Formula milk versus maternal breast milk for feeding preterm or low birth weight infants

Henderson G, Anthony MY, McGuire W

Background - Methods - Results - References - Data Tables and Graphs

Dates

Date edited: 15/08/2007
Date of last substantive update: 09/07/2007
Date of last minor update: 12/11/2003
Date next stage expected 09/07/2009
Protocol first published: Issue 1, 2001
Review first published: Issue 3, 2001

Contact reviewer

Mrs Ginny Henderson, RN BN MSc
Associate Lecturer
School of Nursing and Midwifery
Griffith University
Nathan Campus
226 Grey St, PO Box 3370
South Brisbane
Queensland AUSTRALIA
4104
Telephone 1: 61 7 3735 5317 extension: 55317
Facsimile: 61 7 3735 7984
E-mail: G.Henderson@griffith.edu.au

Contribution of reviewers

William McGuire (WM) and Mary Anthony (MYA) developed the protocol and undertook the original review in 2000. Ginny Henderson (GH) and WM updated the review in 2003 and 2007.

Internal sources of support

Tayside Institute of Child Health, Ninewells Hospital and Medical School. Dundee, UK

External sources of support

Systematic Reviews Training Unit, Institute of Child Health, London and Royal College of Paediatrics and Child Health, UK
Tenovus, Scotland, UK

What's new

This review updates the review "Formula milk versus preterm human milk for feeding preterm or low birth weight infants" published in The Cochrane Library, Issue 3, 2001 (Henderson 2001).

In this update, the structure of the review has been revised in the following manner:
1. The comparison description is now "formula milk versus maternal breast milk." A companion review addresses the comparison of "formula milk versus donor breast milk" (Quigley 2007).
2. The inclusion criteria includes trials that compared feeding with formula versus maternal breast milk as a sole diet or as a supplement to formula milk (previous review restricted to sole diet).

No eligible trials were identified on updated search. The previous review had identified a trial that compared feeding with formula milk versus donor preterm milk. This trial is no longer eligible for inclusion but is now included in the companion review of "formula milk versus donor breast milk" (Quigley 2007).

Dates

Date review re-formatted: / /
Date new studies sought but none found: 28/10/2003
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: / /

Text of review

Synopsis

Formula milk may contain more nutrients than maternal breast milk but it lacks the antibodies and other substances present in breast milk that protect and develop the immature gut of preterm or low birth weight infants. No trials that compared feeding with formula milk rather than their own mother's breast milk were identified. However, since another Cochrane review has found that feeding with formula compared to donor breast milk increases the risk of serious gut problems in preterm or low birth weight infants, it is unlikely that a such a trial would be acceptable to mothers and caregivers.

Abstract

Background

Maternal breast milk may contain less nutrients than artificial formula milk but may confer important non-nutrient advantages for preterm or low birth weight infants.

Objectives

To determine the effect of feeding with formula milk compared with maternal breast milk on rate of growth and developmental outcomes in preterm or low birth weight infants.

Search strategy

The standard search strategy of the Cochrane Neonatal Review Group was used. This included electronic searches of the Cochrane Central Register of Controlled Trials Register (CENTRAL, The Cochrane Library, Issue 3, 2007), MEDLINE (1966 - June 2007) and EMBASE (1980 - June 2007) and CINAHL (1982 to June 2007) (all accessed via OVID) and previous reviews including cross references.

Selection criteria

Randomised controlled trials comparing feeding with formula milk versus preterm human milk in preterm or low birth weight infants.

Data collection & analysis

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

Main results

No eligible trials were identified.

Reviewers' conclusions

There are no data from randomised trials of formula milk versus maternal breast milk for feeding preterm or low birth weight infants. This may relate to a perceived difficulty of allocating an alternative feed to an infant whose mother wishes to feed with her own breast milk. Maternal breast milk remains the default choice of enteral nutrition because observational studies, and meta-analyses of trials comparing feeding with formula milk versus donor breast milk, suggest that feeding with breast milk has major non-nutrient advantages for preterm or low birth weight infants.

Background

Maternal breast milk is the recommended form of enteral nutrition for preterm or low birth weight infants (AAP 1997). A major benefit of feeding with breast milk is that the delivery of immunoprotective and growth factors to the immature gut mucosa may prevent serious adverse outcomes including necrotising enterocolitis and invasive infection (Beeby 1992; Lucas 1990). However, there is concern that the nutritional requirements of preterm or low birth weight infants, who are born with relatively poor nutrient reserves and are subject to additional metabolic stresses compared with term infants, may not be fully met by enteral feeding with breast milk (Tsang 1993; Hay 1994; Schanler 1995). These deficiencies may have adverse consequences for growth and development (Lucas 1994). Evidence exists that supplementation of human milk with nutrient fortifiers increases short-term growth rates (Kuschel 2004).

As an alternative to maternal breast milk, a variety of formula milks (usually modified cow milk) are available for feeding preterm or low birth weight infants. These vary in energy, protein and mineral content. Broadly, formula milk can be considered as:
(a) "Term" formulae; designed for term infants, based on the composition of mature breast milk. The typical energy content is between about 67 to 70 kilocalories per 100 millilitres.
(b) "Preterm" formulae; designed to provide nutrient intakes to match intra-uterine accretion rates. These are energy-enriched (typically up to about 80 kilocalories per 100 millilitres), and variably protein- and mineral-enriched (Fewtrell 1999).

This review focuses on the comparison of feeding preterm or low birth weight infants with formula milk versus maternal breast milk. The comparison of formula milk with donor breast milk is addressed in a separate review (Quigley 2007).

Objectives

To determine the effect of feeding low birth weight or preterm infants with formula milk compared with maternal breast milk on rates of growth and developmental outcomes.

The following subgroup analyses were planned:

1. "Term" formula milk (containing up to 72 kilocalories per 100 millilitres) vs. maternal breast milk.
2. "Preterm" formula milk (containing more than 72 kilocalories per 100 millilitres) vs. maternal breast milk.
3. Formula milk vs. maternal breast milk given as a sole diet.
4. Formula milk vs. maternal breast milk given as a supplement to formula milk.
5. Formula milk vs. nutrient-fortified maternal breast milk (defined as supplementation with more than one of the following components: protein, fat, carbohydrate, or minerals).

Criteria for considering studies for this review

Types of studies

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

Types of participants

Preterm (less than 37 weeks gestational age) or low birth weight (less then 2500 g) infants.

Types of interventions

Feeding with formula milk versus maternal expressed milk.

Types of outcome measures

Primary: Growth and development
1. Growth:
(i) Rates of weight gain (grams per day, or grams per kilogram per day), linear growth (millimetres per week), head growth (millimetres per week), or skinfold thickness growth (millimetres per week) during the trial period.
(ii) Long term growth- weight, height, or head circumference (and/or proportion of infants who remain below the tenth percentile for the index population's distribution) assessed at intervals from 6 months of age (corrected for preterm birth), to 18 months, and beyond.

2. Development:
(i) Neurodevelopmental outcomes at greater than, or equal to, 12 months of age (corrected for preterm birth) measured using validated assessment tools.
(ii) Severe neurodevelopmental disability defined as any one or combination of the following: non-ambulant cerebral palsy, developmental delay (developmental quotient less than 70 or more than two standard deviations below the mean), severe auditory impairment (sensorineural deafness requiring (or too severe to (benefit from) hearing aids) or visual impairment (legal blindness). We plan to analyse each component individually as well as part of the composite outcome.
(iii) Cognitive and educational outcomes at aged more than 5 years old: Intelligence quotient and/or indices of educational achievement measured using a validated assessment tool (including school examination results).

Secondary: Mortality and morbidity
1. Death in the neonatal period (up to 28 days) and death prior to hospital discharge.

2. Necrotising enterocolitis confirmed by at least two of the following features: Abdominal radiograph showing pneumatosis intestinalis or gas in the portal venous system or free air in the abdomen; abdominal distension with abdominal radiograph with gaseous distension or frothy appearance of bowel lumen (or both); blood in stool; lethargy, hypotonia, or apnea (or combination of these); or a diagnosis confirmed at surgery or autopsy.

3. Time after birth to establish full enteral feeding (independently of parenteral nutrition).

4. Feed intolerance defined as a requirement to cease enteral feeds and commence parenteral nutrition.

5. Incidence of invasive infection as determined by culture of bacteria or fungus from blood, cerebro-spinal fluid, urine, or from a normally sterile body space.

Search strategy for identification of studies

The standard search strategy of the Cochrane Neonatal Review Group was used. This consisted of searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2007), MEDLINE (1966 - June 2007), and EMBASE (1980 - June 2007), and CINAHL (1982 - June 2007). The electronic search used the following text words and MeSH terms: [Infant, Newborn OR Infant, Premature OR Infant, Low Birth Weight OR infan* OR neonat*] AND "Infant-Nutrition"/ all subheadings OR Infant Formula OR milk OR formula]. The search outputs were limited with the relevant search filters for clinical trials. No language restriction was applied. References in previous reviews and studies were examined. Abstracts presented at the Society for Pediatric Research, European Society for Pediatric Research, the North American Society of Pediatric Gastroenterology and Nutrition, and the European Society of Paediatric Gastroenterology, Hepatology and Nutrition between 1990 and 2006 were searched. Trials reported only as abstracts were eligible if sufficient information was available from the report, or from contact with the authors, to fulfil the inclusion criteria. The UK National Research Register (http://www.nrr.nhs.uk), and Current Controlled Trials (http://www.controlled-trials.com) websites were searched for completed or ongoing trials.

Methods of the review

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

2. We planned to use the criteria and standard methods of the Cochrane Neonatal Review Group to assess the methodological quality of any included trials in terms of allocation concealment, blinding of parents, carers, and assessors to the intervention, and completeness of assessment in all randomised individuals.

3. We planned to use a data collection form to extract relevant information from each included study. If data from the trial reports were insufficient, we planned to contact the trialists for further information.

4. We planned to present outcomes for categorical data as relative risk, risk difference, and number needed to treat, and for continuous data, the weighted mean difference (with respective 95% confidence intervals).

5. We planned to estimate the treatment effects of individual trials and examine heterogeneity between trial results by inspecting the forest plots and quantifying the impact of heterogeneity in any meta-analysis using a measure of the degree of inconsistency in the studies' results (I- squared statistic). If we detected statistical heterogeneity, we planned to explore the possible causes (for example, differences in study quality, participants, intervention regimens, or outcome assessments) using post hoc sub group analyses. We planned to use a fixed effects model for meta-analyses.

Description of studies

No studies were identified that fulfilled the eligibility criteria. Six studies were excluded (see table: Characteristics of excluded studies). Four were found not to be randomised controlled trials on review of the full text (Armand 1996; Carey 1987; Greer 1988; Lucas 1990). Two studies were excluded because the infants were allocated to receive formula or a mixture of maternal and donor breast milk (Narayanan 1982; Svenningsen 1982).

Methodological quality of included studies

No eligible trials were identified.

Results

No eligible trials were identified.

Discussion

No randomised controlled trials of formula milk versus maternal breast milk for feeding preterm or low birth weight infants were identified. This is likely to be due to reluctance of researchers and consumers to assess an intervention that results in infants not receiving the non-nutritional benefits of breast milk. Observational studies have found lower incidences of necrotising enterocolitis in infants fed a formula milk compared with maternal breast milk (Lucas 1990). Meta-analysis of data from randomised controlled trials indicates that feeding with formula milk, compared with donor breast milk, leads to higher rates of feed intolerance and necrotising enterocolitis in preterm infants (Quigley 2007). Since maternal breast milk contains higher levels of putative immunoprotective factors (secretory immunoglobulin-A, lysozyme, lactoferrin, epidermal growth factors) than donor breast milk (Fewtrell 1999), it is plausible that feeding with maternal breast milk has will have the same protective effect. Furthermore, if there is concern regarding the nutritional adequacy of maternal breast milk, infants can receive supplemental nutrition via multicomponent fortification without losing the non-nutrient benefits of breast milk (Kuschel 2004).

In resource-poor countries, where the risk of infection in the neonatal period is much higher than in resource-rich countries, the anti-infective properties of breast milk may confer further advantages for preterm or low birth weight infants. In India, a randomised trial in low birth weight infants "at risk of infection" found that serious infections (diarrhoea, pneumonia, septicaemia) were statistically significantly less common in infants allocated to receive "expressed human milk" versus formula milk (Narayanan 1982). "Expressed human milk" in this trial referred to a mixture of maternal and donor breast milk. As these could not be separated into subgroups, the data could not be included in the review.

Reviewers' conclusions

Implications for practice

There are no data from randomised controlled trials to determine whether feeding preterm or low birth weight infants with formula milk versus maternal breast milk affects growth, development, or other clinically important outcomes. However, maternal breast milk remains the default choice of nutrition for feeding preterm or low birth weight infants because of its putative non-nutrient advantages, and because nutrient fortification of breast milk can address concerns regarding nutrient content and growth rates.

Implications for research

Mothers who wish to breast feed, and their health care advisors, would require very clear evidence that feeding with formula milk had major advantages for their infants before electing not to feed (or to reduce feeding) with maternal breast milk. It is unlikely that equipoise exists amongst consumers and caregivers to undertake such a trial. Data from observational studies, and meta-analyses of trials that compared feeding with formula milk versus donor breast milk, suggest that feeding with breast milk has major advantages, for preterm or low birth weight infants.

Acknowledgements

Potential conflict of interest

None

Characteristics of excluded studies

Study	Reason for exclusion
Armand 1996	Not randomised.
Carey 1987	Not randomised.
Greer 1988	Not randomised.
Lucas 1990	Not randomised.
Narayanan 1982	Human milk fed infants received a mixture of maternal and donor breast milk.
Svenningsen 1982	Control group received maternal and donor breast milk.

References to studies

References to excluded studies

Armand 1996 {published data only}

Armand M, Hamosh M, Mehta NR, Angelus PA, Philpott JR, Henderson TR et al. Effect of human milk or formula on gastric function and fat digestion in the premature infant. Pediatric Research 1996;40:429-437.

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. American Journal of Diseases of Children 1987;141:511-515.

Greer 1988 {published data only}

Greer FR, McCormick A. Improved bone mineralization and growth in premature infants fed fortified own mother's milk. Journal of Pediatrics 1988;112:961-969.

Lucas 1990 {published data only}

Lucas A, Cole TJ. Breast milk and neonatal necrotising enterocolitis. Lancet 1990;336:1519-1523.

Narayanan 1982 {published data only}

Narayanan I, Prakash K, Prabhakar AK, Gujral VV. A planned prospective evaluation of the anti-infective property of varying quantities of expressed human milk. Acta Paediatrica 1982;71:441-445.

Svenningsen 1982 {published data only}

Svenningsen NW, Lindroth M, Lindquist B. Growth in relation to protein intake of low birth weight infants. Early Human Development 1982;6:47-58.

* indicates the primary reference for the study

Other references

Additional references

AAP 1997

American Academy of Pediatrics and Work Group on Breastfeeding. Breastfeeding and the use of human milk. Pediatrics 1997;100:1035-1039.

Beeby 1992

Beeby PJ, Jeffrey H. Risk factors for necrotising enterocolitis: the influence of gestational age. Archives of Disease in Childhood 1992;67:432-435.

Fewtrell 1999

Fewtrell M, Lucas A. Nutritional physiology: dietary requirements of term and preterm infants. In: Rennie JM, Roberton NRC, editor(s). Textbook of neonatology. 3rd edition. Edinburgh: Churchill Livingstone, 1999:305- 325.

Hay 1994

Hay WW Jr. Nutritional requirements of extremely low birthweight infants. Acta Paediatrica 1994;402:S94-99.

Kuschel 2004

Kuschel CA, Harding JE. Multicomponent fortified human milk for promoting growth in preterm infants. Cochrane Database of Systematic Reviews 2004, Issue 1.

Lucas 1994

Lucas A, Morley R, Cole TJ, Gore SM. A randomised multicentre study of human milk versus formula and later development in preterm infants. Archives of Diserase in Childhood 1994;70:F141-F146.

Quigley 2007

Quigley M, Henderson G, Anthony MY, McGuire W. Formula milk versus donor breast milk for feeding preterm or low birth weight infants. Cochrane Database of Systematic Reviews 2007, Issue 4.

Schanler 1995

Schanler RJ. Suitability of human milk for the low-birthweight infant. Clinics in Perinatology 1995;22:207-22.

Tsang 1993

Tsang RC, Lucas A, Uauy R, Zlotkin S. Nutritional needs for the newborn infant. Scientific basis and practical guidelines. Pawling, New York: Caduceus Medical Publishers, 1993:288-289.

Other published versions of this review

Henderson 2004

Henderson G, Anthony MY, McGuire W. Formula milk versus preterm human milk for feeding preterm or low birth weight infants. Cochrane Database of Systematic Reviews 2004, Issue 1.

McGuire 2001a

McGuire W, Anthony MY. Formula milk versus preterm human milk for feeding preterm or low birth weight infants. Cochrane Database of Systematic Reviews 2001, Issue 3.

Comparisons and data

Comparison or outcome	Studies	Participants	Statistical method	Effect size
01 Formula milk versus preterm human milk
01 Time to regain birth weight (days from birth)	0	0	WMD (fixed), 95% CI	Not estimable
02 Weight gain (g/day)	0	0	WMD (fixed), 95% CI	Not estimable
03 Gain in length (mm/week)	0	0	WMD (fixed), 95% CI	Not estimable
04 Gain in head circumference (mm/week)	0	0	WMD (fixed), 95% CI	Not estimable
05 Feed intolerance	0	0	RR (fixed), 95% CI	Not estimable
06 Necrotising enterocolitis	0	0	RR (fixed), 95% CI	Not estimable

01 Formula milk versus preterm human milk

01.01 Time to regain birth weight (days from birth)

01.02 Weight gain (g/day)

01.03 Gain in length (mm/week)

01.04 Gain in head circumference (mm/week)

01.05 Feed intolerance

01.06 Necrotising enterocolitis

Contact details for co-reviewers

Dr Mary Y Anthony, MD FRCPCH
Consultant Neonatologist
Special Care Baby Unit
John Radcliffe Hospital
Oxford UK
OX3 9DU
E-mail: mary.anthony@orh.nhs.uk

Dr William McGuire
Associate Professor of Neonatology
Department of Paediatrics and Child Health
Australian National University Medical School
Canberra Hospital Campus
Canberra
ACT 2606 AUSTRALIA
Telephone 1: +61 2 62442222
Facsimile: +61 2 62443112
E-mail: william.mcguire@act.gov.au

This review is published as a Cochrane review in The Cochrane Library, Issue 4, 2007 (see http://www.thecochranelibrary.com for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback. The Cochrane Library should be consulted for the most recent version of the review.