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Prebiotics in infants for prevention of allergy

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

Editorial Group: Cochrane Neonatal Group

Published Online: 28 MAR 2013

Assessed as up-to-date: 23 AUG 2012

DOI: 10.1002/14651858.CD006474.pub3

How to Cite

Osborn DA, Sinn JKH. Prebiotics in infants for prevention of allergy. Cochrane Database of Systematic Reviews 2013, Issue 3. Art. No.: CD006474. DOI: 10.1002/14651858.CD006474.pub3.

Author Information

  1. 1

    University of Sydney, Central Clinical School, Discipline of Obstetrics, Gynaecology and Neonatology, Sydney, NSW, Australia

  2. 2

    Royal North Shore Hospital, The University of Sydney, Department of Neonatology, Sydney, New South Wales, Australia

*David A Osborn, Central Clinical School, Discipline of Obstetrics, Gynaecology and Neonatology, University of Sydney, Sydney, NSW, 2050, Australia. david.osborn@email.cs.nsw.gov.au.

Publication History

  1. Publication Status: New search for studies and content updated (conclusions changed)
  2. Published Online: 28 MAR 2013

SEARCH

 

Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

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

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 
Primary objective

To determine the effect of prebiotic given to infants for the prevention of allergy.

 
Secondary objectives

  • To determine the effect of specific prebiotic.
  • To determine the effect of prebiotic in:
    • breast fed infants;
    • human milk fed infants;
    • formula fed infants.
  • To determine the effect of prebiotic used for:
    • early or short term infant feeding;
    • prolonged infant feeding.
  • To determine the effect of prebiotic in:
    • infants not selected for risk of allergy, or at low risk;
    • in infants at high risk of allergy.
  • To determine the effect of prebiotic given to:
    • low birth weight or preterm infants;
    • appropriate weight for gestational age term infants.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

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

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

 

Secondary outcomes

  • Asthma
  • Dermatitis or eczema
  • Allergic rhinitis
  • Cow's milk or soy protein allergy
  • Cow's milk or soy protein allergy
  • Urticaria
  • Anaphylaxis

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

  • history of recurrent and persistent symptoms typical of the allergic disease or food allergy;
  • a clinician diagnosis allergy based on clinical findings supported by the above history;
  • 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:

  • 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 of age;
  • 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):

  • adequate (any truly random process, e.g., random number table; computer random number generator);
  • inadequate (any non-random process, e.g., odd or even date of birth; hospital or clinic record number); or
  • unclear.   

 

(2) Allocation concealment (checking for possible selection bias):

  • adequate (e.g., telephone or central randomisation; consecutively numbered sealed opaque envelopes);
  • inadequate (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth); or
  • unclear.   

 

(3) Blinding (checking for possible performance bias):

  • adequate, inadequate or unclear for participants;
  • adequate, inadequate or unclear for personnel;
  • adequate, inadequate or unclear for outcome assessors.

 

(4) Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations):

  • adequate (less than 20% missing data);
  • inadequate;
  • unclear.

 

(5) Selective reporting bias:

  • 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);
  • 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);
  • 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:

  • yes;
  • no;
  • 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:

  1. prebiotic versus no prebiotic (all studies);
  2. specific prebiotic versus no prebiotic (e.g., fructo-oligosaccharide (FOS), galacto-oligosaccharide (GOS), acidic oligosaccharide (acidic OS) etc.);
  3. specific prebiotic versus other prebiotic.

The following subgroup analyses were pre-specified.

  1. According to infant heredity for allergy:
    1. infants at high risk of allergy (at least one first degree relative with allergic disease or food allergy);
    2. infants at low risk of allergy, or not selected on basis of heredity.
  2. According to method of infant feeding:
    1. infants fed human milk;
    2. infants fed formula.
  3. According to duration of supplementation:
    1. infants given early (in first few days), short term (days) supplementation;
    2. infants given prolonged supplementation (weeks or months).
  4. According to infant maturity or birth weight:
    1. infants born at or near term;
    2. infants born preterm (< 37 weeks gestation) or low birth weight (< 2500 grams).

 

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

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of studies awaiting classification; Characteristics of ongoing 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:

Five studies were assessed as ongoing (Agostoni 2006; Hammerman 2007; Underwood 2009a; Materna Laboratories 2010; Stronati 2010). Of these:

 

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

  • Risk of allergy:
    • infants at high risk of allergy, one study (Moro 2006) enrolled infants at high risk of allergy (first degree affected relatives);
    • infants not selected for allergy risk, two studies (Ziegler 2007; Gruber 2010) enrolled healthy term infants not selected on basis of risk of allergy;
    • 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.
  • Infant feeding:
    • 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;
    • 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;
    • predominantly hydrolysed formula fed, Moro 2006 provided supplements in an extensively hydrolysed whey protein formula for six months.

 
Interventions

  • 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

  • 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:

 

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).

 FigureFigure 1. 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).

 FigureFigure 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.

 FigureFigure 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.

 FigureFigure 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

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

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.

 FigureFigure 5.

 

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.

 

Authors' conclusions

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

 

Implications for practice

Further research is needed before routine use of prebiotics can be recommended for prevention of allergy. 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.

 
Implications for research

Futher large independent trials of prebiotic are needed before prebiotics can be recommended for prevention of allergy in formula fed infants. Current data indicate trials should use preparations of prebiotic that approximate the composition of human milk. Trials are needed both in infants at high risk of allergy and of the routine use of prebiotic in infants not selected by allergy risk. The intervention and measurement of outcomes should be blinded and allergy outcomes measured preferably to two years and beyond using standardised definitions.

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

None made

 

Data and analyses

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
Download statistical data

 
Comparison 1. Prebiotic versus no prebiotic

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

 1 Asthma2226Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.41, 1.19]

    1.1 Infant incidence
2226Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.41, 1.19]

 2 Eczema41220Risk Ratio (M-H, Fixed, 95% CI)0.68 [0.48, 0.97]

    2.1 Infant incidence
41220Risk Ratio (M-H, Fixed, 95% CI)0.68 [0.48, 0.97]

 3 Urticaria1134Risk Ratio (M-H, Fixed, 95% CI)0.15 [0.02, 1.16]

    3.1 Infant incidence
1134Risk Ratio (M-H, Fixed, 95% CI)0.15 [0.02, 1.16]

 
Comparison 2. Prebiotic versus no prebiotic - according to infant risk of allergy

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

 1 Asthma2226Risk Ratio (M-H, Random, 95% CI)0.67 [0.23, 1.91]

    1.1 Infants at high risk of allergy
1134Risk Ratio (M-H, Random, 95% CI)0.37 [0.14, 0.96]

    1.2 Infants not selected for risk of allergy
192Risk Ratio (M-H, Random, 95% CI)1.07 [0.56, 2.06]

 2 Eczema41220Risk Ratio (M-H, Fixed, 95% CI)0.68 [0.48, 0.97]

    2.1 Infants at high risk of allergy
1134Risk Ratio (M-H, Fixed, 95% CI)0.49 [0.24, 1.00]

    2.2 Infants not selected for risk of allergy
31086Risk Ratio (M-H, Fixed, 95% CI)0.76 [0.51, 1.14]

 3 Urticaria1134Risk Ratio (M-H, Fixed, 95% CI)0.15 [0.02, 1.16]

    3.1 Infants at high risk of allergy
1134Risk Ratio (M-H, Fixed, 95% CI)0.15 [0.02, 1.16]

   3.2 Infants not selected for risk of allergy
00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 
Comparison 3. Prebiotic versus no prebiotic - according to type of infant feed

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

 1 Asthma2226Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.41, 1.19]

    1.1 Fed predominately human milk
192Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.56, 2.06]

   1.2 Fed predominately cow's milk formula
00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.3 Fed predominately hydrolysed infant formula
1134Risk Ratio (M-H, Fixed, 95% CI)0.37 [0.14, 0.96]

 2 Eczema41220Risk Ratio (M-H, Fixed, 95% CI)0.68 [0.48, 0.97]

    2.1 Fed predominately human milk
192Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.41, 2.65]

    2.2 Fed predominately cow's milk formula
2994Risk Ratio (M-H, Fixed, 95% CI)0.71 [0.45, 1.11]

    2.3 Fed predominately hydrolysed infant formula
1134Risk Ratio (M-H, Fixed, 95% CI)0.49 [0.24, 1.00]

 3 Urticaria1134Risk Ratio (M-H, Fixed, 95% CI)0.15 [0.02, 1.16]

   3.1 Fed predominately human milk
00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

   3.2 Fed predominately cow's milk formula
00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    3.3 Fed predominately hydrolysed infant formula
1134Risk Ratio (M-H, Fixed, 95% CI)0.15 [0.02, 1.16]

 
Comparison 4. Prebiotic versus no prebiotic - according to type of prebiotic

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

 1 Asthma2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 GOS / FOS (9:1) 8 grams/L versus
1134Risk 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
192Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.56, 2.06]

 2 Eczema41278Risk Ratio (M-H, Fixed, 95% CI)0.71 [0.51, 1.00]

    2.1 Polydextrose and GOS 4 grams/L
1116Risk Ratio (M-H, Fixed, 95% CI)2.5 [0.83, 7.52]

    2.2 Polydextrose, GOS and lactulose 8 grams/L
1106Risk Ratio (M-H, Fixed, 95% CI)0.60 [0.12, 3.16]

    2.3 GOS / FOS (9:1) 8 grams/L
1134Risk 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
1830Risk 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
192Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.41, 2.65]

 3 Urticaria1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

 
Comparison 5. Specific prebiotic versus other prebiotic

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

 1 Polydextrose and GOS 4g/L versus polydextrose, GOS and lactulose 8g/L1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Ezcema
1116Risk Ratio (M-H, Fixed, 95% CI)2.5 [0.83, 7.52]

 

Appendices

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

Appendix 1. MEDLINE search strategy

Searched using OVID 23rd August 2012 (retrieved = 250):

1 infant*

2 exp Infant/

3 newborn*

4 neonat*

4 pediatric*

5 paediatric*

6 1 OR 2 OR 3 OR 4 OR 5

7 prebiotic*

8 exp Prebiotics/

9 oligosaccharide

10 fructo-oligosaccharides

11 galacto-oligosaccharide

12 7 OR 8 OR 9 OR 10 OR 11

13 6 AND 12

14 limit 14 to clinical trial, all

 

Appendix 2. CENTRAL search strategy

Searched 23rd August 2012 (retrieved = 206):

1 prebiotic*

2 oligo*

3 infant

4 #1 OR #2

5 #4 AND #3

 

Appendix 3. EMBASE search strategy

Searched 23rd August 2012 (retrieved = 1126):

1. 'prebiotic'/exp OR prebiotic AND ([controlled clinical trial]/lim OR [randomized controlled trial]/lim)

2. 'oligosaccharide'/exp OR oligosaccharide AND ([controlled clinical trial]/lim OR [randomized controlled trial]/lim) AND ([newborn]/lim OR [infant]/lim OR [preschool]/lim OR [school]/lim OR [child]/lim) AND [humans]/lim)

3. 1 OR 2

 

What's new

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

Last assessed as up-to-date: 23 August 2012.


DateEventDescription

23 August 2012New citation required and conclusions have changedThis is a substantive update with two new included trials and conclusions changed.

Food hypersensitivity no longer reported.

23 August 2012New search has been performedThis updates the review 'Prebiotics in infants for prevention of allergy' (Osborn 2007b).



 

History

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

Protocol first published: Issue 2, 2007
Review first published: Issue 4, 2007


DateEventDescription

14 September 2009New search has been performedUpdate includes new study and updated conclusion.

14 September 2009New citation required and conclusions have changedAddition citations found for previously included studies reporting 2 year outcomes.

25 August 2008AmendedConverted to new review format.

31 May 2007New citation required and conclusions have changedSubstantive amendment



 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

DAO and JKS wrote the protocol.
DAO wrote the review.
Both review authors 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.
For the August 2012 update, DAO and JSK independently assessed studies for eligibility, performed critical appraisal of eligible studies and data extraction, and formed a consensus on the conclusions.

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

KS has been an invited speaker to industry funded meetings.

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

Internal sources

  • No sources of support supplied

 

External sources

  • Australian Satellite of the Cochrane Neonatal Review Group, Australia.
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA.
    Editorial support of the Cochrane Neonatal Review Group has been funded with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN275201100016C.

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to studies awaiting assessment
  21. References to ongoing studies
  22. Additional references
  23. References to other published versions of this review
Gruber 2010 {unpublished data only}
  • Boehm G, Jelinek J. Double-blind, controlled and randomised study with a parallel group design on the effect of formula feeding (IF and FOF) supplemented with a mixture of immunological active neutral and acidic oligosaccharides on the incidence of febrile respiratory and gastrointestinal infections in healthy term born infants during the first year of life. German Clinical Trials Register 2009; Vol. DRKS00000201.
  • Boehm G. European Immuno Programming Study Group. First results of a randomised controlled double blind European multi-centre study with an infant formula supplemented with immunoactive prebiotics. Part II: Effect on atopic dermatitis in healthy infants in the first year of life. 2008. World Congress of Pediatric Gastroenterology, Hepatology and Nutrition:P0874.
  • Eisses AM. Multi-centre Immuno-Programming Study (MIPS). First results of a randomised controlled double blind European multi-centre study with an infant formula supplemented with immunoactive prebiotics. Part I: Effect on frequency of febrile episodes in healthy infants in the first year of life. World Congress of Pediatric Gastroenterology, Hepatology and Nutrition. 2008:P0797.
  • Gruber C, Arslanoglu S, Piemontese P, Eisses A, Macheiner M, Stricker T, et al. Prevention of early atopic dermatitis by an infant formula supplemented with immunoactive prebiotics in low atopy risk infants. Munksgaard Allergy. 2008; Vol. 63 Suppl 88:612–21.
  • Gruber C, van Stuijvenberg M, Mosca F, Moro G, Chirico G, Braegger CP, et al. Reduced occurrence of early atopic dermatitis because of immunoactive prebiotics among low-atopy-risk infants. Journal of Allergy and Clinical Immunology 2010;126(4):791-7.
  • Gruber C, van Stuijvenberg M, Mosca F, Moro G, Chirico G, Braegger CP, et al. Reduced occurrence of early atopic dermatitis because of immunoactive prebiotics among low-atopy-risk infants. Journal of Allergy and Clinical Immunology 2010;126(4):791-7.
  • Piemontese P, Gianni ML, Braegger CP, Chirico G, Gruber C, Riedler J, et al. Tolerance and safety evaluation in a large cohort of healthy infants fed an innovative prebiotic formula: a randomized controlled trial. PLoS One 2011;6(11):e28010.
  • Roggero P, Boehm G, Braegger C, Chirico G, Grüber C, Moro G, et al. First results of a randomised controlled double blind Europeanmulti-centre study with an infant formula supplemented with immunoactive prebiotics Part II:Effect on atopic dermatitis in healthy infants in the first year of life. 1st International Congress of UENPS. 2008.
  • Stam J, van Stuijvenberg M, Garssen J, Knipping K, Sauer PJ. A mixture of three prebiotics does not affect vaccine specific antibody responses in healthy term infants in the first year of life. Vaccine 2011;29(44):7766-72.
  • van Stuijvenberg M, Eisses AM, Gruber C, Mosca F, Arslanoglu S, Chirico G, et al. Do prebiotics reduce the number of fever episodes in healthy children in their first year of life: a randomised controlled trial. The British Journal of Nutrition 2011;106(11):1740-8.
Moro 2006 {published data only}
  • Arslanoglu S, Moro GE, Boehm G. Early supplementation of prebiotic oligosaccharides protects formula-fed infants against infections during the first 6 months of life. Journal of Nutrition 2007;137(11):2420-4.
  • Arslanoglu S, Moro GE, Schmitt J, Tandoi L, Rizzardi S, Boehm G. Early dietary intervention with a mixture of prebiotic oligosaccharides reduces the incidence of allergic manifestations and infections during the first two years of life. Journal of Nutrition 2008;138(6):1091-5.
  • 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(10):814-9.
  • Schouten B, Van Esch BC, Kormelink TG, Moro GE, Arslanoglu S, Boehm G, et al. Non-digestible oligosaccharides reduce immunoglobulin free light-chain concentrations in infants at risk for allergy. Pediatric Allergy and Immunology 2011;22(5):537-42.
  • van Hoffen E, Ruiter B, Faber J, M'Rabet L, Knol EF, Stahl B, et al. A specific mixture of short-chain galacto-oligosaccharides and long-chain fructo-oligosaccharides induces a beneficial immunoglobulin profile in infants at high risk for allergy. Allergy 2009;64(3):484-7.
Westerbeek 2010 {published data only}
  • Niele N, Van Zwol A, Boehm G, Westerbeek EAM, Lafeber HN, Van Elburg RM. Effect of enteral supplementation of neutral and acidic oligosaccharides in preterm infants on allergic and infectious diseases during the first year of life. Journal of Pediatric Gastroenterology and Nutrition 2011;52 Suppl 1:E115-6.
  • Niele N, Westerbeek EAM, Van Zwol A, Lafeber HN, Van Elburg RM. Effect of enteral supplementation of neutral and acidic oligosaccharides in preterm infants on allergic diseases during the first year of life. European Journal of Pharmacology 2011;668 Suppl 1:e14.
  • Westerbeek EA, Hensgens RL, Mihatsch WA, Boehm G, Lafeber HN, van Elburg RM. The effect of neutral and acidic oligosaccharides on stool viscosity, stool frequency and stool pH in preterm infants. Acta Paediatrica 2011;100(11):1426-31.
  • Westerbeek EA, Morch E, Lafeber HN, Fetter WP, Twisk JW, Van Elburg RM. Effect of neutral and acidic oligosaccharides on fecal IL-8 and fecal calprotectin in preterm infants. Pediatric Pesearch 2011;69(3):255-8.
  • Westerbeek EA, van den Berg A, Lafeber HN, Fetter WP, van Elburg RM. The effect of enteral supplementation of a prebiotic mixture of non-human milk galacto-, fructo- and acidic oligosaccharides on intestinal permeability in preterm infants. British Journal of Nutrition 2011;105(1):268-74.
  • Westerbeek EA, van den Berg JP, Lafeber HN, Fetter WP, Boehm G, Twisk JW, et al. Neutral and acidic oligosaccharides in preterm infants: a randomized, double-blind, placebo-controlled trial. American Journal of Clinical Nutrition 2010;91(3):679-86.
  • Westerbeek EA, van Elburg RM, van den Berg A, van den Berg J, Twisk JW, Fetter WP, et al. Design of a randomised controlled trial on immune effects of acidic and neutral oligosaccharides in the nutrition of preterm infants:carrot study. BMC Pediatrics 2008;8:46.
  • Westerbeek EAM, Van Esch BCA, Garssen J, Van Elburg RM. The effect of enteral supplementation of a prebiotic mixture of neutral and acidic oligosaccharides on immunoglobulin free light chains in preterm infants. Journal of Pediatric Gastroenterology and Nutrition 2011;52 Suppl 1:e105-6.
  • Westerbeek EAM, Van Esch ECAM, Garssen J, Van Elburg RM. The effect of enteral supplementation of neutral and acidic oligosaccharides on immunoglobulin free light chains in preterm infants. European Journal of Pharmacology 2011;668 Suppl 1:e46-7.
Ziegler 2007 {published and unpublished data}
  • Vanderhoof JA, Mitmesser SH, Harris CL, Stolz SI, Berseth CL. Formula supplemented with specific prebiotic blends is well tolerated by term infants. EPAS. 2007:8431.4.
  • Ziegler E, Vanderhoof JA, Petschow B, Mitmesser SH, Stolz SI, Harris CL, et al. 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(3):359-64.

References to studies excluded from this review

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to studies awaiting assessment
  21. References to ongoing studies
  22. Additional references
  23. References to other published versions of this review
Alliet 2007 {published data only}
  • Alliet P, Scholtens P, Raes M, Hensen K, Jongen H, Rummens JL, et al. Effect of prebiotic galacto-oligosaccharide, long-chain fructo-oligosaccharide infant formula on serum cholesterol and triacylglycerol levels. Nutrition 2007;23(10):719-23.
  • Raes M, Scholtens PA, Alliet P, Hensen K, Jongen H, Boehm G, et al. Exploration of basal immune parameters in healthy infants receiving an infant milk formula supplemented with prebiotics. Pediatric Allergy and Immunology 2010;21(2 Pt 2):e377-85.
  • Scholtens PA, Alliet P, Raes M, Alles MS, Kroes H, Boehm G, et al. Fecal secretory immunoglobulin A is increased in healthy infants who receive a formula with short-chain galacto-oligosaccharides and long-chain fructo-oligosaccharides. Journal of Nutrition 2008;138(6):1141-7.
Ashley 2008 {unpublished data only}
  • Ashley C, Johnston WH, Harris CL, Stolz SI, Wampler JL, Berseth CL. Growth and tolerance of infants fed formula supplemented with polydextrose (PDX) and/or galactooligosaccharides (GOS): double-blind, randomized, controlled trial. Nutrition Journal 2012;11:38.
  • Berseth CL. The Evaluation of Cow's Milk Formula - Study B. ClinicalTrials.gov identifier: NCT00712608 2008.
Bakker-Zierikzee 2005 {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.
Ben 2004 {published data only}
  • Ben XM, Li J, Feng ZT, Shi SY, Lu YD, Chen R, et al. Low level of galacto-oligosaccharide in infant formula stimulates growth of intestinal Bifidobacteria and Lactobacilli. World Journal of Gastroenterology 2008;14(42):6564-8.
  • 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(6):927-31.
  • Cai JW, Lu YD, Ben XM. Effects of infant formula containing galacto-oligosaccharides on the intestinal microflora in infants. Zhongguo Dangdai Erke Zazhi 2008;10(5):629-32.
Bisceglia 2009 {published data only}
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(3):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(449):31-3.
  • Lidestri M, Agosti M, Marini A, Boehm G. Oligosaccharides might stimulate calcium absorption in formula-fed preterm infants. Acta Paediatrica Supplement 2003;91(441):91-2.
  • Marini A, Negretti F, Boehm G, Li Destri M, Clerici-Bagozzi D, Mosca F, et al. Pro- and pre-biotics administration in preterm infants: colonization and influence on faecal flora. Acta Paediatrica Supplement 2003;91(441):80-1.
Bongers 2007 {published data only}
  • Bongers ME, de Lorijn F, Reitsma JB, Groeneweg M, Taminiau JA, Benninga MA. The clinical effect of a new infant formula in term infants with constipation: a double-blind, randomized cross-over trial. Nutrition Journal 2007;6:8.
Brunser 2006 {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(3):368-76.
Bruzzese 2009 {published data only}
  • Bruzzese E, Volpicelli M, Squeglia V, Bruzzese D, Salvini F, Bisceglia M, et al. A formula containing galacto- and fructo-oligosaccharides prevents intestinal and extra-intestinal infections: an observational study. Clinical Nutrition 2009;28(2):156-61.
Chouraqui 2008 {published data only}
  • Chouraqui JP, Grathwohl D, Labaune JM, Hascoet JM, de Montgolfier I, Leclaire M, et al. Assessment of the safety, tolerance, and protective effect against diarrhea of infant formulas containing mixtures of probiotics or probiotics and prebiotics in a randomized controlled trial. American Journal of Clinical Nutrition 2008;87(5):1365-73.
  • Hascoet JM, Chouraqui JP, Putet G, Gold F, Simeoni U. Evaluation of growth and incidence of diarrhea with a starter infant formula containing Bifidobacterium longum, Lactobacillus rhamnosus or Lactobacillus paracasei and a mixture of prebiotics. EPAS. 2007:7355.6.
Costalos 2008 {published data only}
Decsi 2005 {published data only}
  • Decsi T, Arato A, Balogh M, Dolinay T, Kanjo AH, Szabo E, et al. Randomised placebo controlled double blind study on the effect of prebiotic oligosaccharides on intestinal flora in healthy infants [Prebiotikus hatasu oligoszacharidok egeszseges csecsemok szekletflorajara gyakorolt hatasanak randomizalt, placeboval kontrollalt vizsgalata]. Orvosi Hetilap 2005;146(48):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(2):157-64.
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(2):186-90.
Fanaro 2009 {published data only}
  • Fanaro S, Marten B, Bagna R, Vigi V, Fabris C, Pena-Quintana L, et al. Galacto-oligosaccharides are bifidogenic and safe at weaning: a double-blind randomized multicenter study. Journal of Pediatric Gastroenterology and Nutrition 2009;48(1):82-8.
Indrio 2009a {published data only}
  • Indrio F, Riezzo G, Raimondi F, Bisceglia M, Cavallo L, Francavilla R. Effects of probiotic and prebiotic on gastrointestinal motility in newborns. Journal of Physiology and Pharmacology 2009;60 Suppl 6:27-31.
Indrio 2009b {unpublished data only}
  • Indrio F, Raimondi F, Bisceglia M, Riezzo G, Delvecchio M, Francavilla R, et al. Effects of prebiotic supplementation in the prevention of obesity in early infancy. EPAS. 2009:5500.8.
Indrio 2009c {published data only}
  • Indrio F, Riezzo G, Raimondi F, Francavilla R, Montagna O, Valenzano ML, et al. Prebiotics improve gastric motility and gastric electrical activity in preterm newborns. Journal of Pediatric Gastroenterology and Nutrition 2009;49(2):258-61.
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 2007;83:335-9.
Kim 2007 {published data only}
  • Kim SH, Lee da H, Meyer D. Supplementation of baby formula with native inulin has a prebiotic effect in formula-fed babies. Asia Pacific Journal of Clinical Nutrition. 2007;16(1):172-7.
Knol 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(5):2318-24.
  • 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(1):36-42.
Kukkonen 2006 {published data only}
  • Kuitunen M, Kukkonen K, Juntunen-Backman K, Korpela R, Poussa T, Tuure T, et al. Probiotics prevent IgE-associated allergy until age 5 years in cesarean-delivered children but not in the total cohort. Journal of Allergy and Clinical Immunology 2009;123(2):335-41.
  • Kuitunen M, Kukkonen K, Savilahti E. Pro- and prebiotic supplementation induces a transient reduction in hemoglobin concentration in infants. Journal of Pediatric Gastroenterology and Nutrition 2009;49(5):626-30.
  • Kukkonen K, Kuitunen M, Haahtela T, Korpela R, Poussa T, Savilahti E. High intestinal IgA associates with reduced risk of IgE-associated allergic diseases. Pediatric Allergy and Immunology 2010;21(1 Pt 1):67-73.
  • Kukkonen K, Nieminen T, Poussa T, Savilahti E, Kuitunen M. Effect of probiotics on vaccine antibody responses in infancy--a randomized placebo-controlled double-blind trial. Pediatric Allergy and Immunology 2006;17(6):416-21.
  • Kukkonen K, Savilahti E, Haahtela T, Juntunen-Backman K, Korpela R, Poussa T, et al. Long-term safety and impact on infection rates of postnatal probiotic and prebiotic (synbiotic) treatment: randomized, double-blind, placebo-controlled trial. Pediatrics 2008;122(1):8-12.
  • Kukkonen K, Savilahti E, Haahtela T, Juntunen-Backman K, Korpela R, Poussa T, et al. Probiotics and prebiotic galacto-oligosaccharides in the prevention of allergic diseases: A randomized, double-blind, placebo-controlled trial. Journal of Allergy and Clinical Immunology 2007;119(1):192-8.
  • Marschan E, Honkanen J, Kukkonen K, Kuitunen M, Savilahti E, Vaarala O. Increased activation of GATA-3, IL-2 and IL-5 of cord blood mononuclear cells in infants with IgE sensitization. Pediatric Allergy and Immunology 2008;19(2):132-9.
  • Marschan E, Kuitunen M, Kukkonen K, Poussa T, Sarnesto A, Haahtela T, et al. Probiotics in infancy induce protective immune profiles that are characteristic for chronic low-grade inflammation. Clinical and Experimental Allergy 2008;38(4):611-8.
Magne 2008 {published data only}
  • Magne F, Hachelaf W, Suau A, Boudraa G, Bouziane-Nedjadi K, Rigottier-Gois L, et al. Effects on faecal microbiota of dietary and acidic oligosaccharides in children during partial formula feeding. Journal of Pediatric Gastroenterology and Nutrition 2008;46(5):580-8.
Manzoni 2009 {unpublished data only}
  • Manzoni P, Rinaldi M, Cattani S, Pugni L, Romeo MG, Messner H, et al. Bovine lactoferrin supplementation for prevention of late-onset sepsis in very low-birth-weight neonates: a randomized trial. JAMA 2009;302(13):1421-8.
  • Manzoni P, Stolfi I, Cattani S, Messner H, Laforgia N, Romeo MG, et al. Bovine Lactoferrin supplementation prevents invasive fungal infections in preterm VLBW neonates: Data from a multicenter, randomized, double-blind, placebo-controlled study. E-PAS. 2009:2155.4.
Mihatsch 2006 {published data only}
  • Mihatsch WA, Hoegel J, Pohlandt F. Oligosaccharides reduce stool viscosity and accelerate the gastro-intestinal transport in preterm infants. EPAS. 2005:1302.
  • Mihatsch WA, Hoegel J, Pohlandt F. Prebiotic oligosaccharides reduce stool viscosity and accelerate gastrointestinal transport in preterm infants. Acta Paediatrica 2006;95(7):843-8.
Modi 2010 {published data only}
  • Modi N, Uthaya S, Fell J, Kulinskaya E. A randomised, double-blind, controlled trial of the effect of prebiotic oligosaccharides on enteral tolerance in preterm infants. Pediatric Research 2010;68:440-5.
Moro 2002 {published data only}
  • Moro G, Minoli I, Mosca M, Fanaro S, Jelinek J, Stahl B, et al. Dosage-related bifidogenic effects of galacto- and fructooligosaccharides in formula-fed term infants. Journal of Pediatric Gastroenterology and Nutrition 2002;34(3):291-5.
  • Moro GE, Mosca F, Miniello V, Fanaro S, Jelinek J, Stahl B, et al. Effects of a new mixture of prebiotics on faecal flora and stools in term infants. Acta Paediatrica Supplement 2003;91(441):77-9.
  • 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 Paediatrica 2005;94(449):27-30.
Nakamura 2009 {published data only}
  • Nakamura N, Gaskins HR, Collier CT, Nava GM, Rai D, Petschow B, et al. Molecular ecological analysis of fecal bacterial populations from term infants fed formula supplemented with selected blends of prebiotics. Applied and Environmental Microbiology 2009;75(4):1121-8.
Panigrahi 2008 {published data only}
  • Chandel DS, Tulapurkar ME, Braileanu GT, Panigrahi P. Long-term impact of synbiotic treatment on the developing gut flora of Indian infants. PAS Annual Meeting. 2010.
  • Panigrahi P, Parida S, Pradhan L, Mohapatra SS, Misra PR, Johnson JA, et al. Long-term colonization of a Lactobacillus plantarum synbiotic preparation in the neonatal gut. Journal of Pediatric Gastroenterology and Nutrition 2008;47(1):45-53.
  • Panigrahi P, Parida S, Satpathy R, Pradhan L, Mohapatra SS, Misra PR, et al. Long term colonization of a synbiotic Lactobacillus preparation in the newborn gut. EPAS. 2006:4812.50.
Puccio 2007 {published data only}
  • Puccio G, Cajozzo C, Meli F, Rochat F, Grathwohl D, Steenhout P. Clinical evaluation of a new starter formula for infants containing live Bifidobacterium longum BL999 and prebiotics. Nutrition 2007;23(1):1-8.
Rinne 2005 {published data only}
Riskin 2010 {unpublished data only}
  • Riskin A, Hochwald O, Bader D, Srugo I, Kugelman A, Shaoul R. The effects of lactulose supplementation to enteral feedings in premature infants. A pilot study. EPAS. 2007:6282.10.
  • Riskin A, Hochwald O, Bader D, Srugo I, Naftali G, Kugelman A, et al. The effects of lactulose supplementation to enteral feedings in premature infants: a pilot study. Journal of Pediatrics 2010;156(2):209-14.
  • Shaoul R. Lactulose for the Prevention of Nosocomial Infections in Children. ClinicalTrials.gov identifier: NCT00273949 2006.
Salvini 2011 {published data only}
  • Salvini F, Riva E, Salvatici E, Boehm G, Jelinek J, Banderali G, et al. A specific prebiotic mixture added to starting infant formula has long-lasting bifidogenic effects. The Journal of Nutrition 2011;141(7):1335-9.
Savino 2003 {published data only}
  • Savino F, Cresi F, Maccario S, Cavallo F, Dalmasso P, Fanaro S, et al. "Minor" feeding problems during the first months of life: effect of a partially hydrolysed milk formula containing fructo- and galacto-oligosaccharides. Acta Paediatrica Supplement 2003;91(441):86-90.
Savino 2005 {published data only}
  • Savino F, Maccario S, Castagno E, Cresi F, Cavallo F, Dalmasso P, et al. Advances in the management of digestive problems during the first months of life. Acta Paediatrica Supplement. 2005;94(449):120-4.
  • Savino F, Palumeri E, Castagno E, Cresi F, Dalmasso P, Cavallo F, et al. Reduction of crying episodes owing to infantile colic: A randomized controlled study on the efficacy of a new infant formula. European Journal of Clinical Nutrition 2006;60(11):1304-10.
Scholtens 2006 {published data only}
  • Scholtens PA, Alles MS, Bindels JG, van der Linde EG, Tolboom JJ, Knol J. Bifidogenic effects of solid weaning foods with added prebiotic oligosaccharides: a randomised controlled clinical trial. Journal of Pediatric Gastroenterology and Nutrition 2006;42(5):553-9.
Shadid 2007 {published data only}
  • Shadid R, Haarman M, Knol J, Theis W, Beermann C, Rjosk-Dendorfer D, et al. Effects of galactooligosaccharide and long-chain fructooligosaccharide supplementation during pregnancy on maternal and neonatal microbiota and immunity--a randomized, double-blind, placebo-controlled study. American Journal of Clinical Nutrition 2007;86(5):1426-37.
Singhal 2008 {published data only}
  • Singhal A, Kennedy K, Lanigan J, Clough H, Jenkins W, Elias-Jones A, et al. Dietary nucleotides and early growth in formula-fed infants: A randomized controlled trial. Pediatrics 2010;126(4):e946-53.
  • Singhal A, Macfarlane G, Macfarlane S, Lanigan J, Kennedy K, Elias-Jones A, et al. Dietary nucleotides and fecal microbiota in formula-fed infants: a randomized controlled trial. American Journal of Clinical Nutrition 2008;87(6):1785-92.
Underwood 2009 {published data only}
  • Underwood MA, Salzman NH, Bennett SH, Barman M, Mills DA, Marcobal A, et al. A randomized placebo-controlled comparison of 2 prebiotic/probiotic combinations in preterm infants: impact on weight gain, intestinal microbiota, and fecal short-chain fatty acids. Journal of Pediatric Gastroenterology and Nutrition 2009;48(2):216-25.
van den Berg 2004 {published data only}
  • van den Berg A, Fetter WP, Westerbeek EA, van der Vegt IM, van der Molen HR, van Elburg RM. The effect of glutamine-enriched enteral nutrition on intestinal permeability in very-low-birth-weight infants: a randomized controlled trial. JPEN, Journal of Parenteral and Enteral Nutrition 2006;30(5):408-14.
  • van den Berg A, van Elburg RM, Teerlink T, Lafeber HN, Twisk JW, Fetter WP. A randomized controlled trial of enteral glutamine supplementation in very low birth weight infants: plasma amino acid concentrations. Journal of Pediatric Gastroenterology and Nutrition 2005;41(1):66-71.
  • van den Berg A, van Elburg RM, Twisk JW, Fetter WP. Glutamine-enriched enteral nutrition in very low birth weight infants. Design of a double-blind randomised controlled trial [ISRCTN73254583]. BMC Pediatrics 2004;4:17.
  • van den Berg A, van Elburg RM, Vermeij L, van Zwol A, van den Brink GR, Twisk JW, et al. Cytokine responses in very low birth weight infants receiving glutamine-enriched enteral nutrition. Journal of Pediatric Gastroenterology and Nutrition 2009;48(1):94-101.
  • van den Berg A, van Elburg RM, Westerbeek EA, Twisk JW, Fetter WP. Glutamine-enriched enteral nutrition in very-low-birth-weight infants and effects on feeding tolerance and infectious morbidity: a randomized controlled trial. American Journal of Clinical Nutrition 2005;81(6):1397-404.
  • van den Berg A, van Elburg RM, Westerbeek EA, van der Linde EG, Knol J, Twisk JW, et al. The effect of glutamine-enriched enteral nutrition on intestinal microflora in very low birth weight infants: a randomized controlled trial. Clinical Nutrition 2007;26(4):430-9.
  • van den Berg A, van Zwol A, Moll HA, Fetter WP, van Elburg RM. Glutamine-enriched enteral nutrition in very low-birth-weight infants: effect on the incidence of allergic and infectious diseases in the first year of life. Archives of Pediatrics and Adolescent Medicine 2007;161(11):1095-101.
  • van Zwol A, van den Berg A, Huisman J, Vermeulen RJ, Fetter WP, Twisk JW, et al. Neurodevelopmental outcomes of very low-birth-weight infants after enteral glutamine supplementation in the neonatal period. Acta Paediatrica 2008;97(5):562-7.
  • van Zwol A, van den Berg A, Nieuwenhuis EE, Twisk JW, Fetter WP, van Elburg RM. Cytokine profiles in 1-yr-old very low-birth-weight infants after enteral glutamine supplementation in the neonatal period. Pediatric Allergy and Immunology 2009;20(5):467-70.
Vivatvakin 2010 {published data only}
  • Vivatvakin B, Mahayosnond A, Theamboonlers A, Steenhout PG, Conus NJ. Effect of a whey-predominant starter formula containing LCPUFAs and oligosaccharides (FOS/GOS) on gastrointestinal comfort in infants. Asia Pacific Journal of Clinical Nutrition 2010;19(4):473-80.
Vlieger 2009 {published data only}
  • Vlieger AM, Robroch A, van Buuren S, Kiers J, Rijkers G, Benninga MA, et al. Tolerance and safety of Lactobacillus paracasei ssp. paracasei in combination with Bifidobacterium animalis ssp. lactis in a prebiotic-containing infant formula: a randomised controlled trial. British Journal of Nutrition 2009;102(6):869-75.
Ziegler 2007a {unpublished data only}
  • Ziegler EE, Black B, Lessin H, Jones S, Sun S. Assessment of growth of infants fed a starter infant formula containing prebiotics and probiotics. EPAS. 2007:5888.8.

References to studies awaiting assessment

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to studies awaiting assessment
  21. References to ongoing studies
  22. Additional references
  23. References to other published versions of this review
Campeotto 2011 {unpublished data only}
  • Campeotto F. Evaluation of a Fermented Formula Without Live Bacteria for Preterm Infants: Effects on Microbiota Species and Intestinal Inflammatory Markers. ClinicalTrials.gov identifier: NCT00711633 2008.
  • Campeotto F, Suau A, Kapel N, Magne F, Viallon V, Ferraris L, et al. A fermented formula in pre-term infants: clinical tolerance, gut microbiota, down-regulation of faecal calprotectin and up-regulation of faecal secretory IgA. The British Journal of Nutrition 2011;March 22:1-10 [Epub ahead of print].
Hicks 2010 {unpublished data only}
  • Heubi J. Evaluation of Mineral Absorption in Infants Fed Infant Formula. ClinicalTrials.gov identifier: NCT00366873 2006.
  • Hicks PD, Hawthorne KM, Marunycz J, Berseth CL, Heubi J, Abrams SA. Similar calcium status is present in infants fed formula with and without prebiotics [abstract]. Annual Meeting of the Pediatric Academic Society. 2010; Vol. E-PAS2010:1665.7.
Holscher 2012 {unpublished data only}
  • Faust K, Litov R, Ziegler EE, Lessin H, Hatch T, Sun S, Tappenden KA. Effects of prebiotic-containing infant formula on commensal microbiota [abstract]. Annual Meeting of the Pediatric Academic Societies. 2008; Vol. EPAS:5820.4.
  • Holscher HD, Faust KL, Czerkies LA, Litov R, Ziegler EE, Lessin H, et al. Effects of prebiotic-containing infant formula on gastrointestinal tolerance and fecal microbiota in a randomized controlled trial. Journal of Parenteral and Enteral Nutrition 2012;36(1 Suppl):95S-105S.
Nyankovskyy 2008 {unpublished data only}
  • Nyankovskyy SL, Ivakhnenko OS, Dobryanskyy DD, Shadrin OG, Berezhnyy VV, Aryaev ML. Multicentre open randomized study of the effect of prebiotic infant formula on some immune markers in term infants. World Congress of Pediatric Gastroenterology, Hepatology and Nutrition. 2008:P0996.
Scalabrin 2012 {unpublished data only}
  • Scalabrin D, Harris C, Marunycz J, Mitmesser S. Stooling patterns of infants fed an infant formula supplemented with a novel prebiotic blend. Allergy 2010;65 Suppl 92:313-4.
  • Scalabrin D, Mitmesser S, Harris C, Marunycz J, Walker D, Tolkko S, Salminen S. A more diverse bifidobacterium profile is observed in infants when fed a formula supplemented with polydextrose (PDX) and galactooligosaccharides (GOS). Allergy 2010;65 Suppl 92:751.
  • Scalabrin DM, Harris C, Marunycz J, Mitmesser SH. Positive impact of a novel prebiotic blend on infant stooling patterns and growth. Pediatric Academic Societies Annual Meeting. 2010; Vol. EPAS2010373.
  • Scalabrin DM, Mitmesser SH, Welling GW, Harris CL, Marunycz JD, Walker DC, et al. New prebiotic blend of polydextrose and galacto-oligosaccharides has a bifidogenic effect in young infants. Journal of Pediatric Gastroenterology and Nutrition 2012;54(3):343-52.
  • Walker DC, Scalabrin DMF, Mitmesser SH, Harris C, Marunycz JD, Tölkkö S, et al. A bifidogenic effect is observed in young infants fed infant formula supplemented with galactooligosaccharide (GOS) and polydextrose (PDX). FASEB Journal. 2010; Vol. Meeting Abstracts:24.
Vanderhoff 2010 {published data only}
  • Vanderhoof JA, Mitmesser SH, Harris C, Stolz S, Berseth C. Growth and tolerance of infants fed formula supplemented with polydextrose (PDX) and/or Galacto Oligo Saccharides (GOS). Journal of Pediatric Gastroenterology and Nutrition 2010;50 Suppl 2:E200-1.
Veereman-Wauters 2008 {unpublished data only}
  • Veereman-Wauters G, Assam P, Van de Broek H, Plaskie K, Wesling F, McCartney A. Safety, tolerance and bifidogenic effect of prebiotic supplements in infant formula. World Congress of Pediatric Gastroenterology, Hepatology and Nutrition. 2008:P0797.
  • Veereman-Wauters G, Staelens S, Van de Broek H, Plaskie K, Wesling F, Roger LC, et al. Physiological and bifidogenic effects of prebiotic supplements in infant formulae. Journal of Pediatric Gastroenterology and Nutrition 2011;52(6):763-71.
Zoeren-Grobben 2009 {published data only}
  • van Zoeren-Grobben D. The role of pre- and probiotics in infections in term infants (De role van pre- en probiotica in infecties in a terme geboren kinderen). controlled-trials.com: ISRCTN65140085 2009.

References to ongoing studies

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to studies awaiting assessment
  21. References to ongoing studies
  22. Additional references
  23. References to other published versions of this review
Agostoni 2006 {unpublished data only}
  • Agostoni C. Randomized, Double Blind Study to Evaluate the Safety and Efficacy of an Infant Formula Supplemented With Galacto-oligosaccharides (GOS) in Healthy, Full Term Infants. ClinicalTrials.gov identifier: NCT00486148 2006.
Hammerman 2007 {unpublished data only}
  • Hammerman C, Bin-nun A. Prebiotics vs. Placebo in the Prevention of Necrotizing Enterocolitis in Premature Neonates. ClinicalTrials.gov identifier: NCT00437567 2007.
Materna Laboratories 2010 {published data only}
  • Materna Laboratories. Evaluation of the Effect of Milk Based Infant Formula Supplemented Either With Probiotic Microorganisms and/or With Prebiotic on the Intestinal Microflora During the First 4 Months of Life of Healthy, Full Term Infants and it's Long Term Effect on Morbidity up to the Age of 9 Months. ClinicalTrials.gov Identifier: NCT00836771 2010.
Stronati 2010 {unpublished data only}
  • Stronati M. Double-blind Randomized Controlled Study for the Evaluation of Nutritional Outcomes of a Cow's Milk Based Infant Formula Containing Galacto-oligosaccharides, Beta-palmitate and Acidified Milk. ClinicalTrials.gov identifier: NCT01197365 2010.
Underwood 2009a {unpublished data only}
  • Underwood M. Phase 1A Study of Impact of Oligosaccharides and Bifidobacteria on the Intestinal Microflora of Premature Infants. ClinicalTrials.gov identifier: NCT00810160 2009.

Additional references

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to studies awaiting assessment
  21. References to ongoing studies
  22. Additional references
  23. References to other published versions of this review
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