hydrolyzed milk formula, breast feedding, cow's milk formula feeding, meta analysis, allergy prevention

1. Hydrolyzed Milk Formula for Prevention of Allergy:
an updated meta analysis
Prof Ariyanto Harsono MD PhD SpA(K)

2. Background
Allergies and food reactions are common and
may be associated with foods including
adapted cow’s milk formula. Formulas
containing hydrolyzed proteins have been
used to treat infants with allergy or food
intolerance. However, it is unclear whether
hydrolyzed formula can be advocated for
prevention of allergy and food intolerance in
infants without evidence of allergy or food
intolerance.
2Prof Ariyanto Harsono MD PhD SpA(K)

3. Objectives
To determine the effect of feeding hydrolyzed
formulas on allergy and food intolerance in
infants and children compared to adapted
cow’s milk or human breast milk.
Prof Ariyanto Harsono MD PhD SpA(K) 3

4. Selection criteria
Randomised and quasi-randomised trials that
compare the use of a hydrolysed infant
formula to human milk or cow’s milk formula.
Trials with >80% follow up of participants were
eligible for inclusion.
Prof Ariyanto Harsono MD PhD SpA(K) 4

5. Data collection and analysis
Eligibility of studies for inclusion,
methodological quality and data extraction
were assessed independently by each review
author.
Primary outcomes included clinical allergy,
specific allergies and food intolerance. Meta-
analysis was conducted using a fixed effects
model.
Prof Ariyanto Harsono MD PhD SpA(K) 5

6. Results
Two trials compared early, short term hydrolyzed
formula to human milk feeding. No significant
difference in infant allergy or childhood cow’s
milk allergy (CMA) were reported. No eligible trial
compared prolonged hydrolyzed formula to
human milk feeding. Two trials compared early,
short term hydrolyzed formula to cow’s milk
formula feeding. No significant benefits were
reported. One large quasi random study reported
a reduction in infant CMA of borderline
significance in low risk infants (RR 0.62, 95% CI
0.38, 1.00).
Prof Ariyanto Harsono MD PhD SpA(K) 6

7. Ten eligible studies compared prolonged feeding with
hydrolyzed formula versus cow’s milk formula in high
risk infants. Meta-analysis found a significant reduction
in infant allergy (seven studies, 2514 infants; typical RR
0.79, 95% CI 0.66, 0.94), but not in the incidence of
childhood allergy (two studies, 950 infants; typical RR
0.85, 95% CI 0.69, 1.05). There was no significant
difference in infant eczema (eight studies, 2558 infants,
typical RR 0.84, 95% CI 0.68, 1.04), childhood eczema
incidence (two studies, 950 infants, typical RR 0.83,
95% CI 0.63, 1.10), childhood eczema prevalence (one
study, 872 infants; RR 0.66, 95% CI 0.43, 1.02), or infant
or childhood asthma, rhinitis and food allergy.
Prof Ariyanto Harsono MD PhD SpA(K) 7

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

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

10. One study reported a significant reduction in infants with CMA
with confirmed atopy (RR 0.36, 95% CI 0.15, 0.89).
Subgroup analysis of trials blinded to formula found no
significant difference in infant allergy (four studies, 2156
infants; typical RR 0.87, 95% CI 0.69, 1.08) or childhood
allergy incidence (one study, 872 infants; RR 0.91, 95% CI
0.73, 1.14). No eligible trial examined the effect of
prolonged hydrolysed formula feeding on allergy beyond
early childhood. There is evidence that preterm or low
birthweight infants fed a hydrolysed preterm formula have
significantly reduced weight gain, but not in other growth
parameters (head circumference or length). Studies in term
infants report no adverse effects on growth.
Prof Ariyanto Harsono MD PhD SpA(K) 10

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

12. Subgroup analysis of trials of partially hydrolyzed versus cow’s milk
formula found a significant reduction in infant allergy (six studies,
1391 infants; typical RR 0.79, 95% CI 0.65, 0.97) but not childhood
allergy, or infant or childhood asthma, eczema or rhinitis.
Methodological concerns were the same as for the overall analysis.
Analysis of trials of extensively hydrolyzed formula versus cow’s
milk formula found no significant differences in allergy or food
intolerance. Infants fed extensively hydrolyzed formula compared
with partially hydrolyzed formula had a significant reduction in food
allergy (two studies, 341 infants; typical RR 0.43, 95% CI 0.19, 0.99),
but there was no significant difference in all allergy or any other
specific allergy incidence.
Prof Ariyanto Harsono MD PhD SpA(K) 12

13. Comparing extensively hydrolyzed casein containing
formula with cow’s milk formula, one study (431
infants) reported a significant reduction in childhood
allergy incidence (RR 0.72, 95% CI 0.53, 0.97). Meta-
analysis found a significant reduction in infant
eczema (three studies, 1237 infants; typical RR 0.71,
95% CI 0.51, 0.97). One study reported a significant
reduction in childhood eczema incidence (RR 0.66,
95% CI 0.44, 0.98) and prevalence (RR 0.50, 95% CI
0.27, 0.92).
Prof Ariyanto Harsono MD PhD SpA(K) 13

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

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

16. Discussion
Partially Hydrolyzed Formula: How it should be.
US Nutrition guidelines
*Should contain a small amount of cow’s protein
* The purpose is to induce immune tolerance,
not the elimination of SS or prevent new
sensitization
* Must contain little bit of casein and whey that
going on to induce tolerance to both.
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Prof DR Dr Ariyanto Harsono SpA(K)

17. Induction of Oral Tolerance
T-cells regulation:
1. Intra Epithelial Lymphocytes: extrathymically derived,
have limited TCR repertoir, capable of recognizing
common microbiologic Antigens, and demonstrate
predominantly cytolytic functions
2. Lamina Propria Lymphocytes: thymicaly derived,
contributes to limiting TCR/CD3-mediated signals in the
mucosa
.
Prof DR Dr Ariyanto Harsono SpA(K)

18. IEL
LPL
CD23
Anergy/Tolerance
: Formula HA
: Imunoterapi
: Probiotik
Prof DR Dr Ariyanto Harsono SpA(K)

19. Two trials compared a short period of early
supplemental or sole hydrolyzed formula to
human milk feeding and found no significant
reduction in infant allergy or CMA incidence
up to childhood. No eligible trials were found
that compared prolonged feeding with a
hydrolyzed formula to human milk feeds for
the prevention of allergy or food intolerance.
Prof Ariyanto Harsono MD PhD SpA(K) 19

20. Meta-analysis of seven trials reporting 2514
infants found a significant reduction in infant
allergy from use of a hydrolyzed formula
compared to a cow’s milk formula in infants at
high risk of allergy. Hydrolyzed infant formula
would need to be given to 25 infants (95%CI
12.5, 100) to prevent one infant developing
allergy.
Prof Ariyanto Harsono MD PhD SpA(K) 20

21. Additional subgroup analyses were performed to
determine if there were differences in effects
between different types of hydrolyzed protein
(100% whey or casein containing formulas). Most
trials of partially hydrolyzed formulas used
partially hydrolyzed 100% whey formula with
analyses finding a significant reduction in infant
allergy (six studies, 1391 infants), but no
significant difference in childhood allergy (two
studies, 510 infants), infant or childhood asthma,
eczema or rhinitis.
Prof Ariyanto Harsono MD PhD SpA(K) 21

22. C O N C L U S I O N S
There is no evidence to support feeding with a hydrolyzed formula
compared to exclusive breast feeding for the prevention of allergy
or food intolerance. Until high quality trials are performed that
compare prolonged hydrolyzed formula feeding to breast or
expressed human milk feeding, hydrolyzed formula should not be
routinely offered to infants for the prevention of allergy or food
intolerance in preference to breast milk. There is no evidence of
benefit from the use of a hydrolyzed formula in preference to
human milk for early, short term feeding in low risk infants. In
infants at high risk of allergy who cannot be exclusively breast fed,
there is limited evidence that prolonged supplementation with
hydrolyzed formula as opposed to cow’s milk formula reduces the
risk of allergy. However, there was no significant difference in rates
of asthma, eczema or rhinitis.
Prof Ariyanto Harsono MD PhD SpA(K) 22

23. Effects on allergy did not persist in subgroup analysis of
trials of adequate methodology or where allergy was
proven with testing. There is limited evidence that
use of a partially hydrolyzed formula may prevent
CMA, and that use of an extensively hydrolyzed
formula is better than a partially hydrolyzed formula
at preventing food allergy, although no differences
were found for all allergy, asthma, eczema or rhinitis.
There is limited evidence that use of an extensively
hydrolyzed casein formula prevents allergy,
predominately eczema.
Prof Ariyanto Harsono MD PhD SpA(K) 23

24. Thank you
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