1994;30:350-55.
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}
Reis BB, Hall RT, Schanler RJ, et al. Enhanced growth of preterm infants fed a new powdered human milk fortifer: a randomized, controlled trial. Pediatrics 2000;106:581-88.
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}
Schanler RJ, Abrams SA. Postnatal attainment of intrauterine macromineral accretion rates in low birth weight infants fed fortified human milk. J Pediatr 1995;126:441-47.
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.
* indicates the primary reference for the study
The World Health Organization. 54th World Health Assemby 2001;WHA54.2.
Atkinson SA, Radde IC, Anderson GH. Macromineral balances in premature infants fed their own mothers' milk or formula. J Pediatr 1983;102:99-106.
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 CA, Harding JE. Protein supplementation of human milk to promote growth in preterm infants (Cochrane Review). In: The Cochrane Library, Issue 2, 1999. Oxford: Update Software.
Kuschel CA, Harding JE. Carbohydrate supplementation of human milk to promote growth in preterm infants (Cochrane Review). In: The Cochrane Library, Issue 2, 1999. Oxford: Update Software.
Kuschel CA, Harding JE. Fat supplementation of human milk to promote growth in preterm infants (Cochrane Review). In: The Country Library, Issue 3, 1999. Oxford: Update Software.
Kuschel CA, Harding JE. Calcium and phosphorus supplementation of human milk for preterm infants (Cochrane Review). In: The Cochrane Library, Issue 4, 2001. Oxford: Update Software.
Lucas A, Cole TJ. Breast milk and neonatal necrotising enterocolitis. Lancet 1990;335:1519-23.
McGuire W, Anthony MY. Formula milk versus term human milk for feeding preterm or low birth weight infants (Cochrane Review). In: The Cochrane Library, Issue 4, 2001. Oxford: Update Software.
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 R. Nutrition and cognitive development. Nutrition 1998;14:752-54.
Roberts SB, Lucas A. Energetic efficiency and nutrient accretion in preterm infants fed extremes of dietary intake. Human Nutr - Clin Nutr 1987;41:105-13.
Schanler RJ. The use of human milk for premature infants. Pediatr Clin N Amer 2001;48:207-19.
Sinclair JC, Bracken MB. Effective Care of the Newborn Infant. Oxford: Oxford University Press, 1992.
Kuschel CA, Harding JE. Multicomponent fortified human milk for promoting growth in preterm infants (Cochrane Review). In: The Cochrane Library, Issue 2, 2000. Oxford: Update Software.
01.01 Weight gain (g/kg/day)
01.02 Weight gain (g/day)
01.03 Length gain (cm/week)
01.04 Head growth (cm/week)
01.05 Weight at 12 months (kg)
01.06 Length at 12 months (cm)
01.07 Head circumference at 12 months (cm)
01.08 Weight at 18 months (kg)
01.09 Length at 18 months (cm)
01.10 Head circumference at 18 months (cm)
01.11 Serum alkaline phosphatase (IU/l)
01.12 Bone mineral content (mg/cm)
01.13 Whole body bone mineral content (g)
01.14 Mental development index at 18 months
01.15 Psychomotor development index at 18 months
01.16 Nitrogen retention (mg/kg/day)
01.17 Hypercalcemia
01.18 Feed intolerance
01.19 Necrotizing enterocolitis
01.20 Blood pH
01.21 Blood urea (mmol/l)
01.22 Death
02 Multicomponent fortification vs control (trials without mineral supplementation of the control group)
02.01 Weight gain (g/kg/day)
02.02 Weight gain (g/day)
02.03 Length gain (cm/week)
02.04 Head growth (cm/week)
02.05 Serum alkaline phosphatase (IU/l)
02.06 Bone mineral content (mg/cm)
02.07 Nitrogen retention (mg/kg/day)
02.08 Feed intolerance
02.09 Necrotizing enterocolitis
02.10 Blood urea (mmol/l)
02.11 Death
| Comparison or outcome | Studies | Participants | Statistical method | Effect size |
|---|---|---|---|---|
| 01 Multicomponent fortification vs control (all trials) | ||||
| 01 Weight gain (g/kg/day) | 8 | 450 | WMD (fixed), 95% CI | 2.33 [1.73, 2.93] |
| 02 Weight gain (g/day) | 3 | 55 | WMD (fixed), 95% CI | 4.74 [2.78, 6.70] |
| 03 Length gain (cm/week) | 8 | 416 | WMD (fixed), 95% CI | 0.12 [0.07, 0.18] |
| 04 Head growth (cm/week) | 9 | 428 | WMD (fixed), 95% CI | 0.12 [0.07, 0.16] |
| 05 Weight at 12 months (kg) | 1 | 25 | WMD (fixed), 95% CI | 0.00 [-0.71, 0.71] |
| 06 Length at 12 months (cm) | 1 | 25 | WMD (fixed), 95% CI | -1.00 [-3.50, 1.50] |
| 07 Head circumference at 12 months (cm) | 1 | 25 | WMD (fixed), 95% CI | 0.10 [-2.22, 2.42] |
| 08 Weight at 18 months (kg) | 1 | 245 | WMD (fixed), 95% CI | -0.04 [-0.35, 0.27] |
| 09 Length at 18 months (cm) | 1 | 245 | WMD (fixed), 95% CI | -0.10 [-0.93, 0.73] |
| 10 Head circumference at 18 months (cm) | 1 | 245 | WMD (fixed), 95% CI | 0.00 [-0.28, 0.28] |
| 11 Serum alkaline phosphatase (IU/l) | 8 | 469 | WMD (fixed), 95% CI | 0.22 [-33.99, 34.44] |
| 12 Bone mineral content (mg/cm) | 2 | 79 | WMD (fixed), 95% CI | 8.30 [3.84, 12.76] |
| 13 Whole body bone mineral content (g) | 2 | 101 | WMD (fixed), 95% CI | 1.65 [-1.65, 4.95] |
| 14 Mental development index at 18 months | 1 | 245 | WMD (fixed), 95% CI | 2.20 [-3.35, 7.75] |
| 15 Psychomotor development index at 18 months | 1 | 245 | WMD (fixed), 95% CI | 2.40 [-1.90, 6.70] |
| 16 Nitrogen retention (mg/kg/day) | 2 | 52 | WMD (fixed), 95% CI | 66.05 [35.28, 96.82] |
| 17 Hypercalcemia | 1 | 263 | RR (fixed), 95% CI | 1.18 [0.76, 1.82] |
| 18 Feed intolerance | 3 | 67 | RR (fixed), 95% CI | 2.85 [0.62, 13.08] |
| 19 Necrotizing enterocolitis | 6 | 640 | RR (fixed), 95% CI | 1.33 [0.69, 2.54] |
| 20 Blood pH | 1 | 275 | WMD (fixed), 95% CI | -0.01 [-0.02, 0.00] |
| 21 Blood urea (mmol/l) | 5 | 350 | WMD (fixed), 95% CI | 0.27 [0.14, 0.40] |
| 22 Death | 2 | 603 | RR (fixed), 95% CI | 1.48 [0.66, 3.34] |
| 02 Multicomponent fortification vs control (trials without mineral supplementation of the control group) | ||||
| 01 Weight gain (g/kg/day) | 5 | 136 | WMD (fixed), 95% CI | 3.62 [2.69, 4.55] |
| 02 Weight gain (g/day) | 3 | 55 | WMD (fixed), 95% CI | 4.74 [2.78, 6.70] |
| 03 Length gain (cm/week) | 5 | 102 | WMD (fixed), 95% CI | 0.18 [0.08, 0.28] |
| 04 Head growth (cm/week) | 6 | 114 | WMD (fixed), 95% CI | 0.14 [0.09, 0.20] |
| 05 Serum alkaline phosphatase (IU/l) | 6 | 169 | WMD (fixed), 95% CI | -43.24 [-98.29, 11.81] |
| 06 Bone mineral content (mg/cm) | 2 | 79 | WMD (fixed), 95% CI | 8.30 [3.84, 12.76] |
| 07 Nitrogen retention (mg/kg/day) | 1 | 27 | WMD (fixed), 95% CI | 82.50 [32.53, 132.47] |
| 08 Feed intolerance | 1 | 19 | RR (fixed), 95% CI | 4.55 [0.25, 83.70] |
| 09 Necrotizing enterocolitis | 4 | 261 | RR (fixed), 95% CI | 0.98 [0.44, 2.20] |
| 10 Blood urea (mmol/l) | 3 | 61 | WMD (fixed), 95% CI | 0.96 [0.56, 1.36] |
| 11 Death | 1 | 297 | RR (fixed), 95% CI | 13.33 [0.78, 227.34] |
| This review is published as a Cochrane review in
The Cochrane Library 2004, Issue 1, 2004 (see www.CochraneLibrary.net for
information). Cochrane reviews are regularly updated as new evidence emerges
and in response to comments and criticisms, and The Cochrane Library should
be consulted for the most recent version of the Review. |
