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Prebiotics in infants for prevention of allergic disease and food hypersensitivity

  1. David A Osborn1,*,
  2. John KH Sinn2

Editorial Group: Cochrane Neonatal Group

Published Online: 17 OCT 2007

Assessed as up-to-date: 30 MAY 2007

DOI: 10.1002/14651858.CD006474.pub2


How to Cite

Osborn DA, Sinn JKH. Prebiotics in infants for prevention of allergic disease and food hypersensitivity. Cochrane Database of Systematic Reviews 2007, Issue 4. Art. No.: CD006474. DOI: 10.1002/14651858.CD006474.pub2.

Author Information

  1. 1

    Royal Prince Alfred Hospital, RPA Newborn Care, Camperdown, New South Wales, Australia

  2. 2

    Royal North Shore Hospital, Neonatal Unit, St. Leonards, New South Wales, Australia

*David A Osborn, RPA Newborn Care, Royal Prince Alfred Hospital, Missenden Road, Camperdown, New South Wales, 2050, Australia. david.osborn@email.cs.nsw.gov.au.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 17 OCT 2007

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This is not the most recent version of the article. View current version (28 MAR 2013)

 
Characteristics of included studies [ordered by study ID]
Ben 2004

MethodsRandomisation: yes, method not reported.
Blinding of intervention: yes, used placebo.
Blinding of outcome measurement: yes.
Losses to follow up: 271 recruited, 121 infants received treatment or control formula (and reported), 124 received mixed test formula and breast milk feeds. Unclear how many randomised.
Intention to treat analysis: unclear.


ParticipantsInclusion criteria: when mothers were not able to or decided not to breast-feed, infants were randomly assigned to one of two formula groups within the first week after birth.
Exclusion criteria: infant antibiotic use.


InterventionsTreatment (n = 69): test formula (Frisolac H, Friesland, Netherland) supplemented with GOS 0.24 g/dl.
Control (n = 52): identical formula without oligosaccharide (Frisolac Advanced, Friesland, Netherland) was used as a negative control.
Co-interventions: none reported.


OutcomesPrimary outcomes: intestinal microflora colonization and fermentation in infants.
Other outcomes: Growth, stool characteristics, and side effects recorded at 3 and 6 months. Allergy and food hypersensitivity not reported.


NotesSponsored: Friesland Nutrition Institute of Netherlands and Edward Keller Co. Ltd. of China


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?UnclearB - Unclear

Boehm 2002

MethodsRandomisation: yes, method not reported.
Blinding of intervention: yes, used placebo.
Blinding of outcome measurement: yes.
Losses to follow up: none reported.
Intention to treat analysis: yes.


ParticipantsInclusion criteria: Preterm infants < 32 weeks gestation, when formula feeding commenced.
Exclusion criteria: none reported.


InterventionsEnteral nutrition started with pasteurised mother’s milk. When volume 80 ml/kg/day tolerated, milk supplemented with human milk fortifier. When formula feeding commenced because mother unable to provide milk, infants randomly assigned to one of two formula groups.
Treatment (n = 15): mixture of fructo-oligosaccharides and galacto-oligosaccharides (ratio 1:9) added to standard preterm formula.
Control (n = 15): same formula with maltodextrins added as placebo.
Co-interventions: none reported.


OutcomesPrimary outcomes: effect on the faecal microflora.
Other outcomes: body weight and crown-heel length was measured at the start and end of each feeding period. Allergy and food hypersensitivity not reported.


NotesSponsored: grant from Numico Research Germany.


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?YesA - Adequate

Brunser 2006b

MethodsRandomisation: yes, computer-generated randomization table.
Blinding of intervention: yes, formula products were letter-coded identical formula.
Blinding of outcome measurement: yes.
Losses to follow up: 40/116 (34%)
Intention to treat analysis: yes.


ParticipantsInclusion criteria: Healthy infants born at term, 3.5 months old, birth weight 3000-4200 g
Exclusion criteria: infant antibiotic treatment in the month prior to enrolment, multiple births, presence of any degree of malnutrition, or gastrointestinal, renal or other chronic diseases.


InterventionsTreatment (n = 32): Prebiotic group received the control formula with added FOS concentration of 2g/L (Raftilose P95, Orafti, Tienen, Belgium), or
Treatment 2 (n = 25): probiotic group received control formula enriched with 10*8 Lactobacillus johnsonii per gram of powder.; or
Control (n = 33): Standard infant formula (Nan 2, Nestlé Chile, Santiago, Chile).
Co-interventions: infants should not receive yogurt or any other fermented foodstuffs.


OutcomesPrimary outcomes: colonic microbiota.
Other outcomes: weight and height recorded every 15 days by study nurse. Allergy and food hypersensitivity not reported.


NotesSponsored: not reported. Study authors affiliated with Nestec Ltd., Vevey, Switzerland, and Nestlé Research Center, Vers-chez-les-Blanc, Switzerland.


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?YesA - Adequate

Fanaro 2005

MethodsRandomisation: yes, method not reported.
Blinding of intervention: yes.
Blinding of outcome measurement: not reported.
Losses to follow up: 5/51 (10%)
Intention to treat analysis: yes.


ParticipantsInclusion criteria: vaginally born healthy infants born at term whose mothers were not able to
provide breast milk.
Exclusion criteria: breast feeding longer than 1 week and maternal antibiotic treatment.


InterventionsTerm infant formulae based on intact cow’s milk protein with a 60/40 whey/casein ratio, supplemented with:
Treatment 1 (n = 16): 0.2g/dL of acidic oligosaccharides with 0.6 g/dL maltodextrin;
Treatment 2 (n = 15): 0.2g/dL acidic oligosaccharides and 0.6g/dL of GOS/FOS mixture; or
Control (n = 15): standard formula enriched with 0.8g/dL maltodextrin.
Co-interventions: none reported.


OutcomesPrimary outcomes: Effect on Intestinal Flora,
Stool Characteristics, and pH.
Other outcomes: growth in weight and length reported. Allergy and food hypersensitivity not reported.


NotesSponsored: One of the authors works for a company that produces infant
formulas containing GOS and FOS.
The 2 treatment groups (acidic oligosaccharides + neutral oligosaccharide group, and neutral oligosaccharide group) are combined for the overall analysis.


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?UnclearB - Unclear

Kapiki 2007

MethodsRandomisation: randomly assigned by closed envelopes to one of two formula groups.
Blinding of intervention: yes, placebo used.
Blinding of outcome measurement: yes.
Losses to follow up: 9/65 dropped out due to development of sepsis, necrotizing enterocolitis, ingestion of non-study feeds, inability to collect stools.
Intention to treat analysis: yes.


ParticipantsInclusion criteria: preterm infants <37 weeks. Healthy and exclusively formula fed.
Exclusion criteria: major congenital abnormalities, chromosomal disorders or with disease requiring systemic antibiotic treatment


InterventionsTreatment 1 (n = 41): standard preterm
formula supplemented with fructo-oligosaccharides 0.4 g/100 ml,
Control (n = 24): same but supplemented with 0.4 g of maltodextrins as placebo.
Feed duration 14 days.
Co-interventions: none reported.


OutcomesPrimary outcomes: bifidogenic effect and stool characteristics.
Other outcomes: somatic growth and well-being. Allergy and food hypersensitivity not reported.


NotesSponsored: none reported.


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?YesA - Adequate

Moro 2006

MethodsRandomisation: yes, random numbers table
Blinding of intervention: stated "maintained by coding the two trial formulae with the suffix ‘‘N’’ or ‘‘O’’ to the product name."
Blinding of outcome measurement: yes.
Losses to follow up: 53/259 (20%)
Intention to treat analysis: yes.


ParticipantsInclusion criteria: Term infants with a parental history of atopic eczema, allergic rhinitis, or asthma in either mother or father. Gestational age 37-42 weeks, birth weight appropriate for gestational age, and start of formula feeding within the first two weeks of life.
Exclusion criteria: infant excluded if breast feeding continued beyond 6 weeks.


InterventionsBoth formulae based on extensively hydrolysed cows’ milk whey protein supplemented with:
Treatment (n = 129): 0.8g GOS/FOS per 100 ml, or
Control (n = 130): 0.8g maltodextrin per 100 ml.
Co-interventions: none reported.


OutcomesPrimary outcomes: atopic dermatitis.
Other outcomes: infant examined for atopic dermatitis according to diagnostic criteria described by Harrigan and Rabinowitz and Muraro et al.
Definition:
Atopic dermatitis: pruritus, involvement of the face, skull facial and/or extensor part of
the extremities, and a minimal duration of the symptoms of four weeks. The severity of the skin alterations was scored by the SCORAD index
Anthropometric measurements, recording of crying, regurgitation, vomiting, and stool characteristics.


NotesSponsored: grant from Numico Research Friedrichsdorf, Germany and the EARNEST program.


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?YesA - Adequate

Ziegler 2007

MethodsRandomisation: yes, method not reported.
Blinding of intervention: reported to be double-blind' but details not reported.
Blinding of outcome measurement: reported to be double-blind' but details not reported.
Losses to follow up: yes, 62/226 (27%) did not complete study.
Intention to treat analysis: yes.


ParticipantsInclusion criteria: Healthy term infants, gestational age >37 weeks, birth weight >2500 g,
and solely formula-fed for at least 24 hours before randomization.
Exclusion criteria: history of disease or congenital malformation, evidence of formula intolerance or poor intake, weight at visit 1 of <98% of birth weight, or born large-for-gestational age
from a mother who was diabetic at childbirth


InterventionsFormula feeding began after randomization on visit 1 (14 days of age) and was to be continued through 120 days of age:
Treatment 1 (n = 74): control formula supplemented with 4 g/L of a prebiotic blend containing polydextrose (PDX) and galactooligosaccharides (GOS), 50:50 ratio;
Treatment 2: (n = 76): control formula supplemented with 8 g/L of a prebiotic blend containing PDX, GOS, and lactulose (LOS), 50:33:17 ratio;
Control (n = 76): control group (Enfamil LIPIL with iron, Mead Johnson & Co,
Evansville, IN).
Co-interventions: none reported.


OutcomesPrimary outcomes: overall growth and tolerance in healthy term infants
Other outcomes: anthropometric measurements and adverse events.
Definition: Physician (paediatrician of family doctor) diagnosed eczema entered into participant's diary. No definition given for eczema.


NotesSponsored: Supported by a grant from Mead Johnson & Co. Co-authors from Mead Johnson Nutritionals, Evansville, IN.
Treatment groups 1 and 2 are combined in comparisons 01 and 01 in the review.


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?YesA - Adequate

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Bakker-ZierikzeeRandomised to prebiotic (galacto-oligosaccharide and fructo-oligosaccharide) versus probiotic (bifidobacterium animalis) versus standard formula. Did not report allergy or food hypersensitivity.

Brunser 2006Randomised infants (1-2 years age) after amoxacillin treatment for acute bronchitis to prebiotic supplemented formula or control. Did not report allergy or food hypersensitivity.

Decsi 2005Randomised healthy infants to oligosaccharide supplemented formula or control. Did not report allergy or food hypersensitivity.

Euler 2005Randomised, crossover study of fructo-oligosaccharide supplement.

Haarman 2005Randomised infants to an infant formula supplemented with 0.8 g/100 ml GOS/FOS versus a standard infant formula. Did not report allergy or food hypersensitivity.

Knol 2005Randomised infants to an infant formula supplemented with 0.8 g/100 ml GOS/FOS versus a standard infant formula. Did not report allergy or food hypersensitivity.

Scholtens 2006Randomised infants to FOS prebiotic or placebo. Enrolled infants 4-6 months age. Did not report allergy or food hypersensitivity.

 
Comparison 1. Prebiotic versus no prebiotic

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

 1 Eczema2432Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.40, 1.17]

    1.1 Infant incidence
2432Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.40, 1.17]

 2 Growth in weight (g/day)5Mean Difference (IV, Fixed, 95% CI)Subtotals only

    2.1 Term infants
3416Mean Difference (IV, Fixed, 95% CI)0.93 [0.02, 1.84]

    2.2 Preterm infants
286Mean Difference (IV, Fixed, 95% CI)-1.78 [-4.05, 0.48]

 3 Growth in length (cm/week)4Mean Difference (IV, Fixed, 95% CI)Subtotals only

    3.1 Term infants
2252Mean Difference (IV, Fixed, 95% CI)0.01 [-0.02, 0.04]

    3.2 Preterm infants
286Mean Difference (IV, Fixed, 95% CI)0.17 [0.14, 0.19]

 4 Growth in head circumference (cm/week)2Mean Difference (IV, Fixed, 95% CI)Subtotals only

    4.1 Term infants
1206Mean Difference (IV, Fixed, 95% CI)-0.01 [-0.02, 0.00]

    4.2 Preterm infants
156Mean Difference (IV, Fixed, 95% CI)-0.01 [-0.02, 0.00]

 5 Feed intolerance resulting in formula discontinuation1226Risk Ratio (M-H, Fixed, 95% CI)1.81 [0.82, 3.99]

 
Comparison 2. Prebiotic versus no prebiotic in formula fed infants at high risk of allergy or food hypersensitivity

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

 1 Eczema1206Risk Ratio (M-H, Fixed, 95% CI)0.42 [0.21, 0.84]

    1.1 Infant incidence
1206Risk Ratio (M-H, Fixed, 95% CI)0.42 [0.21, 0.84]

 
Comparison 3. Prebiotic versus no prebiotic in formula fed infants not selected for risk of allergy or food hypersensitivity

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

 1 Eczema1226Risk Ratio (M-H, Fixed, 95% CI)1.62 [0.62, 4.26]

    1.1 Infant incidence
1226Risk Ratio (M-H, Fixed, 95% CI)1.62 [0.62, 4.26]

 
Comparison 4. Specific prebiotic versus no prebiotic

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

 1 Eczema2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 FOS / GOS formula versus placebo formula (Infant incidence)
1206Risk Ratio (M-H, Fixed, 95% CI)0.42 [0.21, 0.84]

    1.2 Polydextrose and GOS versus control
1150Risk Ratio (M-H, Fixed, 95% CI)2.67 [1.00, 7.12]

    1.3 Polydextrose, GOS and lactulose versus control
1152Risk Ratio (M-H, Fixed, 95% CI)0.6 [0.15, 2.42]

 2 Growth in weight (g/day)5Mean Difference (IV, Fixed, 95% CI)Subtotals only

    2.1 FOS / GOS formula versus placebo formula
2236Mean Difference (IV, Fixed, 95% CI)0.88 [-0.12, 1.88]

    2.2 Acidic oligosaccharide with FOS / GOS formula versus placebo formula
130Mean Difference (IV, Fixed, 95% CI)1.90 [-3.34, 7.14]

    2.3 Acidic oligosaccharide formula versus placebo formula
131Mean Difference (IV, Fixed, 95% CI)-2.40 [-7.70, 2.90]

    2.4 Polydextrose and GOS formula versus control fomula
1116Mean Difference (IV, Fixed, 95% CI)0.90 [-1.18, 2.98]

    2.5 Polydextrose, GOS and lactulose formula versus control formula
1106Mean Difference (IV, Fixed, 95% CI)0.90 [-1.32, 3.12]

    2.6 FOS formula versus placebo formula
156Mean Difference (IV, Fixed, 95% CI)-4.60 [-8.24, -0.96]

 3 Growth in length (cm/week)4Mean Difference (IV, Fixed, 95% CI)Subtotals only

    3.1 GOS / FOS formula versus placebo formula
2236Mean Difference (IV, Fixed, 95% CI)0.01 [-0.01, 0.03]

    3.2 Acidic oligosaccharide with GOS / FOS formula versus placebo formula
130Mean Difference (IV, Fixed, 95% CI)Not estimable

    3.3 Acidic oligosaccharide formula versus placebo formula
131Mean Difference (IV, Fixed, 95% CI)-0.04 [-0.22, 0.14]

    3.4 FOS formula versus placebo formula
156Mean Difference (IV, Fixed, 95% CI)0.30 [0.27, 0.33]

 4 Growth in head circumference (cm/week)2Mean Difference (IV, Fixed, 95% CI)Subtotals only

    4.1 GOS / FOS formula versus placebo formula
1206Mean Difference (IV, Fixed, 95% CI)-0.01 [-0.02, 0.00]

    4.2 FOS formula versus placebo formula
156Mean Difference (IV, Fixed, 95% CI)-0.01 [-0.02, 0.00]

 5 Feed intolerance resulting in formula discontinuation1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    5.1 Polydextrose and GOS versus control
1150Risk Ratio (M-H, Fixed, 95% CI)1.32 [0.52, 3.36]

    5.2 Polydextrose, GOS and lactulose versus control
1152Risk Ratio (M-H, Fixed, 95% CI)2.29 [1.00, 5.24]

 
Comparison 5. Specific prebiotic versus other prebiotic

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

 1 Eczema1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Polydextrose and GOS versus polydextrose, GOS and lactulose
1150Risk Ratio (M-H, Fixed, 95% CI)4.45 [1.32, 14.98]

 2 Growth in weight (g/day)2Mean Difference (IV, Fixed, 95% CI)Subtotals only

    2.1 GOS / FOS + acidic OS formula versus GOS / FOS formula
131Mean Difference (IV, Fixed, 95% CI)4.30 [-0.56, 9.16]

    2.2 Polydextrose and GOS versus polydextrose, GOS and lactulose
1106Mean Difference (IV, Fixed, 95% CI)Not estimable

 3 Growth in length (cm/week)1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    3.1 GOS / FOS + acidic OS formula versus GOS / FOS formula
131Mean Difference (IV, Fixed, 95% CI)0.04 [-0.15, 0.23]

 4 Feed intolerance resulting in formula discontinuation1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 Polydextrose and GOS versus polydextrose, GOS and lactulose
1150Risk Ratio (M-H, Fixed, 95% CI)0.58 [0.27, 1.22]