prebiotic, infant, allergy prevention, meta analysis, exzema, growth

1. Prebiotics in infants for prevention of
allergic disease and food
hypersensitivity
A Meta Analysis
1
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.
Prof Ariyanto Harsono MD PhD SpA(K) 2

3. Objectives
To determine the effect of prebiotics given to
infants for the prevention of allergic disease or
food hypersensitivity
Prof Ariyanto Harsono MD PhD SpA(K) 3

4. 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.
Prof Ariyanto Harsono MD PhD SpA(K) 4

5. 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.
Prof Ariyanto Harsono MD PhD SpA(K) 5

6.  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.
Prof Ariyanto Harsono MD PhD SpA(K) 6

7. 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).
Prof Ariyanto Harsono MD PhD SpA(K) 7

8. 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.
Prof Ariyanto Harsono MD PhD SpA(K) 8

9. 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.
Prof Ariyanto Harsono MD PhD SpA(K) 9

10. Results
Main results
Seven studies were eligible for inclusion. Only two studies
reported an allergic disease outcome for 432 infants.
Study quality was reasonable, although Moro 2006
reported 20% post-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).
Prof Ariyanto Harsono MD PhD SpA(K) 10

11. 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.
Prof Ariyanto Harsono MD PhD SpA(K) 11

12. PREBIOTIC VERSUS NO PREBIOTIC (COMPARISON 01):
Allergic disease and / or food hypersensitivity:
No study reported all allergic disease or food
hypersensitivity.
Prof Ariyanto Harsono MD PhD SpA(K) 12

13. 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.
Prof Ariyanto Harsono MD PhD SpA(K) 13

14. Prof Ariyanto Harsono MD PhD SpA(K) 14

15. 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).
Prof Ariyanto Harsono MD PhD SpA(K) 15

16. 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.
Prof Ariyanto Harsono MD PhD SpA(K) 16

17. 17

18. 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);
Prof Ariyanto Harsono MD PhD SpA(K) 18

19. Prof Ariyanto Harsono MD PhD SpA(K) 19

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21. 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.
Prof Ariyanto Harsono MD PhD SpA(K) 21

22. Prof Ariyanto Harsono MD PhD SpA(K) 22

23. PREBIOTIC VERSUS NO PREBIOTIC IN FORMULA FED
INFANTS 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.
Prof Ariyanto Harsono MD PhD SpA(K) 23

24. Prof Ariyanto Harsono MD PhD SpA(K) 24

25. PREBIOTIC VERSUS NO PREBIOTIC IN FORMULA FED
INFANTS NOT SELECTED FOR RISK OF ALLERGY OR
FOOD HYPERSENSITIVITY (COMPARISON 03):
Ziegler 2007 enrolled formula fed infants not
selected on the basis of risk for allergy or food
hypersensitivity and reported no significant
difference in eczema (RR 1.62, 95% CI 0.62,
4.26) up to four months of age. In this
analysis, data for the two prebiotic groups
were combined.
SENSITIVITY ANALYSIS: no study met criteria for
studies of adequate methodology.
Prof Ariyanto Harsono MD PhD SpA(K) 25

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27. 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).
Prof Ariyanto Harsono MD PhD SpA(K) 27

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33. 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.
Prof Ariyanto Harsono MD PhD SpA(K) 33

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36. 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).
Prof Ariyanto Harsono MD PhD SpA(K) 36

37. Prof Ariyanto Harsono MD PhD SpA(K) 37

38. Prof Ariyanto Harsono MD PhD SpA(K) 38

39. 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%).
Prof Ariyanto Harsono MD PhD SpA(K) 39

40. 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.
Prof Ariyanto Harsono MD PhD SpA(K) 40

41. 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.
Prof Ariyanto Harsono MD PhD SpA(K) 41

42. 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.
Prof Ariyanto Harsono MD PhD SpA(K) 42

43. 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.
Prof Ariyanto Harsono MD PhD SpA(K) 43

44. Thank You
Prof Ariyanto Harsono MD PhD SpA(K) 44