Prebiotics in infants for prevention of allergic disease and food hypersensitivity, a meta analysis

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Prebiotics in infants for prevention of allergic disease and food

hypersensitivity

A Meta Analysis

Prof Ariyanto Harsono MD PhD SpA(K)

Prof Ariyanto Harsono MD PhD SpA(K) 2

Background

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


Objectives

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


Selection criteria

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


Interventions

Fructo-oligosaccharides: Brunser 2006 allocated infants to a cow’s milk formula intended for term infants that is supplemented with fructo-oligosaccharide 2 g/L versus the same formula without prebiotic. Kapiki 2007 allocated infants to a standard preterm formula supplemented with fructo-oligosaccharides 0.4 g/dl versus the same formula with maltodextrins 0.4 g/dl for 14 days.

Galacto-oligosaccharides: Ben 2004 allocated infants to a term infant cow’s milk formula supplemented with galacto-oligosaccharide 0.24 g/L versus the same formula without prebiotic.


Prebiotic mixtures: Boehm 2002 allocated infants to a preterm infant formula with added fructo-oligosaccharide and galacto oligosaccharide (ratio 1:9) versus the same preterm infant formula with added malto dextrins. Fanaro 2005 allocated infants to a term infant cow’s milk infant formula with added acidic oligosaccharides 0.2 g/dL and maltodextrin 0.6 g/dL; or same formula with added acidic oligosaccharide 0.2 g/dL and mixture of fructo-oligosaccharide and galacto-oligosaccharide 0.6 g/dL; or the same formula with added maltodextrin 0.8 g/dL. Moro 2006 allocated infants to an extensively hydrolyzed whey protein formula intended for term infants with added mixture of fructo-oligosaccharide and galacto-oligosaccharide 0.8 g/dL versus the same formula with added maltodextrin 0.8 g/dL.


Ziegler 2007 allocated infants to a control formula supplemented with 4 g/L of a prebiotic blend containing polydextrose and galacto-oligosaccharides, 50:50 ratio; a control formula supplemented with 8 g/L of a prebiotic blend containing polydextrose, galacto-oligosaccharides and lactulose (LOS), 50:33:17 ratio; or to a control formula (cow’s milk formula).


Outcomes

Allergic disease and / or food hypersensitivity: Moro 2006 reported eczema at six months of age based on blinded physician examination and standardized criteria. Sensitization (skin prick testing or serum specific IgE) was not reported. Ziegler 2007 reported eczema up to four months of age, but did not prespecify this outcome in methods. Eczema was recorded in the participant’s diary and by the physician who diagnosed it.


Growth: Three studies reported measures of growth in term infants (Fanaro 2005;Moro 2006; Ziegler 2007), with a further two studies reporting measures of growth in preterm infants (Boehm 2002; Kapiki 2007).

Other outcomes: Three studies (Ben 2004; Boehm 2002; Fanaro 2005) reported clinical symptoms and signs including crying, regurgitation, and vomiting. Ziegler 2007 reported feed intolerance resulting in study discontinuation.


Results

Main resultsSeven studies were eligible for inclusion. Only two studies

reported an allergic disease outcome for 432 infants. Study quality was reasonable, although Moro 2006 reported 20% post-randomization losses. Moro 2006 enrolled hydrolyzed formula fed infants at high risk of allergy and reported a significant reduction in eczema in infants up to six months of age (RR 0.42, 95% CI 0.21, 0.84). Ziegler 2007 enrolled formula fed infants who were not selected on the basis of risk for allergy and reported no significant difference in eczema up to four months of age (RR 1.62, 95% CI 0.62, 4.26).


Meta-analysis of the two studies found no significant difference in eczema, but significant heterogeneity was detected. Differences were potentially attributable to differences in infant risk, prebiotic formulation or measurement of eczema. Analysis of five studies reporting measures of infant growth found no consistent adverse effects.


PREBIOTIC VERSUS NO PREBIOTIC (COMPARISON 01):

Allergic disease and / or food hypersensitivity: No study reported all allergic disease or food hypersensitivity.


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



Growth: In term infants, no individual study reported significant differences in growth, weight, length or head circumference when on a prebiotic supplemented formula compared to control. Meta analysis of three studies (Fanaro 2005; Moro 2006; Ziegler 2007) using term formulas in term infants found a significant increase in weight gain (WMD 0.93 g/day, 95%CI 0.02, 1.84) in infants fed a prebiotic formula. Meta-analysis of two studies (Fanaro 2005; Moro 2006) found no significant difference in length gain (WMD 0.01 cm/week, 95%CI -0.02, 0.04).


In term infants fed an extensively hydrolyzed whey formula, Moro 2006 reported no significant difference in head circumference gain (MD -0.01, 95% CI - 0.02, 0.00). In infants born preterm, meta-analysis of two studies (Boehm 2002; Kapiki 2007) found no significant difference in weight gain (WMD-1.78 g/day, 95%CI -4.05, 0.48) but did show a significant increase in length gain (MD 0.17 cm/week, 95% CI 0.14, 0.19) in infants fed prebiotic supplemented preterm infant formula versus preterm infant formula alone.

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Significant and substantial heterogeneity was found in both of these analyses. Kapiki 2007 reported no significant difference in head growth (MD - 0.04, -0.02, 0.00). Ben 2004 reported that weight gain and length increments were similar among the groups (data not reported). Brunser 2006b reported that no significant differences between the study groups were observed for weight, height, weight for height, weight for age and height for age z-scores (using National Center for Health Statistics) during the study (data not reported);




Other outcomes / adverse effects

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



PREBIOTIC VERSUS NO PREBIOTIC IN FORMULA FEDINFANTS AT HIGH RISK OF ALLERGY OR FOOD HY-

PERSENSITIVITY (COMPARISON 02)

Moro 2006 enrolled infants at high risk of allergy or food hypersensitivity defined on the basis of a parental history of eczema, allergic rhinitis or asthma. Moro 2006 reported a significant reduction in infant eczema (RR 0.42, 95% CI 0.21, 0.84) up to six months age in infants receiving a mixture of fructo- and galacto oligosaccharides. No other allergic disease or food hypersensitivity outcomes were reported.



PREBIOTIC VERSUS NO PREBIOTIC IN FORMULA FEDINFANTS NOT SELECTED FOR RISK OF ALLERGY OR

FOOD HYPERSENSITIVITY (COMPARISON 03):

Ziegler 2007 enrolled formula fed infants not selected on the basis of risk for allergy or food hypersensitivity and reported no significant difference in eczema (RR 1.62, 95% CI 0.62, 4.26) up to four months of age. In this analysis, data for the two prebiotic groups were combined.

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



SPECIFIC PREBIOTIC VERSUS NO PREBIOTIC (COMPARISON 04): Mixture of fructo- and galacto-oligosaccharides versus no pre-

biotic:

Moro 2006 reported a significant reduction in infant eczema (RR 0.42, 95% CI 0.21, 0.84) up to six months age in infants receiving a mixture of fructo- and galacto-oligosaccharides. No other allergy or food hypersensitivity outcomes were reported. Meta-analysis of two studies (Boehm2002;Moro 2006) found no significant difference in weight gain (WMD 0.88 g/day, 95% CI -0.12, 1.88) or growth in length (WMD 0.01 cm/week, 95% CI - 0.01, 0.03) in infants treated with a mixture of fructo- and galacto oligosaccharides. Moro 2006 reported no significant difference in head circumference (MD -0.01 cm/week, 95% CI -0.02, 0.00; p = 0.011).







SPECIFIC PREBIOTIC VERSUS OTHER PREBIOTIC(COMPARISON 05):

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




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




D I S C U S S I O N

This review found insufficient evidence to support or refute the use of prebiotics to prevent allergic disease or food hypersensitivity in infants. In high risk infants, one study reported outcomes for 206 infants and found that the addition of prebiotics to infant formula in infants at high risk of allergy may prevent infant eczema up to six months of age. This study used an extensively hydrolyzed whey formula supplemented with a mixture of fructo- and galacto-oligosaccharides 0.8 g/dL. Infants at high risk of allergy based on having a first degree relative with a history of eczema, allergic rhinitis or asthma were enrolled. This finding should be treated with caution given the small sample size and excess post randomization losses (20%).


In infants not selected for risk of allergy, a second study reported no significant difference in eczema in infants up to four months of age. Meta-analysis of the two studies found no significant difference in eczema, but significant heterogeneity between studies was found. Potential explanations for the heterogeneity include differences in selection of infants (high versus low risk), differences in prebiotic formulations and differences in measurement of infant eczema. Evidence of benefit from use of prebiotics is restricted to one report for the prevention of infant eczema in infants at high risk of allergy. Given the lack of reproducibility of findings in studies incorporated in this review, further trials of prebiotics are needed before they can be recommended for routine use in infants at high risk of allergy.


In term infants, meta-analysis of three studies found a significant increase in weight gain for infants fed a prebiotic supplemented formula, although no individual study reported a significant difference. The difference in weight gain (0.93 g/day) may not be clinically important. Given the methodological concerns regarding these studies, further studies are required to confirm this finding. In addition, one study reported increases in infant irritability and diarrhoea from prebiotic formulas supplemented with polydextrose and / or lactulose, and an increased rate of study discontinuation in infants fed a prebiotic formula containing polydextrose, GOS and lactulose.


Both GOS and polydextrose have been demonstrated to have prebiotic effects on probiotic bacteria in vitro, while only GOS has an effect in vivo. Lactitol did not have prebiotic effects in vitro (Probert 2004). In preterm infants, one study reported a significant reduction in weight gain but a significant increase in growth and length. Meta-analysis of two studies found no significant difference in weight gain, but a significant increase in length gain. There was significant heterogeneity between studies found in the analyses of weight and length gain in preterm infants. Given the methodological limitations of the studies, these results should be treated with caution.


C O N C L U S I O N S

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


Thank You

Prebiotics in infants for prevention of allergic disease and food hypersensitivity, a meta analysis

Education

allocated infants

reported eczema

preterm infant formula

enrolled formula

sensitization of infants

term infants fanaro

preterm infants boehm

term infant cows milk