1. WHEN TO USE PARTIAL WHEY HYDROLYSATES

2. The Reference: Breast milk provides best nutrition and supports the infant’s developing digestive- and immune systems
Main building block for growth and development
Regulates the
immune system
Allergic diseases
Less stress on the digestive system
Functional GI disorders
Breast milk
Programmes the metabolic system

3. Protein in Breast Milk - Characteristics >60% Whey Protein, Proteolytic Enzymes, and Partially Broken Down Proteins
Human milk
Analysis of breast milk samples from healthy women identified over 300 milk peptides originating from major and many minor protein components of human milk
Human milk proteolytic enzymes are active (mammary gland, stomach, small intestine)
The digested peptides represent only a minority of the total protein content
Casein 30%
Whey 70%
Cow´s milk
Casein 77%
Whey 23%
Breast milk contains not only intact proteins, but also hundreds of peptides
Dallas DC et al. J Nutr 2014; Holton TA et al. J Proteome Res 2014; Dallas DC et al. J Mammary Gland Biol Neoplasia 2015, J Nutr Disord Ther 2012; J Nutr 2014

4. Protein Source in Infant Formula
Intact
partially hydrolyzed
extensively hydrolyzed
amino acid based

5. Benefits of Partially Hydrolyzed Whey Protein
Less digestive problems and functional gastrointestinal disorders
Why? Partially hydrolyzed whey proteins are easily digestible1; faster GI transit2
Allergy prevention
Why? Partially hydrolyzed whey proteins provides a very low antigenic load (e.g fold lower than cow`s milk1) compared with intact cow’s milk protein.
During digestion partially hydrolysed whey protein barely produces any curd under acidic conditions.
Partially hydrolyzed formula
Whey-predominant
intact formula
Casein-predominant
intact formula
1 Nestle files 2012, 2Billeaud et al. EJCN 1990

6. US FDA approval of health claim
Partially Hydrolyzed Whey Formula (pHF-W): EU and FDA: Regulatory approvals and Health Claims
1991
EEC Directive
Hydrolysed protein infant formula approved for use in all healthy non-breastfed infants
Recognised role of such formula in reducing the risk of developing later allergy
2016
New EU Regulation
Four sources of protein approved for infant and follow-on formulas:
Cow’s milk protein
Goat’s milk protein
Soy protein isolates
Low Protein hydrolysates
2011
US FDA approval of health claim
Scientific evidence deemed appropriate for a qualified health claim regarding the relationship between the consumption of 100% whey protein partially hydrolysed infant formula and a reduced risk of atopic dermatitis

7. LESS DIGESTIVE PROBLEMS in an unselected infant population following an allergen-reduced dietary intervention programme: the ZUFF-STUDY-PROGRAM
Evaluate the effects of an allergen-reduced dietary intervention on infants’ general health status (e.g. gastrointestinal symptoms) and growth
Study objective
Prospective, large-scale, controlled trial in two unselected population-based cohorts
1,130 healthy, term newborns, who were born either in Zug (intervention cohort) or Frauenfeld (control cohort), Switzerland
Methods
After enrolment up to the age of 4 months, feeding of:
Breast milk and/or high quality optimised partially hydrolysed whey protein formula (pHF-W), no complementary feeding; n=564
Breast milk and/or intact cow’s milk protein formula (complementary foods as desired) as control group; n=566
Feeding groups
Physicians’ reports on health status: gastrointestinal problems (diarrhea, constipation, colic and vomiting), skin and respiratory problems, at 6 weeks, 3 and 6 months of age
Growth parameters (measured by a physician) and compliance with the allergen-reduced dietary intervention
Outcomes
Exl BM et al. Eur J Nutr 2000;39:145–56; 2. Exl BM et al. JPGN 2000;31 (suppl 2):S27

8. LESS DIGESTIVE PROBLEMS : Lower incidence of gastrointestinal symptoms
Unselected population of newborn infants
Breastfeeding and/or whey-based partially hydrolysed formula (pHF-W) (n=564)
Breastfeeding and/or intact cow’s milk protein formula (n=566)
p<0.05
Vomiting
Diarrhea
Constipation
Infantile colic *
Cumulative incidence of gastrointestinal symptoms* at 6 months was significantly lower in infants fed partially hydrolysed whey formula
Exl BM et al. Eur J Nutr 2000; 2. Exl BM et al. JPGN 2000

9. Definition: Functional GastroIntestinal Disorders (FGIDs)
After appropriate medical evaluation the symptoms cannot be attributed to another medical condition than a functional disorder
Can coexist with other medical conditions that themselves result in GI symptoms (eg. inflammatory bowel disease).
FGDIs
Benninga MA et al. Gastroenterology 2016;150:1443–1455 ; Hyams JS et al. Gastroenterology 2016;150:1456–1468 9 9 9

10. Functional GastroIntestinal Disorders (FGIDs) - prevalence
FGID Category
Worldwide prevalence
Infant regurgitation
Infant colic
Functional constipation
Functional diarrhoea
Cyclic vomiting syndrome
Infant dyschezia
Infant rumination syndrome
30 to 67 %
5 to 20 %
3 to 27 %
6 to 7 %
3.4 %
2.4 %
1.9 %
Benninga MA et al. Gastroenterology 2016;150:1443–1455; Vandenplas Y et al. JGPN 2015;61(5):

11. Less FGIDs: Partially Hydrolyzed Whey Formula with Starch Reduces Regurgitation Periods in Young Infants
N° ep regurgitation treated control p
Entry
Day
Day
Compared to regular infant formula the use of pHW Formula with starch resulted in a significant reduction of regurgitation episodes:
Between days of treatment (95% CI ; p=0.012)
Between 7-14 days of treatment (95% CI ; p=0.005)
Savino F. Acta Paediatr Suppl. 2005:94; Vandenplas Y. et al Acta Paediatr. 2014;103: Salvatore S, et al Nutrition. 2018;49:51-56

12. Mean Regurgitation Episodes per Day (SD)
LESS FGIDs: Partially Hydrolyzed Whey Formula Supplemented with Starch and L. reuteri DSM Increases Gastric Emptying Rate and Reduces Regurgitation Episodes (RCT) 9
7.4
7.5
5.9
6.4
3.8
6.2
2.9
5.4
2.6
5.3
Test
Control 8 7 * 6
Mean Regurgitation Episodes per Day (SD) 5 ** 4 ** ** 3 2 1
Baseline
Week 1
Week 2
Week 3
Week 4
Test (n=37)
Control (n=35)
Week 0
Week 4
p-Value
Fasting antral area, cm2
2.7 (2.0, 3.1)
3.5 (2.0, 4.6)
2.7 (1.4, 3.1)
4.6 (2.4, 6.0)
0.01 a
GErate percent change from week 0 to week 4, %
12.3 (–3.9, 22.0)
9.1 (–27.0, 25.5)
<0.01 b
GErate: gastric emptying rate. ap-value for between-groups difference at the end of the study. bp-value for between-group difference in GErate percentage change.
Indrio F. Nutrients. 2017;9:1-9.

13. Partially Hydrolyzed Whey Formula (pHF-W) and Allergy Prevention

14. Protein Source in Infant Formula
Intact
partially hydrolyzed
extensively hydrolyzed
amino acid based

15. Influence of Food Protein Size
Intact Protein
Partially Hydrolyzed Proteins
Extensively Hydrolyzed Proteins 90 80 70 60
Allergenic Range 50
Percent 40 30 20 10
700
450
300
200
160
65,000
50,000
24,000
18,000
10,000
4,000
2,000
1,200
1,000,000
Molecular Weight (Dalton)

16. 50% of infants who develop an allergy have no family history
Family history increases allergy risk. But half of infants who develop an allergy have no family history
Low risk
No family history of allergies
High risk
First-degree relative with allergy (parent or sibling))
Both parents with allergy
Very high risk
Family history
Risk of allergy in infant
15%
33%
77 %%
Proportion of all newborns with this risk (%)
70%
25% 5%
Infants who will develop an allergy (out of 100 born) 11 8 3
50% of infants who develop
an allergy have no family history

17. Received study formula
pHF-W AND ALLERGY PREVENTION: Distribution of 2,252 infants in four feeding groups in the GINI study (RCT, intervention 0-4mo; follow-up until 3 years)
CMF
pHF-W
eHF-W
eHF-C
Breast milk
Initial random
allocation
556
557
559
580 –
Received study formula
328
315
302
304
889
Compliant –
12-month follow up
256
241
238
210
865
3-year follow up
245
229
230
200
543
CMF, intact cow’s milk protein based formula; pHF-W, partially hydrolysed whey-based formula; eHF-W, extensively hydrolysed whey-based formula; eHF-C, extensively hydrolysed casein-based formula.
Adapted from von Berg A et al. 2003,111(3): & von Berg A et al. J Allergy Clin Immunology 2007;119(3):

18. pHF-W AND ALLERGY: Risk reduction of allergic manifestations in the general infant population
Incidence of total allergy and atopic dermatitis during the first year of life
7.7% reduction
p<0.05
Breast milk and whey-based partially hydrolysed formula (pHF-W)
Breast milk and intact cow’s milk protein based formula (CMF)
Breast milk
p<0.05
p<0.05
p<0.05
Significantly lower incidence of atopic dermatitis
Similar incidence of atopic dermatitis with pHF-W and breast milk
Adapted from Wen et al. Chin J Perinat Med. 2015;18(12): & Wen et al. ESPGHAN abstract 2016

19. pHF-W AND ALLERGY PREVENTION Cumulative incidence of Atopic Dermatitis 0-3y* * * * * *
von Berg A et al. J Allergy Clin Immunology 2007;119(3):
*p<0.05 for pHF-W and eHF-C vs CMF.
CMF, intact cow’s milk protein based formula; pHF-W, partially hydrolysed whey-based formula; eHF-W, extensively hydrolysed whey-based formula; eHF-C, extensively hydrolysed casein-based formula.

20. pHF-W AND ALLERGY Summary GINI study until 15 years.
pHF-W AND ALLERGY Summary GINI study until 15 years
After 4 months’ intervention with hydrolysates in at-risk children:
Early onset of effect – first 4–6 months
Risk reduction for atopic eczema (cumulative incidence):
eHF-W
pHF-W
eHF-C
To 6 years by
26%
36%
45%
To 10 years by
23%
33%
42%
To 15 years by
29%
55%
No rebound effect
von Berg A et al. J Allergy Clin Immunol 2008;121(6):1442-7; von Berg A et al. J Allergy Clin Immunol 2013; 131(6):1565–73; von Berg A et al. Allergy 2016;71(2):210-9.

21. pHF-W AND ALLERGY: Eczema: incidence and prevalence
Relative risks for cumulative incidence from birth to 15 years  and odds ratios for period prevalence between 11 and 15 years  for the hydrolysed formula compared with cow’s milk formula (intact protein)
Eczema
0.5
1.0
1.5
pHF-W
eHF-W
eHF-C
2.0
e-HF-W
e-HF-C
ITT PP
Cumulative incidence
Prelevance between 11 and 15 years
Relative risk / Odds ratio
von Berg A et al. Allergy 2016;71(2):210-9.

22. All allergic manifestations.
pHF-W AND ALLERGY: All allergic manifestations: incidence and prevalence
Relative risks for cumulative incidence from birth to 15 years  and odds ratios for period prevalence between 11 and 15 years  for the hydrolysed formula compared with cow’s milk formula (intact protein)
All allergic manifestations
ITT PP
1.5
1.0
Relative risk / Odds ratio
0.5
pHF-W
eHF-W
eHF-C
pHF-W
e-HF-W
e-HF-C
Cumulative incidence
Prelevance between 11 and 15 years
von Berg A et al. Allergy 2016;71(2):210-9.

23. Cumulative incidence of atopic dermatitis 0–15 years
pHF-W AND ALLERGY: Protection against later atopic dermatitis in infants at high risk of allergy
GINI study: intact versus hydrolysed formula 0–4 months, 15-year results
Cumulative incidence of atopic dermatitis 0–15 years
42% risk reduction
(OR 0.58; 95% CI: 0.40–0.84)
NNT = 7
Number of infants who need to receive pHF-W to prevent one case of atopic dermatitis up to 15 years † †
von Berg A et al. Allergy 2016;71(2):210-9.

24. pHF-W AND ALLERGY: Risk reduction of later allergic rhinitis and asthma in infants at high risk of allergy
GINI study: intact versus hydrolysed formula 0–4 months, 15-year results
Allergic rhinitis
33%
reduction
Asthma
12%
reduction
OR % CI: 0.52–1.49
(p=ns)
OR % CI: 0.47–0.95
von Berg A et al. Allergy 2016;71(2):210-9.

25. Summary of clinical evidence:
More than 80 clinical trials and observational sudies (e.g. GINI)
Szajewska H, Horvath A. Meta-analysis of the evidence for a partially hydrolysed 100% whey formula for the prevention of allergic diseases. Curr Med Res Opin 2010; 26:423–37.
Risk reduction pHF versus CMF ≈ 42%*
Efficacy of pHF-W = eHF-W = eHF-C
Alexander D, Cabana M. Partially hydrolysed infant formula and reduced risk of atopic dermatitis: a meta analysis. J Pediatr Gastr Nutr 2010;5:1–8.
Risk reduction pHF-W versus CMF ≈ 44–50%
*Intent-to-treat analysis, 0–12 months.
pHF-W, partially hydrolysed whey-based formula; eHF-W, extensively hydrolysed whey-based formula; eHF-C, extensively hydrolysed casein-based formula; CMF, cow's milk protein based formula (intact protein).

26. pHF-W are highly cost-effective in the prevention of atopic dermatitis compared with intact protein based formula, and cost-saving compared with extensively hydrolysed formula
Iskedjian M et al. Economic evaluation of a 100% whey-based, partially hydrolysed formula in the prevention of atopic dermatitis among French children. Curr Med Res Opin 2010;26:2607–26
Su J et al. Cost-effectiveness of partially-hydrolysed formula for prevention of atopic dermatitis in Australia. J Med Econ 2012;15:1064–77
Iskedjian M, et al. Economic evaluation of a 100% whey-based partially hydrolysed infant formula in the prevention of atopic dermatitis among Swiss children. J Med Econ 2012;15:378–93
Iskedjian M et al. Economic evaluation of a 100% whey-based partially hydrolysed infant formula in the prevention of atopic dermatitis among Danish children. J Med Econ 2012;15:394–408

27. Partially Hydrolyzed Formula in Non-exclusively Breastfed Infants: A Systematic Review and Expert Consensus
pHF-W (whey-based partially hydrolyzed formula) is safe; growth during infancy and until 10y (weight, height, BMI) is similar to breastfed infants
pHF-W : allergy preventive effect (until 10y) has been demonstrated in a population at risk for the development of allergic disease
Limited data now available: compared with cow’s milk based formula, the use of pHF is associated with improved gastric emptying, decreased colic incidence, and other common functional gastrointestinal symptoms
Health economic data: cost savings from pHF-W use have been shown from the reduction in atopic dermatitis in at-risk populations
Vandenplas Y et al; Nutrition 57 (2019) ; doi: /j.nut