Prebiotics in infants for prevention of allergic disease and food hypersensitivity

Osborn DA, Sinn JK

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

Dates

Date edited: 21/08/2007
Date of last substantive update: 31/05/2007
Date of last minor update: / /
Date next stage expected 31/08/2009
Protocol first published: Issue 2, 2007
Review first published: Issue 4, 2007

Contact reviewer

Dr David A Osborn
Clinical Associate Professor, Neonatologist
RPA Newborn Care
Royal Prince Alfred Hospital
Missenden Road
Camperdown
New South Wales AUSTRALIA
2050
Telephone 1: +61 2 95158363
Facsimile: +61 2 95504375
E-mail: david.osborn@email.cs.nsw.gov.au

Contribution of reviewers

DAO and JKS wrote the protocol. DAO wrote the review. Both reviewers performed the literature search, independently assessed studies for eligibility, performed critical appraisal of eligible studies and data extraction, and formed a consensus on the conclusions.

Internal sources of support

RPA Newborn Care, Royal Prince Alfred Hospital, Sydney, AUSTRALIA

External sources of support

Centre for Perinatal Health Services Research, University of Sydney, AUSTRALIA

What's new

Dates

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

There is insufficient evidence to recommend the addition of prebiotics to infant feeds for prevention of allergic disease or food reactions.

Reactions to foods and allergies (including asthma, eczema and hay fever) are common and may be increasing in developed countries. Many infants become sensitised to foods, including infant formula, through their gastrointestinal tract, a process that may be affected by the composition of the intestinal bacteria. Attempts to promote the growth of normal gastrointestinal bacteria and prevent sensitisation to foods have included the addition of prebiotics to infant formula. Prebiotics are nondigestible food components that help by selectively stimulating the growth or activity of 'healthy' bacteria in the colon. In formula fed infants at high risk of allergy, this review found one small trial that reported a mixture of prebiotic oligosaccharides added to infant formula reduced the incidence of eczema in infants up to six months of age. A second trial in low risk infants reported no difference in eczema. No consistent adverse effects were found on infant growth. Further studies are needed to confirm these results, and to determine if the effects persist beyond infancy or affect other manifestations of allergic disease.

Abstract

Background

The composition of the intestinal microflora may be different in individuals with atopic eczema from those without this condition, and such differences may precede the development of eczema. Prebiotics are nondigestible food components that benefit the host by selectively stimulating the growth or activity of non-pathogenic bacteria in the colon. Prebiotics (commonly oligosaccharides) added to infant feeds have the potential to prevent sensitisation of infants to dietary allergens.

Objectives

To determine the effect of prebiotics given to infants for the prevention of allergic disease or food hypersensitivity.

Search strategy

This included searches of the Cochrane Central Register of Controlled Trials (Issue 1, 2007), MEDLINE (1966 - February 2007), EMBASE, PREMEDLINE, abstracts of conference proceedings and citations of published articles, and expert informants.

Selection criteria

Randomised and quasi-randomised controlled trials that compared the use of a prebiotic to no prebiotic; or the use a specific prebiotic compared to a different prebiotic.

Data collection & analysis

Assessment of trial quality, data extraction and synthesis of data were performed using standard methods of the Cochrane Neonatal Review Group.

Main results

Seven studies were eligible for inclusion. Only two studies reported an allergic disease outcome for 432 infants. Study quality was reasonable, although Moro 2006 reported 20% post-randomisation losses. Moro 2006 enrolled hydrolysed formula fed infants at high risk of allergy and reported a significant reduction in eczema in infants up to six months of age (RR 0.42, 95% CI 0.21, 0.84). Ziegler 2007 enrolled formula fed infants who were not selected on the basis of risk for allergy and reported no significant difference in eczema up to four months of age (RR 1.62, 95% CI 0.62, 4.26). Meta-analysis of the two studies found no significant difference in eczema, but significant heterogeneity was detected. Differences were potentially attributable to differences in infant risk, prebiotic formulation or measurement of eczema. Analysis of five studies reporting measures of infant growth found no consistent adverse effects.

Reviewers' conclusions

There is insufficient evidence to determine the role of prebiotic supplementation of infant formula for prevention of allergic disease and food hypersensitivity. One small trial of prebiotic oligosaccharides with excess losses reported a reduction in eczema in high risk formula fed infants. Further trials are needed to determine whether this finding persists over a longer period of time, applies to other manifestations of allergic disease, is associated with reductions in allergen sensitisation, and is reproducible.

Background

Food hypersensitivity and allergic disease are prevalent and represent a substantial health problem that may be increasing in developed countries (Burr 1989; Halken 2004; Prescott 2005; Schultz Larsen 1996). Genetic susceptibility plays a large role in the development of food allergy. Although less than half of those who develop childhood allergic disease have a first degree relative with a history of allergy, the risk of development of allergy increases substantially with a positive family history of allergic disease. Approximately 10% of children without an allergic first degree relative develop allergic disease compared to 20 - 30% with an allergic first degree relative (parent or sibling) and 40 - 50% with two affected relatives (Arshad 2005; Bergmann 1997; Hansen 1993; Kjellman 1977). The manifestations of allergic disease are age dependent. Infants commonly present with symptoms and signs of atopic eczema, gastrointestinal symptoms and recurrent wheezing. Asthma and rhinoconjunctivitis become prevalent in later childhood. Sensitization to allergens tends to follow a characteristic pattern (Halken 2004), with sensitization to food allergens in the first two to three years of life, followed by indoor allergens (e.g. house dust mite and pets) and, subsequently, outdoor allergens (e.g. rye and timothy grass). The cumulative prevalence of allergic disease in childhood is high, with up to 7 - 8% developing a food allergy, 15 - 20% atopic eczema, and 31 - 34% developing asthma or recurrent wheezing (Halken 2004). Of these, 7 - 10% will continue to have asthma symptoms beyond five years of age (Halken 2004). Food hypersensitivities affect approximately 6% of infants less than three years of age, with the prevalence decreasing over the first decade (Sampson 2004; Osterballe 2005).

A major focus of current research is the mechanisms for the development of immune tolerance and allergen sensitization in the fetus and newborn as well as primary prevention strategies. This review focuses on the evidence for use of prebiotics in infants for the prevention of food hypersensitivity and allergic disease. A separate review will examine the effects of probiotics compared to no probiotics in infants for prevention of allergic disease and food hypersensitivity (Osborn 2007). Prebiotics are nondigestible food components that benefit the host by selectively stimulating the growth or activity of bacteria in the colon. Prebiotics have frequently been added to infant formula. The most common prebiotic used in infant food is indigestible oligosaccharide, although other nitrogen and lipid containing compounds may also have a prebiotic effect (Agostoni 2004). To be effective, prebiotics should escape digestion and absorption in the upper gastrointestinal tract, reach the large bowel and be used selectively by microorganisms that have been identified as having health promoting properties. To date, studies in infants have demonstrated significant increases in faecal bifidobacteria in response to formula supplementation with oligosaccharides (Boehm 2002; Moro 2002; Moro 2006; Schmelzle 2003; Decsi 2005). One study also demonstrated an increase in fecal lactobacilli (Moro 2002).

An altered microbial exposure in the gastrointestinal tract may be partly responsible for the increase of allergic diseases in populations with a western lifestyle (Holt 1997). Differences in intestinal microflora are found in infants delivered by caesarean section when compared to those delivered vaginally, and in breast fed versus formula fed infants (Agostoni 2004). Breast feeding promotes the colonization of bifidobacteria and lactobacilli that inhibit growth of pathogenic microorganisms and compete with potentially pathogenic bacteria for nutrients and epithelial adhesion sites. The gastrointestinal flora may modulate mucosal physiology, barrier function and systemic immunologic and inflammatory responses (Agostoni 2004; Sudo 1997). Food allergy is a manifestation of an abnormal mucosal immune response to ingested dietary antigens (Sampson 2004 ). The gastrointestinal barrier is a complex physiochemical barrier and cellular barrier. However, some ingested food antigens are absorbed. The efficiency of this gastrointestinal barrier is reduced in the newborn period (Sampson 2004). Perinatal risk factors reported for asthma and / or allergy have included prematurity (Bernsen 2005; Jaakkola 2004; Raby 2004) and fetal growth restriction (Bernsen 2005), both of which are associated with an immature and potentially injured gastrointestinal mucosal barrier. The composition of the intestinal microflora may be different in those with atopic eczema, and such differences may precede the development of eczema. The most consistent finding in such studies is a reduced proportion of bifidobacteria species in the faeces of infants with eczema (Bjorksten 2001; Murray 2005) and atopic sensitization (Kalliomaki 2001), but not in the faeces of children with asthmatic symptoms (Murray 2005). The recognition of the importance of intestinal flora has led to the development of strategies aimed at manipulating bacterial colonization in formula fed infants, including the use of prebiotics and probiotics.

Prevention of allergy is divided into primary prevention, the prevention of immunological sensitization (development of IgE antibodies); and secondary prevention, the prevention of allergic disease following sensitization (Asher 2004). A substantial proportion of infants who develop sensitization will not go on to develop clinical manifestations of allergic disease or food hypersensitivity (Halken 2004). This review focuses on the prevention of clinical allergic disease (including asthma, eczema and allergic rhinitis) and food hypersensitivity, not just sensitization (IgE responses). Since the risk of allergy and food hypersensitivity is affected by heredity, subgroup analysis will examine the effect of prebiotics in populations of infants at high risk of allergy or food hypersensitivity separately from infants at low risk or not selected on the basis of heredity. Since breast feeding promotes the colonization of bifidobacteria and lactobacilli (Agostoni 2004), subgroup analysis examines the effect of prebiotics in human milk fed infants separately from prebiotics in formula fed infants.

Objectives

To determine the effect of prebiotics given to infants for the prevention of allergic disease or food hypersensitivity.
Secondary objectives:

to determine the effect of specific prebiotics;
to determine the effect of prebiotics in 1) breast fed infants, 2) human milk fed infants, and 3) formula fed infants;
to determine the effect of prebiotics used for 1) early / short term infant feeding, and 2) prolonged infant feeding;
to determine the effect of prebiotics in 1) infants not selected for risk of allergy or food hypersensitivity, or at low risk, and 2) in infants at high risk of allergy or food hypersensitivity;
to determine the effect of prebiotics given to 1) low birth weight or preterm infants, and 2) appropriate for gestational age term infants.

Criteria for considering studies for this review

Types of studies

Randomised and quasi-randomised controlled trials that compared the use of a prebiotic to a control (placebo or no treatment); or used a specific prebiotic compared to a different prebiotic.

Types of participants

Infants in the first six months of life without clinical evidence of allergic disease or food hypersensitivity, both with and without risk factors for allergic disease and food hypersensitivity.

Types of interventions

Prebiotics added to human milk or infant formula, whether added in the manufacturing process or given separately, compared to control (placebo or no treatment), or a different prebiotic.

Types of outcome measures

Definitions of allergic disease and food hypersensitivity had to be consistent with the 'Revised nomenclature for allergy for global use: Report of the Nomenclature Review Committee of the World Allergy Organization, October 2003' (Johansson 2004). Specific allergies were identified as atopic when confirmed by demonstration of an IgE response, either through skin testing or serological testing for specific IgE (e.g. RAST or EAST or CAP system).

Primary outcomes:

All allergic disease including asthma, eczema, rhinitis or food allergy (analysis restricted to studies reporting composite manifestations of all allergic disease);
Food hypersensitivity.

Secondary outcomes (specific allergies and food hypersensitivities):

Asthma
Dermatitis / eczema
Allergic rhinitis
Cow's milk or soy protein hypersensitivity
Cow's milk or soy protein allergy
Food allergy
Urticaria
Anaphylaxis

Potential harms:

Growth parameters including head circumference and weight gain when receiving prebiotic supplements;
Costs: Cost analysis including incremental cost per infant for prevention of allergic disease or food hypersensitivity (reported in the currency of the country of assessment). Costs should include all health, family and societal related costs. Cost analyses of trials from different countries and using different methodology will not be combined in meta-analysis, but reported separately if available;
Infant feed refusal;
Infection.

A specific allergic disease or food hypersensitivity may be diagnosed on the basis of:

History of recurrent and persistent symptoms typical of the allergic disease or food hypersensitivity;
A clinician diagnosis of allergic disease or food intolerance based on clinical findings supported by the above history;
Clinical allergic disease and food hypersensitivity confirmed by testing including detection of allergen sensitisation by either skin testing or serological testing for specific IgE (e.g. RAST or EAST or CAP system), asthma confirmed by respiratory function testing for presence of bronchial hyper-responsiveness, and food hypersensitivity confirmed by elimination/challenge.

The following definitions of age of allergic disease were used:

Infant allergic disease incidence: allergic disease occurring up to two years of age;
Childhood allergic disease incidence: allergic disease occurring up to 10 years of age (or up to age of latest report between two and 10 years);
Childhood allergic disease prevalence: allergic disease reported that was present between two and 10 years of age;
Adolescent allergic disease: allergic disease present from 10 to 18 years age.
Adult allergic disease: allergic disease present after 18 years age.

Search strategy for identification of studies

See: Neonatal Review Group 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 (CENTRAL, The Cochrane Library, Issue 1, 2007), MEDLINE (1966 - February 2007), EMBASE (1980 - February 2007) and CINAHL (1982 - February 2007) and previous reviews including cross references (all articles referenced), previous reviews including cross references, abstracts, conferences (Pediatric Academic Societies 1998 - 2007; Perinatal Society of Australia and New Zealand 1998 - 2007; ). The search strategy included the following keywords, using the search fields of abstract, MeSH subject headings, exploded subject heading, publication type, subject heading word, text word, and title: A search on all fields for [infant* OR newborn* OR neonat* OR pediatric* OR paediatric*] AND [prebiotic* OR oligosaccharide OR fructo-oligosaccharides OR galacto-oligosaccharide OR oligo*] will be conducted. The search was limited to: [random* OR trial* OR comparative study OR controlled study]. EMBASE was searched using the following terms: [(infant* OR newborn* OR neonat* OR pediatric* OR paediatric*) AND (prebiotic* OR 'oligosaccharide'/exp OR 'fructo-oligosaccharide'/exp OR oligo* OR 'galacto-oligosaccharide') AND [random* OR clinical trial]/lim]'. CINAHL was searched using the following terms: '[prebiotic$.mp OR prebiotic/exp OR oligosaccharide/ exp' OR oligo$.mp OR fructo$.mp OR galacto$.mp] AND [limited to (infants OR newborn infants' AND 'clinical trial']. No language restriction was applied.

Methods of the review

Eligibility of studies for inclusion was assessed independently by each review author. The criteria and standard methods of the Cochrane Neonatal Review Group were used to assess the methodological quality of the included trials. Quality of the included trials was evaluated in terms of adequacy of randomisation and allocation concealment, blinding of parents or carers and assessors to intervention, and completeness of assessment in all randomised individuals. Each review author extracted the data separately. Data was compared and differences resolved by consensus. The standard methods of the Neonatal Review Group were used to synthesise the data. Effects are expressed as relative risk (RR), risk difference (RD) and 95% confidence intervals (CI) for categorical data, and weighted mean difference (WMD) and 95% CI for continuous data. Data was examined for heterogeneity using the chi-square test for heterogeneity. Heterogeneity is quantified using the I² statistic. The fixed effect model was used for meta-analysis. Sources of heterogeneity are explored in subgroup analysis.

The following comparisons were prespecified:
1. Prebiotics versus no prebiotics (all studies);
2. Specific prebiotics versus no prebiotic (e.g. fructo-oligosaccharides, galacto-oligosaccharides etc);
3. Specific prebiotic versus other prebiotic.

The following subgroup analyses were prespecified:
1. According to infant heredity for allergy or food hypersensitivity:

Infants at high risk of allergy or food hypersensitivity (at least one first degree relative with allergic disease or food hypersensitivity);
Infants at low risk of allergy or food hypersensitivity, or not selected on basis of heredity.

2. According to method of infant feeding:

Infants fed human milk;
Infants fed formula.

3. According to duration of supplementation:

Infants given early (first few days), short term (days) supplementation;
Infants given prolonged supplementation (weeks or months).

4. According to infant maturity or birth weight:

Infants born at or near term;
Infants born preterm (< 37 weeks gestation) or low birth weight (< 2500 g).

Studies that included other allergic disease prevention interventions (e.g. maternal dietary avoidance measures, environmental allergy reduction measures) in the treatment and not the control group were excluded. Studies that had other allergy prevention interventions in both treatment and control groups were eligible.

A sensitivity analysis was prespecified to determine if the findings were affected by including only studies of adequate methodology, defined as adequate randomisation and allocation concealment, blinding of intervention and measurement, and < 10% losses to follow up.

The author of one trial (Ziegler 2007) provided methods for diagnosis for eczema by direct communication. For this study, data for the two prebiotic groups were combined and compared to the placebo group in Comparisons 01 and 03 (see Results section).

Description of studies

Excluded studies and reasons for exclusion from the review are found in 'Table of Excluded Studies'. Seven studies (Ben 2004; Boehm 2002; Brunser 2006b; Fanaro 2005; Kapiki 2007; Moro 2006; Ziegler 2007) were eligible for inclusion, although only two of these studies (Moro 2006; Ziegler 2007) reported outcomes for allergic disease or food hypersensitivity for 432 infants. Commercial sponsorship and / or authors employed by commercial entities were reported by six studies (Ben 2004; Boehm 2002; Brunser 2006b; Fanaro 2005; Moro 2006; Ziegler 2007), with the other study omitting to report whether it was sponsored (Kapiki 2007).

Participants:

Risk of allergy: Moro 2006 enrolled infants at high risk (first degree affected relatives) of allergy or food hypersensitivity. The remaining studies did not screen participants for risk of allergy or food hypersensitivity.
Infant feeding: All studies enrolled infants receiving prolonged formula feeding. Five studies (Ben 2004; Brunser 2006b; Fanaro 2005; Ziegler 2007) enrolled formula-fed term or near term infants. Boehm 2002 enrolled preterm infants when weaned from expressed breast milk. Kapiki 2007 enrolled preterm infants exclusively formula fed. Ziegler 2007 enrolled healthy term infants, gestational age > 37 weeks, birth weight > 2500 g, and solely formula-fed for at least 24 hours before randomisation. Infants were not selected on the basis of allergy or food hypersensitivity.

Interventions:

Fructo-oligosaccharides: Brunser 2006b allocated infants to a cow's milk formula intended for term infants that is supplemented with fructo-oligosaccharide 2 g/L versus the same formula without prebiotic. Kapiki 2007 allocated infants to a standard preterm formula supplemented with fructo-oligosaccharides 0.4 g/dl versus the same formula with maltodextrins 0.4 g/dl for 14 days.
Galacto-oligosaccharides: Ben 2004 allocated infants to a term infant cow's milk formula supplemented with galacto-oligosaccharide 0.24 g/L versus the same formula without prebiotic.
Prebiotic mixtures: Boehm 2002 allocated infants to a preterm infant formula with added fructo-oligosaccharide and galacto-oligosaccharide (ratio 1:9) versus the same preterm infant formula with added maltodextrins. Fanaro 2005 allocated infants to a term infant cow's milk infant formula with added acidic oligosaccharides 0.2 g/dL and maltodextrin 0.6 g/dL; or same formula with added acidic oligosaccharide 0.2 g/dL and mixture of fructo-oligosaccharide and galacto-oligosaccharide 0.6 g/dL; or the same formula with added maltodextrin 0.8 g/dL. Moro 2006 allocated infants to an extensively hydrolysed whey protein formula intended for term infants with added mixture of fructo-oligosaccharide and galacto-oligosaccharide 0.8 g/dL versus the same formula with added maltodextrin 0.8 g/dL. Ziegler 2007 allocated infants to a control formula supplemented with 4 g/L of a prebiotic blend containing polydextrose and galacto-oligosaccharides, 50:50 ratio; a control formula supplemented with 8 g/L of a prebiotic blend containing polydextrose, galacto-oligosaccharides and lactulose (LOS), 50:33:17 ratio; or to a control formula (cow's milk formula).

Outcomes:

Allergic disease and / or food hypersensitivity: Moro 2006 reported eczema at six months of age based on blinded physician examination and standardised criteria. Sensitisation (skin prick testing or serum specific IgE) was not reported. Ziegler 2007 reported eczema up to four months of age, but did not prespecify this outcome in methods. Eczema was recorded in the participant's diary and by the physician who diagnosed it (personal communication).
Growth: Three studies reported measures of growth in term infants (Fanaro 2005; Moro 2006; Ziegler 2007), with a further two studies reporting measures of growth in preterm infants (Boehm 2002; Kapiki 2007).
Other outcomes: Three studies (Ben 2004; Boehm 2002; Fanaro 2005) reported clinical symptoms and signs including crying, regurgitation, and vomiting. Ziegler 2007 reported feed intolerance resulting in study discontinuation.

Methodological quality of included studies

All studies had methodological concerns - see table 'Characteristics of included studies'.

Randomisation and allocation concealment: All studies reported random method of allocation to treatment. However, only three studies (Brunser 2006b; Kapiki 2007; Moro 2006) reported method of allocation. Five studies (Boehm 2002; Brunser 2006b; Kapiki 2007; Moro 2006; Ziegler 2007) reported adequate measures for allocation concealment, while the other studies (Ben 2004; Fanaro 2005) remained unclear.

Blinding of treatment: All studies reported measures to blind treatment.

Blinding of outcome measurement: Five studies (Ben 2004; Boehm 2002; Brunser 2006b; Kapiki 2007; Moro 2006) reported blinding of measurement. The other studies did not report blinding measurement, although treatment was blinded (Fanaro 2005; Ziegler 2007).

Losses to follow up: Losses to follow up were: Ben 2004 - unclear, reported 271 infants recruited, 121 infants received treatment or control formula with outcomes reported, and 124 received mixed test formula and breast milk feeds and outcomes were not reported. However, it is unclear how many randomised; Boehm 2002 - none reported; Brunser 2006b - 34% of randomised infants; Fanaro 2005 - 10% of randomised infants; Kapiki 2007- 14% of randomised infants; Moro 2006 20% of randomised infants; and Ziegler 2007 - 27% of randomised infants.

Intention to treat analysis: Six studies (Boehm 2002; Brunser 2006b; Fanaro 2005; Kapiki 2007; Moro 2006; Ziegler 2007) reported analyses according to group of assignment, while for one study it remained unclear (Ben 2004).

Results

PREBIOTIC VERSUS NO PREBIOTIC (COMPARISON 01):
Allergic disease and / or food hypersensitivity: No study reported all allergic disease or food hypersensitivity.

Eczema: Moro 2006 reported a significant reduction in infant eczema (RR 0.42, 95% CI 0.21, 0.84) up to six months age, whereas Ziegler 2007 reported no significant difference in eczema (RR 1.62, 95% CI 0.62, 4.26) up to four months of age. Meta-analysis of two studies (Moro 2006; Ziegler 2007) found no significant difference in eczema (typical RR 0.69, 95% CI 0.40, 1.17). In this analysis, data for the two prebiotic groups from Ziegler 2007 were combined. Significant (p = 0.03) and substantial (79.7%) heterogeneity was found between the studies. No other allergic disease or food hypersensitivity outcomes were reported.

Growth: In term infants, no individual study reported significant differences in growth, weight, length or head circumference when on a prebiotic supplemented formula compared to control. Meta-analysis of three studies (Fanaro 2005; Moro 2006; Ziegler 2007) using term formulas in term infants found a significant increase in weight gain (WMD 0.93 g/day, 95% CI 0.02, 1.84) in infants fed a prebiotic formula. Meta-analysis of two studies (Fanaro 2005; Moro 2006) found no significant difference in length gain (WMD 0.01 cm/week, 95% CI -0.02, 0.04). In term infants fed an extensively hydrolysed whey formula, Moro 2006 reported no significant difference in head circumference gain (MD -0.01, 95% CI -0.02, 0.00). In infants born preterm, meta-analysis of two studies (Boehm 2002; Kapiki 2007) found no significant difference in weight gain (WMD -1.78 g/day, 95% CI -4.05, 0.48) but did show a significant increase in length gain (MD 0.17 cm/week, 95% CI 0.14, 0.19) in infants fed prebiotic supplemented preterm infant formula versus preterm infant formula alone. Significant and substantial heterogeneity was found in both of these analyses. Kapiki 2007 reported no significant difference in head growth (MD -0.04, -0.02, 0.00). Ben 2004 reported that weight gain and length increments were similar among the groups (data not reported). Brunser 2006b reported that no significant differences between the study groups were observed for weight, height, weight for height, weight for age and height for age z-scores (using National Center for Health Statistics) during the study (data not reported);

Other outcomes / adverse effects: Ziegler 2007 reported no significant difference in feed intolerance resulting in study discontinuation (RR 1.81, 95% CI 0.82, 3.99). Ben 2004 reported that prebiotic supplementation had no influence on the incidence of side effects including crying, regurgitation, and vomiting (data not reported). Boehm 2002 reported no effect of the different diets on the incidence of side effects including crying, regurgitation, vomiting (data not reported). Brunser 2006b reported none of the withdrawals from the study were associated with adverse reactions to the formula (data not reported). Fanaro 2005 reported that the two experimental formulas were well tolerated, and there was also no difference in the incidence of crying, regurgitation, and vomiting episodes (data not reported). No data on costs were reported.

SUBGROUP ANALYSES:

PREBIOTIC VERSUS NO PREBIOTIC IN FORMULA FED INFANTS AT HIGH RISK OF ALLERGY OR FOOD HYPERSENSITIVITY (COMPARISON 02):
Moro 2006 enrolled infants at high risk of allergy or food hypersensitivity defined on the basis of a parental history of eczema, allergic rhinitis or asthma. Moro 2006 reported a significant reduction in infant eczema (RR 0.42, 95% CI 0.21, 0.84) up to six months age in infants receiving a mixture of fructo- and galacto-oligosaccharides. No other allergic disease or food hypersensitivity outcomes were reported.

PREBIOTIC VERSUS NO PREBIOTIC IN FORMULA FED INFANTS NOT SELECTED FOR RISK OF ALLERGY OR FOOD HYPERSENSITIVITY (COMPARISON 03): Ziegler 2007 enrolled formula fed infants not selected on the basis of risk for allergy or food hypersensitivity and reported no significant difference in eczema (RR 1.62, 95% CI 0.62, 4.26) up to four months of age. In this analysis, data for the two prebiotic groups were combined.

SENSITIVITY ANALYSIS: no study met criteria for studies of adequate methodology.

SPECIFIC PREBIOTIC VERSUS NO PREBIOTIC (COMPARISON 04):
Mixture of fructo- and galacto-oligosaccharides versus no prebiotic: Moro 2006 reported a significant reduction in infant eczema (RR 0.42, 95% CI 0.21, 0.84) up to six months age in infants receiving a mixture of fructo- and galacto-oligosaccharides. No other allergy or food hypersensitivity outcomes were reported. Meta-analysis of two studies (Boehm 2002; Moro 2006) found no significant difference in weight gain (WMD 0.88 g/day, 95% CI -0.12, 1.88) or growth in length (WMD 0.01 cm/week, 95% CI -0.01, 0.03) in infants treated with a mixture of fructo- and galacto-oligosaccharides. Moro 2006 reported no significant difference in head circumference (MD -0.01 cm/week, 95% CI -0.02, 0.00; p = 0.011).

Mixture of acidic, fructo- and galacto-oligosaccharides versus no prebiotic: Fanaro 2005 reported no significant difference in weight gain (MD 1.90 g/day, 95% CI -3.34, 7.14) and growth in length (MD 0.00 cm/week, 95% CI -0.16, 0.16) in infants treated with a mixture of acidic, fructo- and galacto-oligosaccharides versus placebo. No allergic disease or food hypersensitivity outcomes were reported.

Acidic oligosaccharides versus no prebiotic: Fanaro 2005 reported no significant difference in weight gain (MD -2.40 g/day, 95% CI -7.70, 2.90) and growth in length (MD -0.04 cm/week, 95% CI -0.22, 0.14) in infants treated with acidic oligosaccharides versus placebo. No allergic disease or food hypersensitivity outcomes were reported.

Polydextrose and galacto-oligosaccharide versus control: Ziegler 2007 reported an increase in eczema of borderline significance (RR 2.67, 95% CI 1.00, 7.12), no significant difference in weight gain (MD 0.90 g/day, 95% CI -1.18, 2.98), and no significant difference in feed intolerance resulting in study discontinuation (RR 1.32, 95% CI 0.52, 3.36). Ziegler 2007 reported statistical difference in diarrhoea (polydextrose and GOS vs. control 18% vs. 4%, P = 0.008).

Polydextrose, galacto-oligosaccharide and lactulose versus control: Ziegler 2007 reported no significant difference in eczema (RR 0.60, 95% CI 0.15, 2.42), or weight gain (MD 0.90 g/day, 95% CI -1.32, 3.12). Ziegler 2007 reported an increase in feed intolerance resulting in study discontinuation of borderline statistical significance (RR 2.9, 95% CI 1.00, 5.24). Ziegler 2007 reported statistical difference in irritability (polydextrose, GOS and lactulose vs. control, 16% vs. 4%, P = 0.027).

Fructo-oligosaccharide versus placebo: Kapiki 2007 reported a significant reduction in weight gain (MD -4.60 g/day, 95% CI -8.24, -0.96), a significant increase in length growth (MD 0.30 cm/week, 95% CI 0.27, 0.33) and no significant difference in head circumference growth (MD -0.01 cm/week, 95% CI -0.02, 0.00).

SPECIFIC PREBIOTIC VERSUS OTHER PREBIOTIC (COMPARISON 05):
Mixture of acidic, fructo- and galacto-oligosaccharides versus acidic oligosaccharides: Fanaro 2005 reported no significant difference in growth of weight (MD 4.30 g/day, 95% CI -0.56, 9.16) or length (MD 0.04 cm/week, 95% CI -0.15, 0.23) in infants fed a term infant formula supplemented with acidic fructo- and galacto-oligosaccharides versus the same formula supplemented with acidic oligosaccharides only. No allergic disease or food hypersensitivity outcome was reported.

Polydextrose and galacto-oligosaccharide versus polydextrose, galacto-oligosaccharide and lactulose: Ziegler 2007 reported a significant increase in eczema (RR 4.45, 95% CI 1.32, 14.98), no significant difference in weight gain (MD 0.00 g/day, 95% CI -2.08, 9.16) or length gain (MD 0.04, 95% CI -0.15, 0.23). Ziegler 2007 reported no significant difference in feed intolerance resulting in study discontinuation (RR 0.58, 95% CI 0.27, 1.22).

Discussion

This review found insufficient evidence to support or refute the use of prebiotics to prevent allergic disease or food hypersensitivity in infants. In high risk infants, one study reported outcomes for 206 infants and found that the addition of prebiotics to infant formula in infants at high risk of allergy may prevent infant eczema up to six months of age. This study used an extensively hydrolysed whey formula supplemented with a mixture of fructo- and galacto-oligosaccharides 0.8 g/dL. Infants at high risk of allergy based on having a first degree relative with a history of eczema, allergic rhinitis or asthma were enrolled. This finding should be treated with caution given the small sample size and excess post-randomisation losses (20%). In infants not selected for risk of allergy, a second study reported no significant difference in eczema in infants up to four months of age. Meta-analysis of the two studies found no significant difference in eczema, but significant heterogeneity between studies was found. Potential explanations for the heterogeneity include differences in selection of infants (high versus low risk), differences in prebiotic formulations and differences in measurement of infant eczema. Evidence of benefit from use of prebiotics is restricted to one report for the prevention of infant eczema in infants at high risk of allergy. Given the lack of reproducibility of findings in studies incorporated in this review, further trials of prebiotics are needed before they can be recommended for routine use in infants at high risk of allergy.

In term infants, meta-analysis of three studies found a significant increase in weight gain for infants fed a prebiotic supplemented formula, although no individual study reported a significant difference. The difference in weight gain (0.93 g/day) may not be clinically important. Given the methodological concerns regarding these studies, further studies are required to confirm this finding. In addition, one study reported increases in infant irritability and diarrhoea from prebiotic formulas supplemented with polydextrose and / or lactulose, and an increased rate of study discontinuation in infants fed a prebiotic formula containing polydextrose, GOS and lactulose. Both GOS and polydextrose have been demonstrated to have prebiotic effects on probiotic bacteria in vitro, while only GOS has an effect in vivo. Lactitol did not have prebiotic effects in vitro (Probert 2004). In preterm infants, one study reported a significant reduction in weight gain but a significant increase in growth and length. Meta-analysis of two studies found no significant difference in weight gain, but a significant increase in length gain. There was significant heterogeneity between studies found in the analyses of weight and length gain in preterm infants. Given the methodological limitations of the studies, these results should be treated with caution.

Further studies are required to determine whether the finding of reduced eczema in one study persists over a longer period of time, applies to other manifestations of allergic disease and/or food hypersensitivity, is associated with reductions in allergen sensitisation, and is reproducible. At present, the goal of prebiotic therapy has been to produce an infant formula that promotes the growth of normal gastrointestinal bacteria mimicking the effects of human breast milk. The effects of different prebiotic mixtures on gastrointestinal bacteria and mucosal function (barrier and immune), and on subsequent development of sensitisation, allergic disease and food hypersensitivity needs further study. Effects on infant growth and adverse effects, including feed intolerance and diarrhoea, should be assessed.

Reviewers' conclusions

Implications for practice

There is insufficient evidence from adequately designed and powered studies to determine the role of prebiotic supplementation of infant formula for prevention of allergic disease and food hypersensitivity. One small randomised trial with excess post-randomisation losses reported a significant reduction in eczema up to six months of age in formula fed infants at high risk of allergy supplemented with a prebiotic mix of oligosaccharides.

Implications for research

Further trials are needed to determine whether this finding persists over a longer period of time, applies to other manifestations of allergic disease and / or food hypersensitivity, is associated with reductions in allergen sensitisation, and is reproducible.

Acknowledgements

Potential conflict of interest

KS has been an invited speaker to industry funded meetings.

Characteristics of included studies

Study	Methods	Participants	Interventions	Outcomes	Notes	Allocation concealment
Ben 2004	Randomisation: 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.	Inclusion 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.	Treatment (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.	Primary 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.	Sponsored: Friesland Nutrition Institute of Netherlands and Edward Keller Co. Ltd. of China	B
Boehm 2002	Randomisation: 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.	Inclusion criteria: Preterm infants < 32 weeks gestation, when formula feeding commenced. Exclusion criteria: none reported.	Enteral 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.	Primary 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.	Sponsored: grant from Numico Research Germany.	A
Brunser 2006b	Randomisation: 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.	Inclusion 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.	Treatment (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.	Primary outcomes: colonic microbiota. Other outcomes: weight and height recorded every 15 days by study nurse. Allergy and food hypersensitivity not reported.	Sponsored: not reported. Study authors affiliated with Nestec Ltd., Vevey, Switzerland, and Nestlé Research Center, Vers-chez-les-Blanc, Switzerland.	A
Fanaro 2005	Randomisation: 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.	Inclusion 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.	Term 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.	Primary outcomes: Effect on Intestinal Flora, Stool Characteristics, and pH. Other outcomes: growth in weight and length reported. Allergy and food hypersensitivity not reported.	Sponsored: 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.	B
Kapiki 2007	Randomisation: 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.	Inclusion criteria: preterm infants <37 weeks. Healthy and exclusively formula fed. Exclusion criteria: major congenital abnormalities, chromosomal disorders or with disease requiring systemic antibiotic treatment	Treatment 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.	Primary outcomes: bifidogenic effect and stool characteristics. Other outcomes: somatic growth and well-being. Allergy and food hypersensitivity not reported.	Sponsored: none reported.	A
Moro 2006	Randomisation: 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.	Inclusion 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.	Both 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.	Primary 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.	Sponsored: grant from Numico Research Friedrichsdorf, Germany and the EARNEST program.	A
Ziegler 2007	Randomisation: 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.	Inclusion 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	Formula 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.	Primary 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.	Sponsored: 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.	A

Characteristics of excluded studies

Study	Reason for exclusion
Bakker-Zierikzee	Randomised to prebiotic (galacto-oligosaccharide and fructo-oligosaccharide) versus probiotic (bifidobacterium animalis) versus standard formula. Did not report allergy or food hypersensitivity.
Brunser 2006	Randomised 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 2005	Randomised healthy infants to oligosaccharide supplemented formula or control. Did not report allergy or food hypersensitivity.
Euler 2005	Randomised, crossover study of fructo-oligosaccharide supplement.
Haarman 2005	Randomised 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 2005	Randomised 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 2006	Randomised infants to FOS prebiotic or placebo. Enrolled infants 4-6 months age. Did not report allergy or food hypersensitivity.

References to studies

References to included studies

Ben 2004 {published data only}

Ben XM, Zhou XY, Zhao WH, Yu WL, Pan W, Zhang WL et al. Supplementation of milk formula with galacto-oligosaccharides improves intestinal micro-flora and fermentation in term infants. Chinese Medical Journal 2004;117:927-31.

Boehm 2002 {published data only}

* Boehm G, Lidestri M, Casetta P, Jelinek J, Negretti F, Stahl B, Marini A. Supplementation of a bovine milk formula with an oligosaccharide mixture increases counts of faecal bifidobacteria in preterm infants. Archives of Disease in Childhood Fetal and Neonatal Edition 2002;86:F178-81.

Knol J, Boehm G, Lidestri M, Negretti F, Jelinek J, Agosti M et al. Increase of faecal bifidobacteria due to dietary oligosaccharides induces a reduction of clinically relevant pathogen germs in the faeces of formula-fed preterm infants. Acta Paediatrica Supplement 2005;94:S449;31-3.

Brunser 2006b {published data only}

Brunser O, Figueroa G,Gotteland M, Haschke-Becher E, Magliola C, Rochat F et al. Effects of probiotic or prebiotic supplemented milk formulas on fecal microbiota composition of infants. Asia Pacific Journal of Clinical Nutrition 2006;15:368-76.

Fanaro 2005 {published data only}

Fanaro S, Jelinek J, Stahl B, Boehm G, Kock R, Vigi V. Acidic oligosaccharides from pectin hydrolysate as new component for infant formulae: effect on intestinal flora, stool characteristics, and pH. Journal of Pediatric Gastroenterology and Nutrition 2005;41:186-90.

Kapiki 2007 {published data only}

Kapiki A, Costalos C, Oikonomidou C, Triantafyllidou A, Loukatou E, Pertrohilou V. The effect of a fructo-oligosaccharide supplemented formula on gut flora of preterm infants. Early Human Development 2006;Prepublication.

Moro 2006 {published data only}

* Moro G, Arslanoglu S, Stahl B, Jelinek J, Wahn U, Boehm G. A mixture of prebiotic oligosaccharides reduces the incidence of atopic dermatitis during the first six months of age. Archives of Disease in Childhood 2006;91:814-9.

Moro GE, Stahl B, Fanaro S, Jelinek R, Boehm G, Coppa GV. Dietary prebiotic oligosaccharides are detectable in the faeces of formula-fed infants. Acta Pædiatrica 2005;94:S449; 27-30.

Ziegler 2007 {published and unpublished data}

Ziegler E, Vanderhoof JA, Petschow B, Mitmesser SH, Stolz SI, Harris CL, Berseth CL. Term infants fed formula supplemented with selected blends of prebiotics grow normally and have soft stools similar to those reported for breast-fed infants. Journal of Pediatric Gastroenterology and Nutrition 2007;44:359-64.

References to excluded studies

Bakker-Zierikzee {published data only}

* Bakker-Zierikzee AM, Alles MS, Knol J, Kok FJ, Tolboom JJ, Bindels JG. Effects of infant formula containing a mixture of galacto- and fructo-oligosaccharides or viable Bifidobacterium animalis on the intestinal microflora during the first 4 months of life. British Journal of Nutrition 2005;94:783-90.

Bakker-Zierikzee AM, Tol EA, Kroes H, Alles MS, Kok FJ, Bindels JG. Faecal SIgA secretion in infants fed on pre- or probiotic infant formula. Pediatric Allergy and Immunology 2006;17:134-40.

Brunser 2006 {published data only}

Brunser O, Gotteland M, Cruchet S, Figueroa G, Garrido D, Steenhout P. Effect of a milk formula with prebiotics on the intestinal microbiota of infants after an antibiotic treatment. Pediatric Research 2006;59:451-6.

Decsi 2005 {published data only}

Decsi T, Arato A, Balogh M, Dolinay T, Kanjo AH, Szabo E, Varkonyi A. Prebiotikus hatasu oligoszacharidok egeszseges csecsemok szekletflorajara gyakorolt hatasanak randomizalt, placeboval kontrollalt vizsgalata. Orvosi Hetilap 2005;146:2445-50.

Euler 2005 {published data only}

Euler AR, Mitchell DK, Kline R, Pickering LK. Prebiotic effect of fructo-oligosaccharide supplemented term infant formula at two concentrations compared with unsupplemented formula and human milk. Journal of Pediatric Gastroenterology and Nutrition 2005;40:157-64.

Haarman 2005 {published data only}

Haarman M, Knol J. Quantitative real-time PCR assays to identify and quantify fecal Bifidobacterium species in infants receiving a prebiotic infant formula. Applied and Environmental Microbiology 2005;71:2318-24.

Knol 2005 {published data only}

Knol J, Scholtens P, Kafka C, Steenbakkers J, Gro S, Helm K et al. Colon microflora in infants fed formula with galacto- and fructo-oligosaccharides: more like breast-fed infants. Journal of Pediatric Gastroenterology and Nutrition 2005;40:36-42.

Scholtens 2006 {published data only}

Scholtens PA, Alles MS, Willemsen LE, van den Braak C, Bindels JG, Boehm G, Govers MJ. Dietary fructo-oligosaccharides in healthy adults do not negatively affect faecal cytotoxicity: a randomised, double-blind, placebo-controlled crossover trial. British Journal of Nutrition. 95 2006;95:1143-9.

* indicates the primary reference for the study

Other references

Additional references

Agostoni 2004

Agostoni C, Axelsson I, Goulet O, Koletzko B, Michaelsen KF, Puntis JW et al. Prebiotic oligosaccharides in dietetic products for infants: a commentary by the ESPGHAN Committee on Nutrition. Journal of Pediatric Gastroenterology and Nutrition 2004;39:465-73.

Arshad 2005

Arshad SH, Kurukulaaratchy RJ, Fenn M, Matthews S. Early life risk factors for current wheeze, asthma, and bronchial hyperresponsiveness at 10 years of age. Chest 2005;127:502-8.

Asher 2004

Asher I, Baena-Cagnani C, Boner A, Canonica GW, Chuchalin A, Custovic A et al. World Allergy Organization guidelines for prevention of allergy and allergic asthma. International Archives of Allergy and Immunology 2004;135:83-92.

Bergmann 1997

Bergmann RL, Edenharter G, Bergmann KE, Guggenmoos-Holzmann I, Forster J, Bauer CP. Predictability of early atopy by cord blood-IgE and parental history. Clinical and Experimental Allergy 1997;27:752-60.

Bernsen 2005

Bernsen RM, de Jongste JC, Koes BW, Aardoom HA, van der Wouden JC. Perinatal characteristics and obstetric complications as risk factors for asthma, allergy and eczema at the age of 6 years. Clinical and Experimental Allergy 2005;35:1135-40.

Bjorksten 2001

Bjorksten B, Sepp E, Julge K, Voor T, Mikelsaar M. Allergy development and the intestinal microflora during the first year of life. Journal of Allergy and Clinical Immunology 2001;108:516-20.

Burr 1989

Burr ML, Butland BK, King S, Vaughan-Williams E. Changes in asthma prevalence: two surveys 15 years apart. Archives of Disease in Childhood 1989;64:1452-6.

Halken 2004

Halken S. Prevention of allergic disease in childhood: clinical and epidemiological aspects of primary and secondary allergy prevention. Pediatric Allergy and Immunology 2004;15 Suppl 16:4-5.

Hansen 1993

Hansen LG, Halken S, Host A, Moller K, Osterballe O. Prediction of allergy from family history and cord blood IgE levels. A follow-up at the age of 5 years. Cord blood IgE. IV. Pediatric Allergy and Immunology 1993;4:34-40.

Holt 1997

Holt PG, Sly PD, Björkstén B. Atopic versus infectious diseases in childhood: a question of balance? Pediatric Allergy and Immunology 1997;8:53-8.

Jaakkola 2004

Jaakkola JJ, Gissler M. Maternal smoking in pregnancy, fetal development, and childhood asthma. American Journal of Public Health 2004;94:136-40.

Johansson 2004

Johansson SG, Bieber T, Dahl R, Friedmann PS, Lanier BQ, Lockey RF et al. Revised nomenclature for allergy for global use: Report of the Nomenclature Review Committee of the World Allergy Organization, October 2003. Journal of Allergy and Clinical Immunology 2004;113:832-6.

Kalliomaki 2001

Kalliomaki M, Kirjavainen P, Eerola E, Kero P, Salminen S, Isolauri E. Distinct patterns of neonatal gut microflora in infants in whom atopy was and was not developing. Journal of Allergy and Clinical Immunology 2001;107:129-34.

Kjellman 1977

Kjellman NI. Atopic disease in seven-year-old children. Incidence in relation to family history. Acta Paediatrica Scandinavica 1997;66:465-71.

Moro 2002

Moro G, Minoli I, Mosca M, Fanaro S, Jelinek J, Stahl B, Boehm G. Dosage-related bifidogenic effects of galacto- and fructooligosaccharides in formula-fed term infants. Journal of Pediatric Gastroenterology and Nutrition 2002;34:291-5.

Murray 2005

Murray CS, Tannock GW, Simon MA, Harmsen HJ, Welling GW, Custovic A, Woodcock A. Fecal microbiota in sensitized wheezy and non-sensitized non-wheezy children: a nested case-control study. Clinical and Experimental Allergy 2005;35:741-5.

Osborn 2007

Osborn DA, Sinn JK. Probiotics in infants for prevention of allergy and food hypersensitivity. Cochrane Database of Systematic Reviews 2007, Issue 4.

Osterballe 2005

Osterballe M, Hansen TK, Mortz CG, Host A, Bindslev-Jensen C. The prevalence of food hypersensitivity in an unselected population of children and adults. Pediatric Allergy and Immunology 2005;16:567-73.

Prescott 2005

Prescott SL, Tang ML, Australasian Society of Clinical Immunology and Allergy. The Australasian Society of Clinical Immunology and Allergy position statement: Summary of allergy prevention in children. Medical Journal of Australia 2005;182:464-7.

Probert 2004

Probert HM, Apajalahti JH, Rautonen N, Stowell J, Gibson GR. Polydextrose, lactitol, and fructo-oligosaccharide fermentation by colonic bacteria in a three-stage continuous culture system. Applied and environmental microbiology 2004;70:4505-11.

Raby 2004

Raby BA, Celedon JC, Litonjua AA, Phipatanakul W, Sredl D, Oken E. Low-normal gestational age as a predictor of asthma at 6 years of age. Pediatrics 2004;114:e327-32.

Sampson 2004

Sampson HA. Update on food allergy. Journal of Allergy and Clinical Immunology 2004;113:805-19.

Schmelzle 2003

Schmelzle H, Wirth S, Skopnik H, Radke M, Knol J, Bockler HM. Randomized double-blind study of the nutritional efficacy and bifidogenicity of a new infant formula containing partially hydrolyzed protein, a high beta-palmitic acid level, and nondigestible oligosaccharides. Journal of Pediatric Gastroenterology and Nutrition 2003;36:343-51.

Schultz Larsen 1996

Schultz Larsen F. Atopic dermatitis: an increasing problem. Pediatric Allergy and Immunology 1996;7:51-3.

Sudo 1997

Sudo N, Sawamura S, Tanaka K, Aiba Y, Kubo C, Koga Y. The requirement of intestinal bacterial flora for the development of an IgE production system fully susceptible to oral tolerance induction. Journal of Immunology 1997;159:1739-45.

Comparisons and data

Comparison or outcome	Studies	Participants	Statistical method	Effect size
01 Prebiotic versus no prebiotic
01 Eczema	2	432	RR (fixed), 95% CI	0.69 [0.40, 1.17]
02 Growth in weight (g/day)			WMD (fixed), 95% CI	Subtotals only
03 Growth in length (cm/week)			WMD (fixed), 95% CI	Subtotals only
04 Growth in head circumference (cm/week)			WMD (fixed), 95% CI	Subtotals only
05 Feed intolerance resulting in formula discontinuation	1	226	RR (fixed), 95% CI	1.81 [0.82, 3.99]
02 Prebiotic versus no prebiotic in formula fed infants at high risk of allergy or food hypersensitivity
01 Eczema	1	206	RR (fixed), 95% CI	0.42 [0.21, 0.84]
03 Prebiotic versus no prebiotic in formula fed infants not selected for risk of allergy or food hypersensitiv
01 Eczema	1	226	RR (fixed), 95% CI	1.62 [0.62, 4.26]
04 Specific prebiotic versus no prebiotic
01 Eczema			RR (fixed), 95% CI	Subtotals only
02 Growth in weight (g/day)			WMD (fixed), 95% CI	Subtotals only
03 Growth in length (cm/week)			WMD (fixed), 95% CI	Subtotals only
04 Growth in head circumference (cm/week)			WMD (fixed), 95% CI	Subtotals only
05 Feed intolerance resulting in formula discontinuation			RR (fixed), 95% CI	Subtotals only
05 Specific prebiotic versus other prebiotic
01 Eczema			RR (fixed), 95% CI	Subtotals only
02 Growth in weight (g/day)			WMD (fixed), 95% CI	Subtotals only
03 Growth in length (cm/week)			WMD (fixed), 95% CI	Subtotals only
04 Feed intolerance resulting in formula discontinuation			RR (fixed), 95% CI	Subtotals only

01 Prebiotic versus no prebiotic

01.01 Eczema

01.01.01 Infant incidence

01.02 Growth in weight (g/day)

01.02.01 Term infants

01.02.02 Preterm infants

01.03 Growth in length (cm/week)

01.03.01 Term infants

01.03.02 Preterm infants

01.04 Growth in head circumference (cm/week)

01.04.01 Term infants

01.04.02 Preterm infants

01.05 Feed intolerance resulting in formula discontinuation

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

02.01 Eczema

02.01.01 Infant incidence

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

03.01 Eczema

03.01.01 Infant incidence

04 Specific prebiotic versus no prebiotic

04.01 Eczema

04.01.01 FOS / GOS formula versus placebo formula (Infant incidence)

04.01.02 Polydextrose and GOS versus control

04.01.03 Polydextrose, GOS and lactulose versus control

04.02 Growth in weight (g/day)

04.02.01 FOS / GOS formula versus placebo formula

04.02.02 Acidic oligosaccharide with FOS / GOS formula versus placebo formula

04.02.03 Acidic oligosaccharide formula versus placebo formula

04.02.04 Polydextrose and GOS formula versus control fomula

04.02.05 Polydextrose, GOS and lactulose formula versus control formula

04.02.06 FOS formula versus placebo formula

04.03 Growth in length (cm/week)

04.03.01 GOS / FOS formula versus placebo formula

04.03.02 Acidic oligosaccharide with GOS / FOS formula versus placebo formula

04.03.03 Acidic oligosaccharide formula versus placebo formula

04.03.04 FOS formula versus placebo formula

04.04 Growth in head circumference (cm/week)

04.04.01 GOS / FOS formula versus placebo formula

04.04.02 FOS formula versus placebo formula

04.05 Feed intolerance resulting in formula discontinuation

04.05.01 Polydextrose and GOS versus control

04.05.02 Polydextrose, GOS and lactulose versus control

05 Specific prebiotic versus other prebiotic

05.01 Eczema

05.01.01 Polydextrose and GOS versus polydextrose, GOS and lactulose

05.02 Growth in weight (g/day)

05.02.01 GOS / FOS + acidic OS formula versus GOS / FOS formula

05.02.02 Polydextrose and GOS versus polydextrose, GOS and lactulose

05.03 Growth in length (cm/week)

05.03.01 GOS / FOS + acidic OS formula versus GOS / FOS formula

05.04 Feed intolerance resulting in formula discontinuation

05.04.01 Polydextrose and GOS versus polydextrose, GOS and lactulose

Contact details for co-reviewers

Dr John KH Sinn
Staff Specialist
Neonatal Unit
Royal North Shore Hospital
Level 5, Douglas Building
Pacific Hwy
St. Leonards
New South Wales AUSTRALIA
2065
E-mail: jsinn@med.usyd.edu.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.