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Fat supplementation of human milk for promoting growth in preterm infants

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Authors

Kuschel CA, Harding JE

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


Dates

Date edited: 28/05/2002
Date of last substantive update: 13/12/1999
Date of last minor update: 05/10/2002
Date next stage expected / /
Protocol first published: Issue 3, 1997
Review first published: Issue 3, 1999

Contact reviewer

Dr Carl A Kuschel

Staff Neonatologist
Newborn Services
National Women's Hospital
Private Bag 92 189
Auckland
NEW ZEALAND
Telephone 1: +64 9 638 9919 extension: 3200
Facsimile: +64 9 630 9753

E-mail: CarlK@ahsl.co.nz

Contribution of reviewers

Intramural sources of support

National Women's Hospital, Auckland, NEW ZEALAND
University of Auckland, Auckland, NEW ZEALAND

Extramural sources of support

  • None noted.

What's new

This is an update of the existing review of "Fat supplementation of human milk for promoting growth in preterm infants", The Cochrane Library, Issue 3, 1999.

No new trials were located in the search done in April 2002, and as a result, no substantive changes were made in the review. There was no change to the conclusion that there is insufficient evidence evaluating the supplementation of human milk with fat in preterm infants to make recommendations for practice.

Dates

Date review re-formatted: 03/09/1999
Date new studies sought but none found: 10/04/2002
Date new studies found but not yet included/excluded: / /
Date new studies found and included/excluded: / /
Date reviewers' conclusions section amended: / /
Date comment/criticism added: / /
Date response to comment/criticisms added: / /

Synopsis

  • Synopsis pending.

Abstract

Background

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. There are potential short term and long term benefits from human milk, although observational studies have suggested that infants fed formula have a higher rate of growth than infants who are breast fed.

Objectives

The main objective is to determine if addition of supplemental fat to human milk leads to improved growth and neurodevelopmental outcomes without significant adverse effects in preterm infants.

Search strategy

The standard search strategy of the Cochrane Neonatal Collaborative Review Group was used. This includes searches of the Oxford Database of Perinatal Trials, MEDLINE (1966-Apr 2002), Cochrane Controlled Trials Register (The Cochrane Library, Issue 2, 2002), previous reviews including cross references, abstracts, conferences and symposia proceedings, expert informants, journal handsearching mainly in the English language.

Selection criteria

All trials utilizing random or quasi-random allocation to supplementation of human milk with fat or no supplementation in preterm infants within a hospital were eligible.

Data collection & analysis

Data were extracted using the standard methods of the Cochrane Neonatal Collaborative 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.

Main results

Results are available for only one small study evaluating the effects of fat supplementation. There are insufficient data to evaluate short term or long term growth outcomes and neurodevelopmental outcomes. There are insufficient data to comment on potential adverse effects.

Reviewers' conclusions

There is insufficient evidence to make recommendations for practice. Further research should evaluate the practice of supplementation of human milk with fat. This may best be done in the context of the development of multicomponent fortifiers. Both short term growth outcomes and long term growth and neurodevelopmental outcomes should be evaluated. Adverse effects should be evaluated.

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Background

Human milk is the recommended nutritional source for full-term infants in at least the first six months of postnatal life. 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 preterm infants is less well defined. The nutrient content of preterm human milk provides insufficient quantities of protein, sodium, phosphate and calcium to meet the estimated needs of the infant. In addition, large fluid volumes may be required to provide sufficient calories to maintain adequate growth. Studies have shown that preterm infants fed human milk have lower than expected growth rates than infants fed a modified, preterm infant formula (Cooper 1984, Lucas 1984, Calvert 1985, Roberts 1985).

Fat provides approximately 50% of the calories supplied in human milk, although the exact content can vary both between and within individuals, depending on the time of the day and the phase of lactation at which milk is collected (for example, hindmilk obtained at the end of nursing has a higher fat content). Fat separates from human milk when left standing and may adhere to collection containers and delivery devices, so the delivery method may impact on the eventual provision of calories. Preterm infants have relatively poor digestion and absorption of fat, due partly to immaturity of the various lipases in the gut (Zoppi 1972, Lebenthal 1980) and decreased bile salt secretion (Norman 1972, Signer 1974, Watkins 1975). The presence of bile-salt stimulated lipase in human milk may be important in improving the availability of the contained lipids to preterm infants (Hamosh 1987). An alternative approach is to provide fat supplements as medium-chain triglycerides (MCT), which are absorbed without the need for initial cleavage in the gut, and may therefore be more readily used by the preterm infant.

For a detailed discussion of the suitability of human milk for low-birthweight infants, see Schanler 1995.

Objectives

To determine if addition of fat to human milk leads to improved growth and neurodevelopmental outcomes without significant adverse effects in preterm infants.

Criteria for considering studies for this review

Types of studies

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

Types of participants

Preterm infants receiving care within a hospital.

Types of interventions

All randomised controlled trials evaluating the supplementation of human milk with fat or medium-chain triglycerides, in which treatment was compared with unsupplemented human milk, are included.

It was intended to perform subgroup analyses of supplementation with MCT, and of supplementation with other forms of fat.

Types of outcome measures

  1. Primary outcomes
    1. Short term growth parameters
      1. Weight gain
      2. Linear growth
      3. Head growth
    2. Long term growth parameters
      1. Weight
      2. Length
      3. Head circumference
    3. Neurodevelopmental outcomes
      1. Neurodevelopmental outcome at 12 to 18 months
  2. Secondary outcomes
    1. Adverse effects
      1. Gastrointestinal disturbance
      2. Feeding intolerance
      3. Diarrhea
      4. Necrotizing enterocolitis (NEC)

Search strategy for identification of studies

Searches of the Oxford Database of Perinatal Trials, MEDLINE (1966-Apr 2002), Cochrane Controlled Trials Register (The Cochrane Library, Issue 2, 2002), previous reviews including cross references, abstracts, conferences and symposia proceedings, expert informants, journal handsearching mainly in the English language.

The MEDLINE search included the search terms "Milk, -Human", "Infant, -Newborn", and "Lipids", including all subheadings for each term.

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Methods of the review

The criteria and standard methods of the Cochrane Neonatal Collaborative 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 Cochrane Neonatal Collaborative Review Group was used to synthesize the data. Results were expressed as relative risk and weighted mean difference.

Description of studies

Only two studies were identified which met the inclusion criteria (Polberger 1989, Rönnholm 1982). Data were extractable only for Polberger 1989. Details of this study are included in the table "Characteristics of Included Studies".

Polberger 1989 assigned infants to receive either fat (1g human milk fat per 100ml of human milk) or no supplementation. Two other arms of the study evaluated supplementation with protein alone and protein and fat. The intervention was commenced once the infants were tolerating enteral feeds at 170ml/kg/day and was ceased when the infants were breast fed or weighed 2200g. Supplemental vitamins and minerals (calcium and phosphate) were given to all infants.

The study by Rönnholm 1982 was excluded. Infants were randomised by alternate allocation to no supplementation, supplementation with protein, supplementation with fat (medium-chain triglyceride, MCT), or supplementation with both protein and fat (MCT). The authors state that there was no apparent effect from the addition of fat alone and, therefore, combined the groups according to protein supplementation. Data were not able to be extracted for the group of infants receiving only MCT.

Methodological quality of included studies

Polberger 1989 randomised by sealed envelopes and investigators were double-blinded. Eight infants were randomised to the fat supplementation arm and eight to the unsupplemented (control) arm. Results are reported for seven infants in each group, and additional information has been received for the two infants excluded (Dr S.Polberger). One control infant was excluded because of apnoea, and one treatment infant was excluded because of feeding intolerance.

Growth was calculated using a regression of growth parameters against time. The slope of the regression was converted to units of g/kg/day and cm/week for the study period.

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Results

Results for this single trial are reported for only 14 infants.

There were no significant differences in weight gain (WMD 0.60 g/kg/day, 95% CI -2.36 to 3.56 g/kg/day), linear (WMD 0.10 cm/week, 95% CI -0.08 to 0.28 cm/week) or head growth (WMD 0.15 cm/week, 95% CI -0.07 to 0.37 cm/week) over the short term study period.

There were no cases of necrotizing enterocolitis in those infants for whom results are reported. Feeding intolerance (undefined) occurred in one infant in the treatment group.

This study did not evaluate any of the other prespecified outcomes (long term growth, neurodevelopmental outcome, or other adverse gastrointestinal disturbance).

No subgroup analysis could be performed to separately assess the effects of MCT supplementation and other forms of fat supplementation.

Discussion

The evidence concerning the effects of supplementation of human milk with fat is scanty. A single trial did not show any short term benefit of the addition of fat to human milk in preterm infants. Although the study by Rönnholm 1982 was excluded, the authors similarly commented that fat supplementation did not demonstrate any effect on growth. However, the numbers of infants studied is too small to say that the addition of fat to human milk is associated either with benefits or adverse events.

Fat is a component in some commercial multicomponent human milk fortifiers - often in very low quantities. Fat has some theoretical advantages over other energy sources such as protein and carbohydrate in that it provides more calories per gram than protein and carbohydrate, does not appear to be associated with metabolic imbalance (unlike protein), and may result in a lower respiratory quotient and therefore less carbon dioxide production than carbohydrate supplementation (Pereira 1994). There are concerns, however, about the quality of growth in preterm infants - namely, that fat accretion or deposition in these infants may be greater than that of fetuses in utero even when not supplemented with excessive quantities of fat (Reichman 1981, Putet 1984, de Gamarra 1987). It is unknown whether this results in any long term advantage or disadvantage.

Reviewers' conclusions

Implications for practice

There is insufficient evidence evaluating the supplementation of human milk with fat in preterm infants to make recommendations for practice.

Implications for research

Research should be directed towards evaluating short term and long term growth outcomes in preterm infants supplemented with fat, although it may be most appropriate to do so in the context of evaluation of the effects of different formulations of multicomponent (carbohydrate, protein, minerals) fortifiers. Research should take into account adverse effects such as feed intolerance, necrotizing enterocolitis, and diarrhea. Studies should also evaluate potential effects on neurodevelopmental outcomes. The number of subjects required to evaluate long term outcomes would be extremely large.

Acknowledgements

  • None noted.

Potential conflict of interest

  • None noted.

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Characteristics of studies

Characteristics of Included Studies

Study Methods Participants Interventions Outcomes Notes Allocation concealment
Polberger 1989 Randomised trial. Single center
Method of randomisation: Sealed envelopes
Blinding of intervention: Double blind
Complete follow-up: No
Blinding of outcome measure: Adequate
Number of treatment infants randomised: 8
Number of control infants randomised: 8
Preterm infants < 1500g, appropriate for gestational age
Enteral feeds tolerated at 170ml/kg/day
Exclusions: major illness or abnormality, oxygen dependency
1.0g human milk fat per 100ml human (unpasteurized maternal or unpasteurized term banked donor) milk vs. unsupplemented human milk.
Intervention ceased at 2200g or when breast fed.
All infants were supplemented with additional vitamins, calcium lactate (30mg/kg/day) and sodium phosphate (20mg/kg/day). From 4 weeks, 2mg/kg/day elemental iron was given to all infants.
Short term growth This study had four arms - unsupplemented vs. supplemented with protein, vs. supplemented with fat, vs. supplemented with fat and protein. Supplementation with protein alone and protein in combination with fat are discussed in other reviews on protein and multicomponent fortification respectively. 34 infants were enrolled in all four study arms - 6 infants were withdrawn following randomization (reasons discussed in separate reviews). 7 infants were left in each arm.
There were large fluctuations in the energy intake for all four groups across the study.
A

Characteristics of excluded studies

Study Reason for exclusion
Rönnholm 1982 Unable to extract data for infants supplemented with fat alone.

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References to studies

Included studies

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;25:414-419.

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;86:909-915.

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;86:916-921.

Excluded studies

Rönnholm 1982

{published data only}

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;101:243-247.

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;74:792-799.

Rönnholm KAR, Perheentupa J, Siimes MA. Supplementation with human milk protein improves growth of small premature infants fed human milk. Pediatrics 1986;77:649-653.

* indicates the primary reference for the study

Other references

Additional references

Calvert 1985

Calvert SA, Soltesz G, Jenkins PA, Harris D, Newman C, Adrian TE, Bloom SR, Aynsley-Green A. Feeding premature infants with human milk or preterm milk formula. Effects on postnatal growth and on circulating concentrations of intermediary metabolites, amino acids, and regulatory peptides. Biol Neonate 1985;47:189-198.

Cooper 1984

Cooper PA, Rothberg AD, Pettifor JM, Bolton KD, Devenhuis S. Growth and biochemical response of premature infants fed pooled preterm milk or special formula. J Pediatr Gastroenterol Nutr 1984;3:749-54.

de Gamarra 1987

de Gamarra ME, Schutz Y, Catzeflis C, et al. Composition of weight gain during the neonatal period and longitudinal growth follow-up in premature babies. Biol Neonate 1987;52:181-187.

Hamosh 1987

Hamosh M. Lipid metabolism in premature infants. Biol Neonate 1987;52(Suppl 1):50-64.

Lebenthal 1980

Lebenthal E, Lee PC. Development of functional response in human exocrine pancreas. Pediatrics 1980;66:556-560.

Lucas 1984

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;59:722-730.

Norman 1972

Norman A, Strandvik B, Ojamae O. Bile acids and pancreatic enzymes during absorption in the newborn. Acta Paediatr Scand 1972;61:571-576.

Pereira 1994

Pereira GR, Baumgart S, Bennett MJ, et al. Use of high-fat formula for premature infants with bronchopulmonary dysplasia: metabolic, pulmonary, and nutritional studies. J Pediatr 1994;124:605-611.

Putet 1984

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

Reichman 1981

Reichman B, Chessex P, Putet G, Verellen G, Smith JM, Heim T, Swyer PR. Diet, fat accretion, and growth in premature infants. New Engl J Med 1981;305:1495-1500.

Roberts 1985

Roberts SB, Lucas A. The effects of two extremes of dietary intake on protein accretion in preterm infants. Early Hum Dev 1985;12:301-7.

Schanler 1995

Schanler RJ. Suitability of human milk for the low-birthweight infant. Clin Perinatol 1995;22:207-222.

Signer 1974

Signer E, Murphy GM, Edkins S. Role of bile salts in fat malabsorption of premature infants. Arch Dis Child 1974;49:174-180.

Watkins 1975

Watkins JB, Szczepanik P, Gould JB, Klein P, Lester R. Bile salt metabolism in the human premature infant. Preliminary observations of pool size and synthesis rate following prenatal administration of dexamethasone and phenobarbital. Gastroenterology 1975;69:706-713.

Zoppi 1972

Zoppi G, Andreotti G, Pajo-Ferrara F, Njai DM, Gaburro D. Exocrine pancreatic function in premature and full-term neonates. Pediatr Res 1972;6:880-886.

Other published versions of this review

Kuschel 1999

Kuschel CA, Harding JE. Fat supplementation of human milk for promoting growth in preterm infants (Cochrane Review). In: The Cochrane Library, Issue 3, 1999. Oxford: Update Software.

Kuschel 2000

Kuschel CA, Harding JE. Fat supplementation of human milk for promoting growth in preterm infants (Cochrane Review). In: The Cochrane Library, Issue 1, 2000. Oxford: Update Software.

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Data and analyses

01 Fat supplementation vs control

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
01.01 Weight gain [g/kg/day] 1 14 WMD [Fixed] [95% CI] 0.60 [-2.36, 3.56]
01.02 Linear growth [cm/week] 1 14 WMD [Fixed] [95% CI] 0.10 [0.08, 0.28]
01.03 Head growth [cm/week] 1 14 WMD [Fixed] [95% CI] 0.15 [-0.07, 1.37]
01.04 Feeding intolerance 1 16 Relative Risk [Fixed] [95% CI] 3.00 [0.14, 64.27]

Additional tables

  • None noted.

Amended sections

  • None noted.

Contact details for co-reviewers

Prof Jane JE Harding

Professor of Neonatology
Department of Paediatrics
University of Auckland
Private Bag 92 019
Auckland
NEW ZEALAND
1001
Telephone 1: +64 9 373 7599 extension: 6439
Telephone 2: +64 9 638 9909
Facsimile: +64 9 373 7497

E-mail: j.harding@auckland.ac.nz

Secondary address:
National Women's Hospital
Claude Road, Epsom
Auckland
NEW ZEALAND


This review is published as a Cochrane review in The Cochrane Library, Issue 3, 1999 (see http://www.thecochranelibrary.com External Web Site Policy for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback, and The Cochrane Library should be consulted for the most recent recent version of the review.