Prebiotics in infants for prevention of allergy
Abstract
Background
Prebiotics (commonly oligosaccharides) added to infant feeds have the potential to prevent sensitisation of infants to dietary allergens.
Objectives
To determine the effect of prebiotic given to infants for the prevention of allergy.
Search methods
We performed an updated search in August 2012 of the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 8), MEDLINE, EMBASE, conference proceedings, citations, expert informants and clinical trials registries.
Selection criteria
Randomised and quasi‐randomised controlled trials that compared the use of a prebiotic to no prebiotic, or a specific prebiotic compared to a different prebiotic in infants for prevention of allergy.
Data collection and analysis
Assessment of trial quality, data extraction and synthesis of data were performed using the standard methods of The Cochrane Collaboration.
Main results
The 2012 update identified 13 studies classified as ongoing or awaiting classification (yet to report allergy outcomes). Forty‐three studies were excluded, primarily as no allergy data were reported, although none of these enrolled infants were at high risk of allergy. Four studies enrolling 1428 infants were eligible for inclusion. All studies were at high risk of attrition bias. Allergy outcomes were reported from four months to two years of age.
Meta‐analysis of two studies (226 infants) found no significant difference in infant asthma although significant heterogeneity was found between studies. Meta‐analysis of four studies found a significant reduction in eczema (1218 infants, typical risk ratio 0.68, 95% CI 0.48 to 0.97; typical risk difference ‐0.04, 95% CI ‐0.07 to ‐0.00; number needed to treat to benefit (NNTB) 25, 95% CI 14 to > 100; P = 0.03). No statistically significant heterogeneity was found between studies. One study reported no significant difference in urticaria.
No statistically significant subgroup differences were found according to infant risk of allergy or type of infant feed. However, individual studies reported a significant reduction in asthma and eczema from supplementation with a mixture of galacto‐ and fructo‐oligosaccharide (GOS/FOS 9:1 ratio) (8 g/L) in infants at high risk of allergy; and in eczema from supplementation with GOS/FOS (9:1) (6.8 g/L) and acidic oligosacccharide (1.2 g/L) in infants not selected for allergy risk.
Authors' conclusions
Further research is needed before routine use of prebiotics can be recommended for prevention of allergy in formula fed infants. There is some evidence that a prebiotic supplement added to infant feeds may prevent eczema. It is unclear whether the use of prebiotic should be restricted to infants at high risk of allergy or may have an effect in low risk populations; or whether it may have an effect on other allergic diseases including asthma.
PICOs
Plain language summary
Prebiotics in infants for prevention of allergic disease and food allergy
There is some evidence that prebiotic added to infant formula may prevent eczema and asthma in infants. However, there is some concern about the reliability of the evidence due to not all trials reporting allergy outcomes and trials not reporting the outcome for all infants. Reactions to foods and allergies (including asthma, eczema and hay fever) are common and may be increasing. 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 prebiotic to infant formula. Prebiotics are nondigestible food components that help by selectively stimulating the growth or activity of 'healthy' bacteria in the colon. This review found some evidence that a prebiotic supplement added to infant feeds may prevent eczema in infants up to two years of age. It is unclear whether the use of prebiotic should be restricted to infants at high risk of allergy or may have an effect in low risk populations; or whether it may have an effect on other allergic diseases including asthma. However, further research is needed to confirm the findings before routine use of prebiotics can be recommended for prevention of allergy.
Authors' conclusions
Background
Description of the condition
Food allergy and allergic disease are prevalent and represent a substantial health problem that may be increasing in developed countries (Burr 1989; Schultz Larsen 1996; Halken 2004; Prescott 2005). 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% to 30% with an allergic first degree relative (parent or sibling) and 40% to 50% with two affected relatives (Kjellman 1977; Hansen 1993; Bergmann 1997; Arshad 2005). 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 (for example, house dust mite and pets) and, subsequently, outdoor allergens (for example, rye and timothy grass). The cumulative prevalence of allergic disease in childhood is high, with up to 7% to 8% developing a food allergy, 15% to 20% atopic eczema, and 31% to 34% developing asthma or recurrent wheezing (Halken 2004). Of these, 7% to 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).
Description of the intervention
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 focused on the evidence for use of prebiotic in infants for the prevention of food allergy and allergic disease. A separate review examines the effects of probiotics compared to no probiotics in infants for prevention of allergic disease and food allergy (Osborn 2007a). 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, prebiotic 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; Schmelzle 2003; Decsi 2005; Moro 2006). One study also demonstrated an increase in fecal lactobacilli (Moro 2002).
How the intervention might work
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 (Sudo 1997; Agostoni 2004). 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 or allergy, or both, have included prematurity (Jaakkola 2004; Raby 2004; Bernsen 2005) 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 allergy (Halken 2004). This review focused on the prevention of clinical allergic disease (including asthma, eczema and allergic rhinitis) and food allergy. Since the risk of allergy and food allergy is affected by heredity, subgroup analysis examined the effect of prebiotic in populations of infants at high risk of allergy 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 examined the effect of prebiotic in human milk fed infants separately from prebiotic in formula fed infants.
Why it is important to do this review
Food allergy and allergic disease are prevalent and represent a substantial health problem. Dietary interventions have the potential for preventing or delaying the onset of these conditions. This review focused on the evidence for use of prebiotic in infants for the prevention of food allergy and allergic disease.
Objectives
Primary objective
To determine the effect of prebiotic given to infants for the prevention of allergy.
Secondary objectives
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To determine the effect of specific prebiotic.
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To determine the effect of prebiotic in:
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breast fed infants;
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human milk fed infants;
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formula fed infants.
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To determine the effect of prebiotic used for:
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early or short term infant feeding;
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prolonged infant feeding.
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To determine the effect of prebiotic in:
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infants not selected for risk of allergy, or at low risk;
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in infants at high risk of allergy.
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To determine the effect of prebiotic given to:
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low birth weight or preterm infants;
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appropriate weight for gestational age term infants.
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Methods
Criteria for considering studies for this review
Types of studies
We included 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.
We excluded studies that included other allergic disease prevention interventions (for example, maternal dietary avoidance measures, environmental allergy reduction measures) in the treatment group and not the control group. We considered as eligible studies that had other allergy prevention interventions in both treatment and control groups.
Types of participants
Infants in the first six months of life without clinical evidence of allergy, both with and without risk factors for allergic disease and food allergy.
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.
Prebiotics are nondigestible food components that benefit the host by selectively stimulating the growth or activity of bacteria in the colon that provide a health benefit.
Types of outcome measures
Definitions of allergic disease and food allergy 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). Clinical manifestations of allergy, including asthma, eczema, rhinitis and urticaria, are commonly IgE mediated so a clinical diagnosis of disease was accepted. However, as the majority of food reactions are not associated with proven allergic mechanisms, only those food reactions likely to be allergic (for example, causing urticaria and angioedema) and those proven to be caused by allergic mechanisms were accepted.
Primary outcomes
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All allergic disease including asthma, eczema, rhinitis or food allergy (analysis restricted to studies reporting composite manifestations of all allergic disease)
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Food allergy
Secondary outcomes
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Asthma
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Dermatitis or eczema
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Allergic rhinitis
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Cow's milk or soy protein allergy
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Cow's milk or soy protein allergy
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Urticaria
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Anaphylaxis
A specific allergic disease or food allergy may be diagnosed on the basis of:
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history of recurrent and persistent symptoms typical of the allergic disease or food allergy;
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a clinician diagnosis allergy based on clinical findings supported by the above history;
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clinical allergic disease and food allergy confirmed by testing including detection of allergen sensitisation by either skin testing or serological testing for specific IgE (e.g., radioallergosorbent test (RAST) or enzyme allergosorbent test (EAST) or coated allergen particle (CAP) system), asthma confirmed by respiratory function testing for presence of bronchial hyper‐responsiveness, and food allergy confirmed by elimination and challenge.
The following definitions of age of allergic disease were used:
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infant allergic disease incidence, allergic disease occurring up to two years of age;
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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);
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childhood allergic disease prevalence, allergic disease reported that was present between two and 10 years of age;
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adolescent allergic disease, allergic disease present from 10 to 18 years of age;
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adult allergic disease, allergic disease present after 18 years of age.
Search methods for identification of studies
See: Cochrane Neonatal Review Group search strategy (http://neonatal.cochrane.org/).
Electronic searches
2012 update: an updated search was performed of CENTRAL (The Cochrane Library 2012, Issue 8), MEDLINE (1948 to August 2012), and EMBASE (1974 to August 2012). Principle authors from conference presentations and published articles were searched in MEDLINE via PubMed (1966 to August 2012).
Searching other resources
A search of previous reviews including cross references (all articles referenced), abstracts, conferences (Pediatric Academic Societies (PAS) 1998 to 2007; Perinatal Society of Australia and New Zealand (PSANZ) 1998 to 2007).
An updated search was performed of abstracts of conferences (PAS 2000 to 2012 and PSANZ 2008 to 2012), recent review citations and expert informants.
We also searched clinical trials registries for ongoing or recently completed trials (clinicaltrials.gov; controlled‐trials.com; and who.int/ictrp), updated August 2012.
Data collection and analysis
The author of one trial (Ziegler 2007) provided their methods for diagnosis of eczema by direct communication. For this study, data for the two prebiotic groups were combined and compared to the placebo group in Comparisons 1 and 3 (see Effects of interventions).
The author of one trial (Gruber 2010) provided the original study protocol and survival analysis data for first development of eczema (atopic dermatitis) up to 12 months of age.
Data for infant asthma and eczema from one included study (Westerbeek 2010) were obtained from the abstract of conference proceedings and have not been published at the time of this analysis.
Selection of studies
Eligibility of studies for inclusion was assessed independently by each review author.
Data extraction and management
Each review author extracted the data separately. Data were compared and differences resolved by consensus. In the 2012 update, all analyses were performed using the Review Manager software (RevMan 2011).
Assessment of risk of bias in included studies
We used the criteria and standard methods of the Cochrane Neonatal Review Group to assess the methodological quality of the included trials. The quality of included trials was evaluated in terms of adequacy of randomisation and allocation concealment, blinding of parents or caregivers and assessors to the intervention, and completeness of assessment in all randomised individuals.
For the 2010 update, the previous assessments were incorporated into RevMan 5 'Risk of bias' tables. Risk of bias for each study was assessed using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
(1) Sequence generation (checking for possible selection bias):
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adequate (any truly random process, e.g., random number table; computer random number generator);
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inadequate (any non‐random process, e.g., odd or even date of birth; hospital or clinic record number); or
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unclear.
(2) Allocation concealment (checking for possible selection bias):
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adequate (e.g., telephone or central randomisation; consecutively numbered sealed opaque envelopes);
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inadequate (open random allocation; unsealed or non‐opaque envelopes, alternation; date of birth); or
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unclear.
(3) Blinding (checking for possible performance bias):
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adequate, inadequate or unclear for participants;
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adequate, inadequate or unclear for personnel;
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adequate, inadequate or unclear for outcome assessors.
(4) Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations):
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adequate (less than 20% missing data);
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inadequate;
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unclear.
(5) Selective reporting bias:
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adequate (where it is clear that all of the study’s pre‐specified outcomes and all expected outcomes of interest to the review have been reported);
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inadequate (where not all the study’s pre‐specified outcomes have been reported; one or more reported primary outcomes were not pre‐specified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported);
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unclear.
(6) Other sources of bias:
The possibility of other possible sources of bias (for example, early termination of trial due to data‐dependant process, extreme baseline imbalance, etc.) was assessed as:
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yes;
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no;
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unclear.
(7) Overall risk of bias:
Explicit judgements were made about whether studies were at high risk of bias, according to the criteria given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). With reference to (1) to (6) above, the likely magnitude and direction of the bias and whether it was likely to impact on the findings were assessed. We explored the impact of the level of bias by undertaking sensitivity analyses (see: Sensitivity analysis).
Measures of treatment effect
We used the standard methods of the Cochrane Neonatal Review Group to synthesise the data. Effects were expressed as risk ratio (RR) and risk difference (RD) with 95% confidence intervals (CI) for categorical data, and weighted mean difference (WMD) and 95% CI for continuous data.
Unit of analysis issues
The unit of analysis was the infant.
Dealing with missing data
We recorded missing data in the 'Risk of bias' tables. We assessed the effect of missing data in the sensitivity analysis.
Assessment of heterogeneity
We used the two formal statistics described below.
1) The Chi2 test, to assess whether observed variability in effect sizes between studies is greater than would be expected by chance. Since this test has low power when the number of studies included in the meta‐analysis is small, we planned to set the probability at the 10% level of significance.
2) The I2 statistic to ensure that pooling of data is valid. We planned to grade the degree of heterogeneity as 0% to 30%: might not be important; 31% to 50%: moderate heterogeneity; 51% to 75%: substantial heterogeneity; 76% to 100%: considerable heterogeneity.
Where there was evidence of apparent or statistical heterogeneity, we planned to assess the source of the heterogeneity using sensitivity and subgroup analysis looking for evidence of bias or methodological differences between trials.
Assessment of reporting biases
Studies that reported using a prebiotic in a potentially eligible infant population but which did not report allergy related outcomes have been documented in the table 'Characteristics of excluded studies'. We assessed reporting and publication bias by examining the degree of asymmetry of a funnel plot.
Data synthesis
We used the fixed‐effect model using Mantel‐Haenszel methods for meta‐analysis.
Subgroup analysis and investigation of heterogeneity
The following comparisons were pre‐specified:
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prebiotic versus no prebiotic (all studies);
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specific prebiotic versus no prebiotic (e.g., fructo‐oligosaccharide (FOS), galacto‐oligosaccharide (GOS), acidic oligosaccharide (acidic OS) etc.);
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specific prebiotic versus other prebiotic.
The following subgroup analyses were pre‐specified.
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According to infant heredity for allergy:
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infants at high risk of allergy (at least one first degree relative with allergic disease or food allergy);
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infants at low risk of allergy, or not selected on basis of heredity.
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According to method of infant feeding:
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infants fed human milk;
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infants fed formula.
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According to duration of supplementation:
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infants given early (in first few days), short term (days) supplementation;
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infants given prolonged supplementation (weeks or months).
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According to infant maturity or birth weight:
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infants born at or near term;
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infants born preterm (< 37 weeks gestation) or low birth weight (< 2500 grams).
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Sensitivity analysis
A sensitivity analysis was pre‐specified to determine if the findings were affected by including only studies at low risk of bias, defined as adequate randomisation and allocation concealment, blinding of intervention and measurement, and < 10% losses to follow up.
Results
Description of studies
Results of the search
The 2012 search identified two additional eligible studies (Gruber 2010; Westerbeek 2010), although one of these reported allergy related outcomes in the abstract of conference proceedings only (Westerbeek 2010). Additional reports were found for two previously included studies (Moro 2006; Ziegler 2007).
There are 43 reports of excluded studies. See table 'Characteristics of excluded studies'.
Eight studies are awaiting classification (see 'Studies awaiting classification') as they have completed enrolment but are yet to publish allergy related outcomes (Nyankovskyy 2008; Veereman‐Wauters 2008; Zoeren‐Grobben 2009; Hicks 2010; Vanderhoff 2010; Campeotto 2011; Holscher 2012; Scalabrin 2012). Of these:
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Campeotto 2011 enrolled preterm infants but has not reported allergy related outcomes to date;
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Nyankovskyy 2008; Veereman‐Wauters 2008; Hicks 2010; Vanderhoff 2010; Holscher 2012; Scalabrin 2012 enrolled healthy term infants not selected for allergy risk and have not reported allergy outcomes to date;
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Zoeren‐Grobben 2009 enrolled term infants with intercurrent disease including diarrhoea and respiratory infections and has not reported allergy related outcomes to date.
Five studies were assessed as ongoing (Agostoni 2006; Hammerman 2007; Underwood 2009a; Materna Laboratories 2010; Stronati 2010). Of these:
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Agostoni 2006; Materna Laboratories 2010; Stronati 2010 enrolled healthy term infants not selected for allergy risk and have not reported allergy outcomes to date; and
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Hammerman 2007; Underwood 2009a enrolled preterm infants and have not reported allergy outcomes to date.
Included studies
Four studies (Moro 2006; Ziegler 2007; Gruber 2010; Westerbeek 2010) enrolling 1428 infants were assessed as eligible for inclusion. See table 'Characteristics of included studies'.
Participants
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Risk of allergy:
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infants at high risk of allergy, one study (Moro 2006) enrolled infants at high risk of allergy (first degree affected relatives);
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infants not selected for allergy risk, two studies (Ziegler 2007; Gruber 2010) enrolled healthy term infants not selected on basis of risk of allergy;
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sick or preterm or low birth weight infants, Westerbeek 2010 enrolled preterm infants < 32 weeks or birth weight < 1500 grams, or both, not selected on basis of risk of allergy.
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Infant feeding:
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predominantly human milk fed, Westerbeek 2010 enrolled preterm or low birth weight infants predominately human milk fed and supplemented with prebiotics from day three to day 30;
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predominantly cow's milk formula fed, two studies (Ziegler 2007; Gruber 2010) fed infants a cow's milk formula supplemented with prebiotic or control. Gruber 2010 provided supplements from weaning of breast feeding and continued them in follow on formula for infants up to 12 months age. Ziegler 2007 provided supplements in formula from 14 days and continued to 120 days of age;
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predominantly hydrolysed formula fed, Moro 2006 provided supplements in an extensively hydrolysed whey protein formula for six months.
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Interventions
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Prebiotic mixtures: Gruber 2010 allocated infants to receive a regular cow’s milk formula with added neutral GOS and FOS (ratio 9:1) and acidic oligosaccharides (OS) (total 8 g/L) versus a control group who received cow’s milk based formula without added oligosaccharides. Moro 2006 allocated infants to an extensively hydrolysed whey protein formula intended for term infants with an added mixture of FOS and GOS (0.8 g/dL) versus the same formula with added maltodextrin (0.8 g/dL). Westerbeek 2010 allocated infants to receive acidic and neutral oligosaccharides supplementation (20%:80%) in increasing doses to a maximum of 1.5 g/kg/day or placebo supplementation (maltodextrin) between days three and 30 of life added to breast milk or preterm formula. Ziegler 2007 allocated infants to formula supplemented with polydextrose and GOS (50:50 ratio) (4 g/L); formula supplemented with polydextrose, GOS and lactulose (LOS) (50:33:17 ratio) (8 g/L); or to control formula (cow's milk formula).
Outcomes
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Allergic disease or food allergy, or both: Gruber 2010 reported atopic dermatitis diagnosed according to the criteria recommended by the European Task Force on Atopic Dermatitis to one year. Moro 2006 reported eczema up to two years of age based on blinded physician examination and standardised criteria. Westerbeek 2010 reported physician‐diagnosed atopic dermatitis and bronchial hyper‐reactivity to one year. Ziegler 2007 reported eczema to four months of age, but did not pre‐specify this outcome in the methods. Eczema was recorded in the participant's diary and by the physician who diagnosed it (personal communication).
Excluded studies
Excluded studies (n = 43) and reasons for exclusion from the review are found in the table 'Characteristics of excluded studies'. The majority of these were excluded as they did not report allergy outcomes. Assessment of the excluded studies found:
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19 studies (Moro 2002; Bakker‐Zierikzee 2005; Decsi 2005; Fanaro 2005; Knol 2005; Brunser 2006; Scholtens 2006; Alliet 2007; Bongers 2007; Ashley 2008; Chouraqui 2008; Costalos 2008; Magne 2008; Bisceglia 2009; Bruzzese 2009; Fanaro 2009; Indrio 2009a; Indrio 2009b; Nakamura 2009) enrolled healthy term infants and compared use of a prebiotic versus no prebiotic but did not report allergy outcomes;
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five studies (Boehm 2002; Ben 2004; Kapiki 2007; Indrio 2009c; Modi 2010) enrolled preterm or low birth weight infants and compared use of a prebiotic versus no prebiotic but did not report allergy outcomes;
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one study (Shadid 2007) reporting infant eczema enrolled healthy pregnant women and randomised them to prebiotic versus placebo, which was ceased at delivery. The study was excluded as infants were not treated;
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one study enrolled infants at high risk of allergy and randomised them to receive a mixture of prebiotic and probiotic for prevention of allergy (Kukkonen 2006). This study is included in the probiotic review (Osborn 2007a);
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none of the other studies enrolled infants at high risk of allergy with the goal of preventing allergy.
Risk of bias in included studies
All studies had methodological concerns (see: table 'Characteristics of included studies', Figure 1). The studies were evaluated as being at high risk of bias, particularly due to attrition bias (Moro 2006; Ziegler 2007; Gruber 2010; Westerbeek 2010).
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Allocation
Random sequence generation was evaluated as low risk for three studies (Moro 2006; Gruber 2010; Westerbeek 2010). Ziegler 2007 did not report the method of sequence generation.
Allocation concealment was evaluated as low risk for four studies (Moro 2006; Ziegler 2007; Gruber 2010; Westerbeek 2010).
Blinding
All four studies (Moro 2006; Ziegler 2007; Gruber 2010; Westerbeek 2010) reported measures to blind treatment.
Three studies (Moro 2006; Gruber 2010; Westerbeek 2010) reported blinding of measurement. Ziegler 2007 did not report blinding of measurement, although treatment was blinded.
Incomplete outcome data
Gruber 2010 reported 11% of randomised infants lost at 12 months. It was also unclear if 300 breast fed women that were not included in the analysis were part of the initial randomisation.
Moro 2006 reported 20% of randomised infants lost at six months and 48% at two years; Westerbeek 2010 reported 10/102 (10%) of survivors not followed for allergy related outcomes; and Ziegler 2007 reported 27% of randomised infants lost at four months. All studies reported study losses that were related to the intervention.
Selective reporting
Three studies (Moro 2006; Gruber 2010; Westerbeek 2010) were considered as at low risk of reporting bias with pre‐specified definitions and time points for reporting allergy outcomes.
Ziegler 2007 used diary entries and physician‐diagnosed eczema, no definition was reported.
Other potential sources of bias
All studies (Moro 2006; Ziegler 2007; Gruber 2010; Westerbeek 2010) reported analyses according to the group of assignment and groups appeared well balanced after randomisation. Gruber 2010 reported the target sample size of 1500 infants but only 1130 were enrolled. The reason for premature stopping was not reported in the publication. No other potential biases were identified.
Effects of interventions
All analyses related to infant incidence of allergy.
Prebiotic versus no prebiotic (Comparison 1)
Asthma (Outcome 1.1)
Meta‐analysis of two studies (Moro 2006; Westerbeek 2010) found no significant difference in asthma (226 infants, RR 0.70, 95% CI 0.41 to 1.19, fixed‐effect model). Statistically significant (P = 0.07) and substantial heterogeneity (I² = 70%) was found between studies. Moro 2006 reported a significant reduction in asthma (134 infants, RR 0.37, 95% CI 0.14 to 0.96) whereas Westerbeek 2010 reported no significant difference (92 infants, RR 1.07, 95% CI 0.56 to 2.06).
Eczema (Outcome 1.2)
Meta‐analysis of four studies (Moro 2006; Ziegler 2007; Gruber 2010; Westerbeek 2010) found a significant reduction in eczema (1218 infants, typical RR 0.68, 95% CI 0.48 to 0.97; typical RD ‐0.04, 95% CI ‐0.07 to ‐0.00; number needed to benefit (NNTB) 25, 95% CI 14 to > 100). No statistically significant (P = 0.21) although potentially important (I² = 34%) heterogeneity was found between studies.
Urticaria (Outcome 1.3)
Moro 2006 reported no significant difference in urticaria (134 infants, RR 0.15, 95% CI 0.02 to 1.16) up to two years.
Subgroup analyses
Prebiotic versus no prebiotic ‐ according to infant risk of allergy (Comparison 2)
Asthma (Outcome 2.1)
Infants at high risk of allergy: Moro 2006 reported a significant reduction in asthma (134 infants, RR 0.37, 95% CI 0.14 to 0.96) to two years.
Infants not selected for risk of allergy: Westerbeek 2010 reported no significant difference in asthma to one year (92 infants, RR 1.07, 95% CI 0.56 to 2.06).
The test for subgroup differences according to risk of allergy found a borderline statistically significant (P = 0.07) and substantial (I² = 69.0%) difference.
Eczema (Outcome 2.2)
Infants at high risk of allergy: Moro 2006 reported a decrease in eczema of borderline statistical significance (134 infants, RR 0.49, 95% CI 0.24 to 1.00; RD ‐0.14, 95% CI ‐0.28 to ‐0.01; NNTB 7, 95% CI 4 to 100) to two years.
Infants not selected for risk of allergy: meta‐analysis of three studies (Ziegler 2007; Gruber 2010; Westerbeek 2010) found no significant difference in eczema (1084 infants, RR 0.76, 95% CI 0.51 to 1.14). There was no statistically significant (P = 0.18) but a potentially important (I² = 42%) heterogeneity between studies (Figure 2).
Funnel plot of comparison: 2 Prebiotic versus no prebiotic ‐ according to infant risk of allergy, outcome: 2.2 Eczema.
The funnel plot of the comparison according to infant risk of allergy is displayed in Figure 2. The test for subgroup differences according to risk of allergy found no statistically significant (P = 0.29) or important (I² = 9.0%) difference.
Urticaria (Outcome 2.3)
Infants at high risk of allergy: Moro 2006 reported no significant difference in urticaria (134 infants, RR 0.15, 95% CI 0.02 to 1.16) up to two years.
Infants not selected for risk of allergy: no study reported urticaria.
Prebiotic versus no prebiotic ‐ according to type of infant feed (Comparison 3)
Asthma (Outcome 3.1)
Fed predominately human milk: Westerbeek 2010 reported no significant difference in asthma (92 infants, RR 1.07, 95% CI 0.56 to 2.06).
Fed predominately hydrolysed infant formula: Moro 2006 reported a significant decrease in asthma (134 infants, RR 0.37, 95% CI 0.14 to 0.96; RD ‐0.13, 95% CI ‐0.25 to ‐0.01; NNT 8, 95% CI 4 to 100).
The test for subgroup differences according to risk of allergy found a borderline statistically significant (P = 0.07) and substantial (I² = 69.0%) difference.
Eczema (Outcome 3.2)
Fed predominately human milk: Westerbeek 2010 reported no significant difference in eczema (92 infants, RR 1.05, 95% CI 0.41 to 2.65).
Fed predominately cow's milk formula: meta‐analysis of two studies (Ziegler 2007; Gruber 2010) found no statistically significant difference in eczema (992 infants, typical RR 0.71, 95% CI 0.45 to 1.11). There was statistically significant (P = 0.09) and substantial (I² = 65%) heterogeneity between studies.
Fed predominately hydrolysed infant formula: Moro 2006 reported a decrease in eczema of borderline statistical significance (134 infants, RR 0.49, 95% CI 0.24 to 1.00; RD ‐0.14, 95% CI ‐0.28 to ‐0.01; NNTB 7, 95% CI 4 to 100).
Fed predominately human milk versus cow's milk formula: the test for subgroup differences found no statistically significant (P = 0.46) or important (I² = 0%) difference.
Fed predominately human milk versus hydrolysed infant formula: the test for subgroup differences found no statistically significant (P = 0.20) but a potentially important (I² = 38.6%) difference. The funnel plot of the comparison according to type of infant feed is displayed in Figure 3.
Funnel plot of comparison: 3 Prebiotic versus no prebiotic ‐ according to type of infant feed, outcome: 3.2 Eczema.
Urticaria (Outcome 3.3)
Fed predominately human milk: no study reported urticaria.
Fed predominately hydrolysed infant formula: no study reported urticaria.
Fed predominately hydrolysed infant formula: Moro 2006 reported no significant difference in urticaria (134 infants, RR 0.15, 95% CI 0.02 to 1.16) to two years.
Prebiotic versus no prebiotic ‐ according to type of prebiotic (Comparison 4)
Asthma (Outcome 4.1)
GOS/FOS (9:1) (8 g/L): Moro 2006 reported a significant reduction in asthma (134 infants, RR 0.37, 95% CI 0.14 to 0.96; RD ‐0.13, 95% CI ‐0.25 to ‐0.01; NNT 8, 95% CI 4 to 100).
GOS/FOS and acidic oligo saccharide (OS) (4:1) (1.5 g/kg/day): Westerbeek 2010 reported no significant difference in asthma (92 infants, RR 1.07, 95% CI 0.56 to 2.06).
The test for subgroup differences found a borderline significant (P = 0.07) and substantial (I² = 69.0%) subgroup difference.
Eczema (Outcome 4.2)
Polydextrose and GOS (4 g/L): Ziegler 2007 reported no significant difference in eczema (116 infants, RR 2.50, 95% CI 0.83 to 7.52) to four months.
Polydextrose, GOS and lactulose (8 g/L): Ziegler 2007 reported no significant difference in eczema (106 infants, RR 0.60, 95% CI 0.12 to 3.16) to four months.
GOS/FOS (9:1) (8 g/L): Moro 2006 reported a decrease in eczema of borderline statistical significance (134 infants, RR 0.49, 95% CI 0.24 to 1.00; RD ‐0.14, 95% CI ‐0.28 to ‐0.01; NNTB 7, 95% CI 4 to 100).
GOS/FOS (9:1) (6.8 g/L) and acidic OS (1.2 g/L): Gruber 2010 reported a significant reduction in eczema (828 infants, RR 0.58, 95% CI 0.35 to 0.97; RD ‐0.04, 95% CI ‐0.07 to ‐0.00; NNTB 25, 95% CI 14 to > 100).
GOS/FOS and acidic OS (4:1) (1.5 g/kg/day): Westerbeek 2010 reported no significant difference in eczema (92 infants, RR 1.05, 95% CI 0.41 to 2.65) to one year.
The funnel plot of the comparison according to type of prebiotic is displayed in Figure 4.
Funnel plot of comparison: 4 Prebiotic versus no prebiotic ‐ according to type of prebiotic, outcome: 4.2 Eczema.
Urticaria (Outcome 4.3)
GOS/FOS (9:1) (8 g/L): Moro 2006 reported no significant difference in urticaria (134 infants, RR 0.15, 95% CI 0.02 to 1.16) to two years.
Specific prebiotic versus other prebiotic (Comparison 5)
Eczema (Outcome 5.1)
Polydextrose and GOS (4 g/L) versus polydextrose, GOS and lactulose (8 g/L): Ziegler 2007 reported no significant difference in eczema (116 infants, RR 2.50, 95% CI 0.83 to 7.52) to four months.
Sensitivity analysis
Prebiotic versus no prebiotic ‐ studies at low risk of bias (Comparison 6)
Three studies (Moro 2006; Gruber 2010; Westerbeek 2010) reported methods of treatment allocation and blinding that were at low risk of bias. However, no study met the criteria for low risk of bias due primarily to the risk of attrition bias: Gruber 2010 11%, Moro 2006 20% to 48%, Westerbeek 2010 10%, and Ziegler 2007 27%.
All studies reported commercial sponsorship.
Discussion
Summary of main results
The 2012 update identified 13 studies classified as ongoing or awaiting classification (yet to report allergy outcomes). Forty‐three studies were excluded primarily as no allergy data were reported, although none of these enrolled infants at high risk of allergy. Four studies enrolling 1428 infants were eligible for inclusion. All studies were at high risk of attrition bias. Allergy outcomes were reported from four months to two years of age.
Meta‐analysis of two studies (226 infants) found no significant difference in infant asthma although significant heterogeneity was found between the studies. Meta‐analysis of four studies found a significant reduction in eczema (1218 infants, typical RR 0.68, 95% CI 0.48 to 0.97; typical RD ‐0.04, 95% CI ‐0.07 to ‐0.00; NNTB 25, 95% CI 14 to > 100; P =0.03). No statistically significant heterogeneity was found between studies. One study reported no significant difference in urticaria.
No statistically significant subgroup differences were found according to infant risk of allergy or type of infant feed. However, individual studies reported a significant reduction in asthma and eczema from supplementation with galacto‐oligosaccharide and fructo‐oligosaccharide (GOS/FOS) (9:1) (8 g/L) in infants at high risk of allergy; and in eczema from supplementation with GOS/FOS (9:1) (6.8 g/L) and acidic OS (1.2 g/L) in infants not selected for allergy risk.
The GRADE profile (Figure 5) found the quality of the evidence for use of prebiotics for prevention of asthma was very low, the quality was low for prevention of eczema, and the quality very low for prevention of urticaria. We recommend further research is needed before routine use of prebiotics can be recommended for prevention of allergy. No studies reported food allergy.
Overall completeness and applicability of evidence
Only one study (Moro 2006) reported the effect of prebiotic in infants at high risk of allergy. The other included studies enrolled healthy term infants (Ziegler 2007; Gruber 2010) or preterm, low birth weight infants (Westerbeek 2010). There is concern regarding the potential for publication bias for studies not enrolling high risk infants. The 2012 search identified seven studies awaiting classification as they have completed enrolment but are yet to publish allergy related outcomes, although none of these has enrolled infants at high risk of allergy. Six studies were assessed as ongoing, although again none of these enrolled infants at high risk of allergy. Forty‐three studies that compared a prebiotic versus no prebiotic were excluded, with 19 of these enrolling healthy term infants but not reporting allergy. Five studies enrolled preterm or low birth weight infants but did not report allergy. None of the other studies enrolled infants at high risk of allergy with the goal of preventing allergy.
Potential benefits for prebiotics are restricted to studies providing supplements for the duration of formula feeding using combinations of prebiotic similar to that found in human milk. Studies reporting a significant reduction in eczema used a GOS/FOS (9:1) combination with or without acidic oligosaccharides at a concentration of 8 g/L. The duration of prebiotic supplementation was prolonged, for the duration of formula feeding (six to 12 months), in two studies with both studies reporting a significant reduction in infant eczema. The duration of prebiotic supplementation was more limited in the other two studies (30 to 120 days). These reported no significant difference in infant eczema. In addition, the studies used differing prebiotic preparations at differing concentrations.
It is unclear if the potential benefit of prebiotic persists beyond infancy. Of the included studies, Ziegler 2007 reported eczema to only four months; Gruber 2010 reported eczema to 12 months; Westerbeek 2010 reported bronchial hyper‐reactivity and eczema to 12 months; and Moro 2006 reported asthma, eczema and urticaria to two years.
Quality of the evidence
There is potential for publication bias, particularly regarding studies that do not enrol infants at high risk of allergy. There are a substantial number of studies of prebiotic enrolling healthy, sick, preterm or low birth weight infants that have not reported allergy outcomes. All included studies were assessed as being at high risk of attrition bias. It was also unclear as to whether 300 breast fed infants were part of the initial randomisation and the reason for premature stopping of one trial (Gruber 2010). Only two studies provided prolonged supplementation of prebiotic for the duration of the formula feed and only one study reported the allergy outcome to two years, and none beyond. Only Moro 2006 enrolled infants at high risk of allergy with the primary goal of preventing allergy.
It is unclear if the effect of prebiotic in preventing eczema is clinically important. Meta‐analysis found a significant reduction in infant eczema (NNTB 25, 95% CI 14 to > 100; P = 0.03) with the upper confidence limit including a benefit of unclear clinical importance. The single study that enrolled infants at high risk of allergy was also insufficiently powered to determine if the effect on infant eczema was clinically important (NNTB 7, 95% CI 4 to 100; P = 0.05). However, there is some evidence for a possible dose effect with a larger risk decrease in high risk infants compared to low risk infants, although the difference is not statistically significant (high risk infants RD ‐0.14, 95% CI ‐0.28 to ‐0.01; low risk infants RD ‐0.02, 95% CI ‐0.06 to 0.01).
Only a single study pre‐specified a primary allergy related outcome. All studies appear to have been commercially sponsored.
Potential biases in the review process
The review conducted extensive searches of the published and unpublished literature for trials of prebiotics. However, there is substantial potential for publication bias from under reporting of negative trials in infants not selected for allergy risk. Many of the trials that did not report allergy assessed infants for adverse events and tolerance. The reported trials to date and with positive results have a common commercial sponsor.
In an attempt to avoid publication bias, the review included data from one study reported in an abstract of conference proceedings (Westerbeek 2010), and from another study which had unclear definitions of allergy related outcomes (Ziegler 2007). The review combines studies reporting outcomes at multiple times and differing time periods. The risk of selective reporting bias was minimised in the review by pre‐specifying the data from the latest time point reported by each study (infant up to two years).
Two review authors have independently assessed the trials and extracted data. Outcomes included in this review were compatible with standardised definitions of clinical allergy. Surrogate outcomes (sensitisation) including results of skin tests and serological evidence of atopy without clinical allergy were not included as pre‐specified outcomes in this review. However, where infants with clinical allergy were confirmed as atopic by skin tests or serological markers, this was pre‐specified for inclusion. The authors of this review have no financial or material conflicts of interest.
Agreements and disagreements with other studies or reviews
There are no other systematic reviews of the use of prebiotics in infants for prevention or treatment of allergy found in our search of The Cochrane Library and MEDLINE to August 2012. No systematic reviews were found of the use of prebiotics for treatment of infants with allergy. A 2009 systematic review of trials of prebiotic supplemented formula in full‐term infants reported the formula to be well tolerated and to increase stool colony counts of bifidobacteria and lactobacilli and result in stools similar to those of breast fed neonates without affecting weight gain (Rao 2009). A 2009 systematic review of the efficacy and safety of prebiotic oligosaccharide supplementation of formula in preterm neonates born at ≤ 37 weeks gestation reported in one trial that necrotising enterocolitis (NEC) did not occur in any of the enrolled neonates, and meta‐analysis found that the prebiotic supplemented formula increased stool colony counts of bifidobacteria and lactobacilli without adversely affecting weight gain (Srinivasjois 2009).
In a related Cochrane systematic review 'Probiotics in infants for prevention of allergy' (Osborn 2007a), one study (Kukkonen 2006) reported a significant reduction in eczema in infants receiving a synbiotic versus no synbiotic (925 infants, RR 0.81, 95% CI 0.66 to 0.99; RD ‐0.06, 95% CI ‐0.12 to ‐0.00; NNTB 17, 95% CI 12 to > 100). The study used a synbiotic preparation containing Lactobacillus rhamnosus GG, Lactobacillus rhamnosus LC705, Bifidobacterium breve, Propionibacterium freudenreichii and GOS 8 g/L and reported a reduction in infant eczema but not all allergic disease. The study was rated as at high risk of attrition bias and had unclear allocation concealment.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Funnel plot of comparison: 2 Prebiotic versus no prebiotic ‐ according to infant risk of allergy, outcome: 2.2 Eczema.
Funnel plot of comparison: 3 Prebiotic versus no prebiotic ‐ according to type of infant feed, outcome: 3.2 Eczema.
Funnel plot of comparison: 4 Prebiotic versus no prebiotic ‐ according to type of prebiotic, outcome: 4.2 Eczema.
Comparison 1 Prebiotic versus no prebiotic, Outcome 1 Asthma.
Comparison 1 Prebiotic versus no prebiotic, Outcome 2 Eczema.
Comparison 1 Prebiotic versus no prebiotic, Outcome 3 Urticaria.
Comparison 2 Prebiotic versus no prebiotic ‐ according to infant risk of allergy, Outcome 1 Asthma.
Comparison 2 Prebiotic versus no prebiotic ‐ according to infant risk of allergy, Outcome 2 Eczema.
Comparison 2 Prebiotic versus no prebiotic ‐ according to infant risk of allergy, Outcome 3 Urticaria.
Comparison 3 Prebiotic versus no prebiotic ‐ according to type of infant feed, Outcome 1 Asthma.
Comparison 3 Prebiotic versus no prebiotic ‐ according to type of infant feed, Outcome 2 Eczema.
Comparison 3 Prebiotic versus no prebiotic ‐ according to type of infant feed, Outcome 3 Urticaria.
Comparison 4 Prebiotic versus no prebiotic ‐ according to type of prebiotic, Outcome 1 Asthma.
Comparison 4 Prebiotic versus no prebiotic ‐ according to type of prebiotic, Outcome 2 Eczema.
Comparison 4 Prebiotic versus no prebiotic ‐ according to type of prebiotic, Outcome 3 Urticaria.
Comparison 5 Specific prebiotic versus other prebiotic, Outcome 1 Polydextrose and GOS 4g/L versus polydextrose, GOS and lactulose 8g/L.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Asthma Show forest plot | 2 | 226 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.70 [0.41, 1.19] |
| 1.1 Infant incidence | 2 | 226 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.70 [0.41, 1.19] |
| 2 Eczema Show forest plot | 4 | 1220 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.68 [0.48, 0.97] |
| 2.1 Infant incidence | 4 | 1220 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.68 [0.48, 0.97] |
| 3 Urticaria Show forest plot | 1 | 134 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.15 [0.02, 1.16] |
| 3.1 Infant incidence | 1 | 134 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.15 [0.02, 1.16] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Asthma Show forest plot | 2 | 226 | Risk Ratio (M‐H, Random, 95% CI) | 0.67 [0.23, 1.91] |
| 1.1 Infants at high risk of allergy | 1 | 134 | Risk Ratio (M‐H, Random, 95% CI) | 0.37 [0.14, 0.96] |
| 1.2 Infants not selected for risk of allergy | 1 | 92 | Risk Ratio (M‐H, Random, 95% CI) | 1.07 [0.56, 2.06] |
| 2 Eczema Show forest plot | 4 | 1220 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.68 [0.48, 0.97] |
| 2.1 Infants at high risk of allergy | 1 | 134 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.49 [0.24, 1.00] |
| 2.2 Infants not selected for risk of allergy | 3 | 1086 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.76 [0.51, 1.14] |
| 3 Urticaria Show forest plot | 1 | 134 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.15 [0.02, 1.16] |
| 3.1 Infants at high risk of allergy | 1 | 134 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.15 [0.02, 1.16] |
| 3.2 Infants not selected for risk of allergy | 0 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Asthma Show forest plot | 2 | 226 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.70 [0.41, 1.19] |
| 1.1 Fed predominately human milk | 1 | 92 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.07 [0.56, 2.06] |
| 1.2 Fed predominately cow's milk formula | 0 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 1.3 Fed predominately hydrolysed infant formula | 1 | 134 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.37 [0.14, 0.96] |
| 2 Eczema Show forest plot | 4 | 1220 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.68 [0.48, 0.97] |
| 2.1 Fed predominately human milk | 1 | 92 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.05 [0.41, 2.65] |
| 2.2 Fed predominately cow's milk formula | 2 | 994 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.71 [0.45, 1.11] |
| 2.3 Fed predominately hydrolysed infant formula | 1 | 134 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.49 [0.24, 1.00] |
| 3 Urticaria Show forest plot | 1 | 134 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.15 [0.02, 1.16] |
| 3.1 Fed predominately human milk | 0 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 3.2 Fed predominately cow's milk formula | 0 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 3.3 Fed predominately hydrolysed infant formula | 1 | 134 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.15 [0.02, 1.16] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Asthma Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.1 GOS / FOS (9:1) 8 grams/L versus | 1 | 134 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.37 [0.14, 0.96] |
| 1.2 GOS / FOS and acidic OS (4:1) 1.5 grams/kg/day | 1 | 92 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.07 [0.56, 2.06] |
| 2 Eczema Show forest plot | 4 | 1278 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.71 [0.51, 1.00] |
| 2.1 Polydextrose and GOS 4 grams/L | 1 | 116 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.5 [0.83, 7.52] |
| 2.2 Polydextrose, GOS and lactulose 8 grams/L | 1 | 106 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.60 [0.12, 3.16] |
| 2.3 GOS / FOS (9:1) 8 grams/L | 1 | 134 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.49 [0.24, 1.00] |
| 2.4 GOS / FOS (9:1) 6.8 grams/ and acidic OS 1.2 grams/L | 1 | 830 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.58 [0.35, 0.97] |
| 2.5 GOS / FOS and acidic OS (4:1) 1.5 grams/kg/day | 1 | 92 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.05 [0.41, 2.65] |
| 3 Urticaria Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Polydextrose and GOS 4g/L versus polydextrose, GOS and lactulose 8g/L Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.1 Ezcema | 1 | 116 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.5 [0.83, 7.52] |
