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World Nutrition Journal |eISSN 2580-7013
ARTICLE REVIEW
World.Nutr.Journal | 53
Received 10 October 2020
Accepted 30 October 2020
Link to DOI:
10.25220/WNJ.V05.i1.0008
Journal Website:
www.worldnutrijournal.org
Partially hydrolized whey protein: A review of current evidence,
implementation, and further directions
Badriul Hegar1, Zakiudin Munasir1, Ahmad Suryawan2, I Gusti Lanang Sidhiarta3, Ketut Dewi
Kumara Wati3, Erfi Prafiantini4, Irene5, Yvan Vandenplas6
1.
Department of Child Health, Faculty of Medicine, University of Indonesia, Dr. Cipto
Mangunkusumo Hospital, Jakarta, Indonesia
2.
Department of Child Health, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
3.
Department of Child Health, Faculty of Medicine, Universitas Udayana/Sanglah General
Hospital, Denpasar, Bali, Indonesia
4.
Department of Nutrition, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia
5.
Nestle Nutrition Institute, Jakarta, Indonesia
6.
KidZ Health Castle, UZ Brussel, Brussels, Belgium
Abstract
Background: Human milk is known to be the best nutrition for infants as it provides many health benefits. For
non-breastfed infants, cow's milk based infant formula is the most optimal option to provide the needed
nutrition. However, approximately 2-5% of all formula-fed infants experience cow’s milk allergy during their
first year of life. Partially hydrolyzed whey formula (pHF-W) have been widely recommended to prevent the
development of allergic disease in infants. However, according to epidemiological data, approximately half of
the infants developing allergy are not part of the at-risk group.
Objectives and Methods: This article aims to review the effects of pHF-W in preventing allergy, especially
atopic disease, in all non-breastfed infants, as well as the safety aspect of pHF-W if used as routine formula.
The role of pHF-W in the management of functional gastro-intestinal (GI) disorders is also reviewed.
Results: Several clinical studies showed that pHF-W decrease the number of infants with eczema. The
strongest evidence is provided by the 15-year follow up of the German Infant Nutritional Intervention study
which showed reduction in the cumulative incidence of eczema and allergic rhinitis in pHF-W (OR 0.75, 95% CI
0.59-0.96 for eczema; OR 0.67, 95% CI 0.47-0.95 for allergic rhinitis) and casein extensively hydrolysed formula
group (OR 0.60, 95% CI 0.46-0.77 for eczema; OR 0.59, 95% CI 0.41-0.84 for allergic rhinitis), compared to CMF
as a control, after 15 years of follow-up. pHF-W was also found to be beneficial in the management of
functional GI disorders such as regurgitation, constipation and colic.
Conclusions: The use of pHF-W in allergic infants has been recommended in various guidelines across the
countries, as a primary prevention of allergic disease. One pHF-W has been approved by the US FDA and the
European Commission's European Food Safety Authority (EFSA) for its safety and suitability as a routine infant
formula for all healthy infants. According to the data obtained in the management of functional GI disorders,
pHF-W is better tolerated than formula with intact protein. Further studies assessing the effect of routine use
of pHF-W in a larger population of non-breastfed infants should also be conducted, in order to observe any
potential harm and to determine the benefit and cost-effectiveness ratio.
Keywords allergy, breast feeding, formula, functional gastrointestinal disorder, infant, partial hydrolysate,
whey
Introduction
Human breast milk is known to be the best nutrition
for infants. Breast milk is found to provide
protection for the children against infection and
malocclusion, as well as improve the intelligence.
Growing evidence also suggests that breastfeeding
Corresponding author:
Yvan Vandenplas
KidZ Health Castle, UZ Brussel, Vrije Universiteit Brussel,
Laarbeeklaan, 101, 1090, Brussels, Belgium
Email: yvan.vandenplas@uzbrussel.be
World.Nutr.Journal | 54
might protect against overweight and diabetes later
in life.1
Nevertheless, due to various circumstances, a
large proportion of infants cannot receive human
milk.1,2 Globally, only 38% of the infants are found
to be exclusively breastfed.2 For nonbreastfed
infants, infant formula is the most optimal option to
provide the needed nutrition. Infant formula is
usually prepared from industrially modified cow’s
milk and processed to adjust the nutritional content
according to the needs of infants. However, as cow’s
milk proteins constitute the most common food
allergens in infants, cow’s milk formula is one of the
most frequent causes of food allergy in infants.3,4
Approximately 2-5% of all formula-fed infants
experience cow’s milk allergy during their first year
of life.5,6 Cow’s milk allergy (CMA) is often
associated with manifestations in various organ
systems, such as gastrointestinal, respiratory tract,
and skin. CMA may cause failure to thrive and even
sometimes cause life-threatening anaphylactic
reactions.5,7 In order to reduce the allergenic
potential, cow’s milk protein in the infant formulas
can be modified by hydrolyzation processes to
reduce the size of the peptides, and therefore could
induce tolerance without sensitization.3,4
Hydrolyzed formulas (HF), according to clinical
studies, may give beneficial effects in reducing the
risk of several allergic diseases, especially infants
born in families with atopic disease (high-risk
infants). Several reports have recommended the use
of HF for the at-risk infants. 8-10 Of all HFs available,
the partially hydrolyzed whey formula (pHF-W)
have been widely recommended to prevent the
development of allergies in infants.13-16 However,
according to epidemiological data, approximately
half of the infants developing allergy are not part of
the at-risk group. This is because the number of
infants in the non-at-risk group is significantly larger
than that in the at-risk group.11 The infants in non-
at-risk group have approximately 15% risk of
developing allergies.12
Therefore, this article aims to evaluate and
review the effects of pHF-W in preventing allergies,
especially atopic diseases, in all non-breastfed
infants, both the high-risk and non-at-risk infants, as
well as the safety aspect of pHF-W to be used as a
routine formula.
Partially hydrolyzed whey formula (pHF-W)
Milk proteins consist of two fractions: casein and
whey. Casein is the coagulum portion of milk, which
becomes clots or curds inside the stomach. It
contains the larger and more complex protein
molecules, which are harder to digest. Casein
protein also contains more allergenic proteins,
which are responsible for the majority of milk
allergies. On the other hand, whey is the liquid
portion of milk, which makes it easier to digest. It
also contains less allergenic proteins. From this
standpoint, the casein protein is considered to be
more likely to trigger allergies or general indigestion
than the whey protein.2,17
The composition of casein and whey in cow’s
milk is different from that in human breast milk.
Cow’s milk protein is 77% casein and 23% whey,
meanwhile breast milk protein is approximately
30% casein and 70% whey, even though the
casein/whey ratio in breast milk may fluctuate
between 70/30 and 80/20 in early lactation and
decrease to 50/50 in late lactation.2 Other than that,
the whey and casein proteins in cow’s milk and
breast milk might also differ in fraction number,
amino acid composition, as well as the peptide
mappings. Therefore, raw cow’s milk must be
processed and modified to resemble the human
breast milk composition before it is considered safe
for infant consumption.2
Hydrolyzed formulas (HFs) are typically derived
from cow’s milk proteins, either whey or casein,
which have undergone several procedures to
breakdown these natural proteins into lower
molecular-weight peptides. These protein
modification procedures may include heating, ultra-
filtration, and enzymatic cleavage. Depending on the
degree of hydrolysis and modification, the
hydrolyzed cow’s milk formulas can be
differentiated into partially hydrolyzed formula
(pHF), of which the molecular weight is 3-10 kDA,
and extensively hydrolyzed formulas (eHF), of
which the molecular weight is <3 kDa. Compared to
the nonhydrolyzed (intact) formula with the
molecular weight of 14-68 kDA, hydrolyzed
formula have lower molecular weight peptides,
which are thought to induce oral tolerance without
causing sensitization. Thus, hydrolyzed formula is
thought to reduce the risk of allergic disease
World.Nutr.Journal | 55
compared to the intact formula.3,4
The allergy-preventing property of hydrolyzed
formula, however, seems to not only depend on the
degree of hydrolisation but also on the method of
hydrolisation, as well as other factors. The
qualitative changes of the peptides due to the
hydrolysis process may also affect the potential
benefit of the formula. There are at least three factors
affecting the allergy-preventing effect of a
hydrolyzed formula, which are the protein source
(whey and casein), method of hydrolysis
(temperature, pH, and the type of enzyme used), and
the degree of hydrolysis.
Due to these reasons, it is safe to say that every
HF is different and might even have contradictory
characteristics from one to another, even with the
same degree of hydrolysis. Nutten et al also
confirms this statement. They studied the
physicochemical profile of 76 commercially
available whey- and casein-based eHF (eHF-W and
eHF-C) products and found significant variability in
the molecular weight profile of the peptides, amino
acid components, as well as the allergenicity of the
products, which would eventually affect the
effectiveness of each product in preventing
allergies.18 Researches studying the effect of HFs
should, therefore, evaluate every HFs individually.
Pooling together various hydrolysates (HFs) would
be inappropriate, as it may cause bias and the results
could not represent any of the individual HFs.3,4
Partially hydrolyzed whey formula (pHF-W) is
one of the partially hydrolyzed formulas composed
of 100% whey protein. pHF-W has been
demonstrated to result in positive effects on
preventing the development of allergies, particularly
atopic dermatitis, in infants.13-16 As yet, only one
routine infant pHF-W has been granted a qualified
health claim by the U.S. Food and Drug
Administration for risk reduction of atopic
dermatitis.4,19 The following sections discuss the
current evidences found regarding the effect of pHF-
W in preventing atopic disease, as well as the
possibility of pHF-W to be used as a routine
formula.
pHF-W and prevention of atopic disease
Atopic diseases are a group of diseases caused by an
exaggerated IgE immune response to otherwise
harmless allergens.20 Pediatric atopic disease may
include atopic dermatitis (eczema), asthma, allergic
rhinitis, as well as food allergy. International Study
of Asthma and Allergies in Childhood (ISAAC)
reported a significant increase in the worldwide
prevalence of pediatric atopic diseases in both
developed and developing countries. Approximately
8% of children aged less than 3 years are affected by
food allergy, meanwhile the prevalence of children
with eczema is estimated to be as high as 30%.21,22
In general, the development of allergy is influenced
by several factors, which are the genetic
predisposition, allergen exposure (including time,
dose, frequency of exposure, processing and
consumption of food proteins such as hydrolysate,
gastro-intestinal microbiome, LCPUFAs), and other
contributing factors (such as cesarean section at
birth, early exposure to antibiotics, seasonal
variations, pollution, passive smoking,
industrialization, pets at home, infections, lifestyle,
and vitamin D). In order to prevent the development
of allergic disease, current guidelines recommend
several preventive measures, which include no
maternal food restriction during pregnancy and
lactation, exclusive breastfeeding for the first 4-6
months of life of the infants, timing of introduction
of the complementary foods, and also the use of HFs
with demonstrated efficacy when breastfeeding is
not possible.9
The partially hydrolyzed whey formula (pHF-W)
has been observed clinically to decrease the number
of infants with eczema. Several studies have
assessed the effectiveness of initial exposure to
pHF-W to reduce the risk of eczema. Two different
meta-analyzes published in 2010 showed that
healthy infants with a family history of allergies who
are fed with pHF-W have a lower risk of atopic
dermatitis compared to babies who are fed the intact
cow's milk protein formula (CMF). Subanalysis
conducted in the meta-analyses showed that the risk
reduction of eczema was approximately 52 and 55%,
respectively, at the age of 12 months, and
approximately 38 and 36%, respectively, at that age
of >30 months.3,23,24
Baumgartner reported that the number of infants
who developed atopic symptoms if fed a pHF-W
was only 25% of those fed CMF (OR 0.25, 95% CI
0.18-0.36).24 The analysis also showed that the
effect of pHF-W in reducing the allergic
World.Nutr.Journal | 56
manifestations is equivalent to breast milk,
especially for long-term prevention.25 A literature
review of 8 clinical trials also confirmed that pHF-
W supports normal growth in infants, and showed
that the risk of atopic dermatitis in infants who are
not fully breastfed in the general population also
decreases after administration of specific pHF-W,
compared to CMF, in the first 4-6 months of life.26
The strongest evidence is provided by the 15-year
follow up of the German Infant Nutritional
Intervention (GINI) study, which studied the effect
of pHF-W, eHF-W, and eHF-C in 2,252
participants, compared to CMF as the control, in
reducing the cumulative incidence and prevalence of
pediatric allergic diseases. The result showed that
there was reduction in the cumulative incidence of
eczema and allergic rhinitis in pHF-W (OR 0.75,
95% CI 0.59-0.96 for eczema; OR 0.67, 95% CI
0.47-0.95 for allergic rhinitis) and eHF-C groups
(OR 0.60, 95% CI 0.46-0.77 for eczema; OR 0.59,
95% CI 0.41-0.84 for allergic rhinitis), compared to
CMF as a control, after 15 years of follow-up.27
While the above studies showed positive effect of
pHF-W for preventing allergies, several other
studies showed contradictory results with other HFs.
Several issues and weaknesses, however, are found
in the methodology of each study that needs to be
taken into account.13,28-30 The common issue is that
these meta-analysis pool together different types of
pHF from multiple manufacturers, which would
give rise to different characteristics of the resulting
peptides. Hence, the results of these studies might
not be useful, as the collective results could not
represent any of the protein hydrolysate.3,4
Systematic review and meta-analysis by Boyle
found no consistent evidence that both pHF, not only
limited to pHF-W, and eHF can reduce the risk of
allergies or autoimmune outcomes in babies with a
high risk of allergies. This might be due to the
inclusion criteria of this study, which included
multiple interventions and retrospective cohort
studies, excluded 7 pHF interventional studies, as
well as the unusual segmentation of age (0-4 years,
compared to other meta-analyses in which the
segmentations were at 0-1 year).28
A randomized-controlled trial (RCT) by Boyle
analyzed the use of pHF and prebiotic
supplementation, compared to standard formulas, in
preventing eczema in high-risk infants. The results
showed that there was no difference in incident of
eczema between the intervention of pHF+prebiotic
and standard formula in high-risk infants within 12
months of follow-up. This might be due to the
methodology, such as the use of different pHF and
the randomization process which was performed at
the age of <1 month (not at birth), which could lead
to biased results.29
A Cochrane meta-analysis by Osborn also stated
that there is no evidence that pHF provides positive
effect in preventing allergies, compared to exclusive
breastfeeding. However, the analysis of the studies
performed in preterm and term infants were
combined. Other than that, the study also analyzed
different types of pHFs, which could cause the
findings of this meta-analysis to be considered
invalid, as different pHFs might exhibit different
effect on preventing allergies.30
The RCT by Lowe et al13 also revealed that pHF-
W could not reduce the risk of allergic
manifestations, compared to standard formulas.
However, some weaknesses were also found in the
methodology of the study as; the end point was
conducted by telephone interview, only 50% of
infants received formula at 4 months of age, 16.5%
never received the allocated formula, and that the
study was single blind.
pHF-W for all non-breastfed infants: safety
aspects
The use of pHF, including pHF-W, in allergic
infants has been recommended in various guidelines
across the countries, as a primary prevention of
allergic disease, mainly atopic dermatitis, in high-
risk infants.8-10 However, the compliance rates for
these guidelines are relatively low. The Pouessel et
al31 study in 2006 revealed that there are still around
50% of children born with genetic risk not given
hydrolyzed formulas, including pHF-W, as a form
of prevention. The 2008 ASCIA annual meeting also
concluded that in practice, guidelines were not
followed, and in fact only 2.5% of children born
with genetic risk were given a hydrolyzed formula.8
Although the use of pHF-W has been
recommended for at-risk infants,13-16 The fact is that
half of all infants who develop allergies are not part
of the at-risk group, as mentioned above. This is
because the number of infants in the non-risk group
World.Nutr.Journal | 57
is significantly larger than the number of infants in
the risk group.11 Therefore, it is under debate on
whether pHF-W should be considered as a routine
formula for all nonbreastfed infants, regardless of
their risk of allergies.4
One pHF-W has been approved by the US FDA and
the European Commission's European Food Safety
Authority (EFSA) for its safety and suitability as a
routine infant formula for all healthy infants,
regardless of its relationship to its use in preventing
allergies.20,33 In terms of nutritional content, pHF-W
is very similar to CMF, except that the protein
content in several pHF-Ws is slightly higher than in
CMF. This makes pHF-W also meets all nutrient
requirements as required for standard CMF.6 pHF-
W typically contains 67 kcal/100 mL of energy, 11.2
g/100 kcal of carbohydrate, 5.1 g/100 kcal of fat,
with the protein content varied in the range of 1.8-
2.2 g/100 kcal. Meanwhile, CMF contains 67
kcal/100 mL of energy, 11 g/100 kcal of
carbohydrate, 5.3 g/100 kcal of fat, and 1.8 g/100
kcal of protein.33,34
Based on limited data of the long-term effect of
pHF-W in healthy infants, it was found that there
was no significant difference between the growth of
pHF-W infants and CMF infants.27 For the long-
term use, Rzehak et al found no significant
differences between the BMI trajectory in the pHF-
W group, extensively hydrolyzed whey formula
(eHF-W), CMF, and breast milk groups after 6 years
of follow-up. In fact, it was found that pHF-W
shows the closest growth rate to breast milk, among
the other infant formula.35 In another study, the Z-
score trajectories showed that the weight gain in
pHF infants is normative, despite the accelerated
weight gain in CMF infants.36 A systematic review
and expert consensus also concluded that pHF-W
was as safe as CMF in terms of supporting normal
development. There was no difference found in the
nutritional value and safety of pHF-W compared to
CMF.37
Data regarding the effects of pHF-W in hormonal
response and metabolism of healthy infants were
also limited. Hoppe et al reported that whey protein
increased fasting insulin by 21% (p=0.006) in young
boys aged 8 years in 7 days, with no change in IGF-
1 (p=0.27), suggesting an increase in insulin
resistance. This would naturally arise concern that
pHF-W may induce the development of diabetes
mellitus.38 However, as to anticipate this concern,
the FDA-approved pHF-W has undergone the
process of removing the caseino-Glyco-
MacroPeptide (cGMP), resulting in the formation of
modified sweet whey (MSW) formula.34 This
formula is found to have lower plasma level of a
number of amino acids, such as leucine, isoleucine,
threonine, and valine, which are considered to be
insulin secretagogues (insulinogenic amino acids).
This formula would, therefore, lead to a reduced risk
of developing diabetes, compared to the classical
pHF-W.34,39 It was also found that the administration
of pHF, including pHF-W, in infants with a genetic
risk of developing type 1 diabetes mellitus did not
increase incidence of type 1 diabetes.40
pHF and functional gastro-intestinal disorders
Functional gastro-intestinal disorders (FGIDs)
FGIDs are a frequent cause of parental concern and
consequent impaired infants and relatives’ quality of
life, and impose a financial burden to health care,
insurance and families.41 Management of these
FGIDs should focus on improving both infants
symptoms and family quality of life. If more than
parental reassurance is needed, available evidence
suggests that nutritional advice is recommended as
it is effective and most of the time devoid of adverse
effects.
Troublesome regurgitation occurs in about 25 %
of all infants and usually improves spontaneously
within the first year after birth.42 A thickened pHF-
W was reported to be more effective than a
thickened formula with intact protein.43
Infant colic is reported to occur in about 20 % of
all infants.42 Frequent and extensive auto-
medication by parents of infants with colic has been
reported.44,45 Therefore, management should focus
on sustaining parents to cope with their child’s
excessive crying and distressed behavior by
informing the parents that in general crying peaks at
about four to six weeks after birth, may last up to
three hours per day in otherwise normal infants and
steadily diminishes from 12 weeks onwards.46 In
formula fed infants, when CMPA is an unlikely
diagnosis, a partial hydrolysate with prebiotics and
beta-palmitate; or a synbiotic formula with reduced
lactose and partially hydrolyzed protein may be
beneficial.47
World.Nutr.Journal | 58
Functional constipation occurs in about 10% of
all infants.42 A pHF-W, (a mixture of) prebiotics,
probiotics, synbiotcs, and beta-palmitate and/or a
formula with high magnesium content (but within
normal ranges) may offer some benefit.41
pHF-W has also been shown to have some beneficial
effect on functional GI manifestations, such as
regurgitation and constipation.9 A review by
Vandenplas et al. showed that there was a significant
decrease in the number of regurgitation events per
day with the use of pHF-W. In addition, stool in the
infants group with pHF-W was also found to be
softer compared to stool in the standard formula33,43
and soy-based formulas.43 Other data also showed
that the use of pHF-W in non-breastfed infants can
accelerate gastric emptying, reduce the incidence of
infantile colic, and other functional gastrointestinal
symptoms, when compared to CMF.37
Conclusion
Breast milk is still the best nutrition for babies. In
nonbreastfed infants, CMF can provide adequate
nutrition to support normal growth and
development. However, CMF is known to often
induce cow's milk allergic reaction. In a large-scale
GINI study and several other studies, pHF-W has
been proven as a formula which is superior in
reducing atopic disease and has been recommended
in several guidelines to prevent atopic disease in
high-risk group infants. Even so, more large-scale
clinical studies replicating these studies, particularly
GINI study, might be needed to confirm the
effectiveness of pHF-W.
As the number of infants developing allergy is
greater in the non-at-risk group compared to the at-
risk group, the use of pHF-W should not be limited
to the at-risk group only. Despite some reported
differences in studies, pHF-W has always shown
superior benefits among all the available infant
formulas, with minimal potential harm for healthy
term infants. According to a comparative
pharmacoeconomic analysis, pHF-W is also
superior over the standard formula in the aspect of
family and societal perspectives, as well as the
attractive cost-effectiveness.47 Further studies
assessing the effect of routine use of pHF-W in a
larger population of nonbreastfed infants should also
be conducted, in order to observe any potential harm
and to determine the benefit and cost-effectiveness
ratio.
Conflict of Interest
Authors declared no conflict of interest regarding
this article.
Open Access
This article is distributed under the terms of the
Creative Commons Attribution 4.0 International
Licence
(http://creativecommons.org/licenses/by/4.0/),
which permits unrestricted use, distribution, and
reproduction in any medium, provided you give
appropriate credit to the original author(s) and the
source, provide a link to the Creative Commons
license, and indicate if changes were made.
References
1. Victora CG, Bahl R, Barros AJD, França GVA, Horton
S, Krasevec J, et al. Breastfeeding in the 21st century:
epidemiology, mechanisms, and lifelong effect. Lancet.
2016;387(10017):475–90.
2. Martin C, Ling P-R, Blackburn G. Review of infant
feeding: key features of breast milk and infant formula.
Nutrients]. 2016;8(5):279.
3. Cabana MD. The role of hydrolyzed formula in allergy
prevention. Ann Nutr Metab. 2017;70(2):38–45.
4. Vandenplas Y, Munasir Z, Hegar B, Kumarawati D,
Suryawan A. A perspective on partially hydrolyzed
protein infant formula in nonexclusively breastfed
infants. Korean J Pediatr 2019;62(5):149–54.
5. Koletzko S, Niggemann B, Arato A, Dias JA,
Heuschkel R, Husby S, et al. Diagnostic approach and
management of cowʼs-milk protein allergy in infants
and children. J Pediatr Gastroenterol Nutr.
2012;55(2):221–9.
6. Vandenplas Y. Prevention and management of cow’s
milk allergy in non-exclusively breastfed Infants.
Nutrients. 2017;9(7):731.
7. von Berg A. Modified proteins in allergy prevention. In:
Microbial host-interaction: tolerance versus allergy.
Nestle Nutr Workshop Ser Pediatr Program.
2009;64:239-47.
8. Joshi PA, Smith J, Vale S, Campbell DE. The
Australasian Society of Clinical Immunology and
Allergy infant feeding for allergy prevention guidelines.
Med J Aust. 2019;210(2):89-93.
9. Fleischer DM, Venter C, Vandenplas Y. Hydrolyzed
formula for every infant? Nestle Nutr Inst Workshop
Ser. 2016;86:51-65.
10. Chan ES, Cummings C. Dietary exposures and allergy
World.Nutr.Journal | 59
prevention in high-risk infants. Paediatr Child Health.
2013;18(10):545–9.
11. Halken S. Prevention of allergic disease in childhood:
clinical and epidemiological aspects of primary and
secondary allergy prevention. Pediatr Allergy Immunol.
2004;15(s16):9–32.
12. Exl BM, Deland U, Secretin M-C, Preysch U, Wall M,
Shmerling DH. Improved general health status in an
unselected infant population following an allergen
reduced dietary intervention programme The ZUFF-
STUDY-PROGRAMME. Eur J Nutr. 2000;39(3):89–
102.
13. Lowe AJ, Hosking CS, Bennett CM, Allen KJ, Axelrad
C, Carlin JB, et al. Effect of a partially hydrolyzed whey
infant formula at weaning on risk of allergic disease in
high-risk children: A randomized controlled trial. J
Allergy Clin Immunol. 2011;128(2):360-365.e4.
14. Prescott SL, Tang ML. The Australasian Society of
Clinical Immunology and Allergy position statement:
summary of allergy prevention in children. Med J Aust.
2005;182(9):464–7.
15. Heine RG, Tang ML. Dietary approaches to the
prevention of food allergy. Curr Opin Clin Nutr Metab
Care. 2008;11(3):320–8.
16. Pali-Schöll I, Renz H, Jensen-Jarolim E. Update on
allergies in pregnancy, lactation, and early childhood. J
Allergy Clin Immunol. 2009;123(5):1012–21.
17. Wal JM. Cow’s milk proteins/allergens. Ann Allergy,
Asthma Immunol. 2002;89(6 Suppl1):3–10.
18. Nutten S, Maynard F, Järvi A, Rytz A, Simons PJ,
Heine RG, et al. Peptide size profile and residual
immunogenic milk protein or peptide content in
extensively hydrolyzed infant formulas. Allergy.
2020;75(6):1446-9..
19. Chung CS, Yamini S, Trumbo PR. FDA’s Health Claim
Review: Whey-protein partially hydrolyzed infant
formula and atopic dermatitis. Pediatrics
2012;130(2):e408–14.
20. Moreno MA. Atopic diseases in children. JAMA
Pediatr. 2016;170(1):96.
21. Asher MI, Montefort S, Björkstén B, Lai CK, Strachan
DP, Weiland SK, et al. Worldwide time trends in the
prevalence of symptoms of asthma, allergic
rhinoconjunctivitis, and eczema in childhood: ISAAC
Phases One and Three repeat multicountry cross-
sectional surveys. Lancet. 2006;368(9537):733–43.
22. Al-Herz W. A systematic review of the prevalence of
atopic diseases in children on the Arabian peninsula.
Med Princ Pract. 2018;27(5):436–42.
23. Szajewska H, Horvath A. Meta-analysis of the evidence
for a partially hydrolyzed 100% whey formula for the
prevention of allergic diseases. Curr Med Res Opin.
2010;26(2):423–37.
24. Alexander DD, Cabana MD. Partially hydrolyzed 100%
whey protein infant formula and reduced risk of atopic
dermatitis: a meta-analysis. J Pediatr Gastroenterol
Nutr. 2010;50(4):1.
25. Baumgartner M, Brown CA, Exl B-M, Secretin M-C,
van’t Hof M, Haschke F. Controlled trials investigating
the use of one partially hydrolyzed whey formula for
dietary prevention of atopic manifestations until 60
months of age: An overview using meta-analytical
techniques. Nutr Res. 1998;18(8):1425–42.
26. Sauser J, Nutten S, de Groot N, Pecquet S, Simon D,
Simon H-U, et al. Partially hydrolyzed whey infant
formula: literature review on effects on growth and the
risk of developing atopic dermatitis in infants from the
general population. Int Arch Allergy Immunol.
2018;177(2):123–34.
27. von Berg A, Filipiak-Pittroff B, Schulz H, Hoffmann U,
Link E, Sußmann M, et al. Allergic manifestation 15
years after early intervention with hydrolyzed formulas
- the GINI Study. Allergy. 2016;71(2):210–9.
28. Boyle RJ, Ierodiakonou D, Khan T, Chivinge J,
Robinson Z, Geoghegan N, et al. Hydrolysed formula
and risk of allergic or autoimmune disease: systematic
review and meta-analysis. BMJ. 2016;352:974.
29. Boyle RJ, Tang MLK, Chiang WC, Chua MC, Ismail I,
Nauta A, et al. Prebiotic-supplemented partially
hydrolysed cow’s milk formula for the prevention of
eczema in high-risk infants: a randomized controlled
trial. Allergy. 2016;71(5):701–10.
30. Osborn DA, Sinn JKH, Jones LJ. Infant formulas
containing hydrolysed protein for prevention of allergic
disease. Cochrane Database Syst Rev. 2018;
10(10):CD003664.
31. Pouessel G, Michaud L, Guimber D, Mention K,
Gottrand F, Turck D. Adherence to guidelines for the
primary prevention of food allergy. Ital J Pediatr.
2006;32:333–7.
32. Scientific Opinion on the essential composition of
infant and follow-on formulae. EFSA J. 2014
Jul;12(7):3760.
33. Czerkies LA, Kineman BD, Cohen SS, Reichert H,
Carvalho RS. A Pooled analysis of growth and
tolerance of infants exclusively fed partially hydrolyzed
whey or intact protein-based infant formulas. Int J
Pediatr. 2018; 2018:4969576.
34. Macé K, Steenhout P, Klassen P, Donnet A. Protein
quality and quantity in cow’s milk-based formula for
healthy term infants: past, present and future. In: Protein
and energy requirements in infancy and childhood.
Nestle Nutr Workshop Ser Pediatr Program.
2006;58:189-203
35. Rzehak P, Sausenthaler S, Koletzko S, Reinhardt D, von
Berg A, Krämer U, et al. Short- and long-term effects
of feeding hydrolyzed protein infant formulas on
growth at ≤6 y of age: results from the German Infant
Nutritional Intervention Study. Am J Clin Nutr.
2009;89(6):1846–56.
36. Mennella JA, Ventura AK, Beauchamp GK.
Differential growth patterns among healthy infants fed
protein hydrolysate or cow-milk formulas. Pediatrics.
2011;127(1):110–8.
37. Vandenplas Y, Latiff AHA, Fleischer DM, Gutiérrez-
Castrellón P, Miqdady M-IS, Smith PK, et al. Partially
hydrolyzed formula in non-exclusively breastfed
infants: A systematic review and expert consensus.
World.Nutr.Journal | 60
Nutrition. 2019;57:268–74.
38. Hoppe C, Mølgaard C, Dalum C, Vaag A, Michaelsen
KF. Differential effects of casein versus whey on
fasting plasma levels of insulin, IGF-1 and IGF-
1/IGFBP-3: results from a randomized 7-day
supplementation study in prepubertal boys. Eur J Clin
Nutr. 2009;63(9):1076–83.
39. Salehi A, Gunnerud U, Muhammed SJ, Östman E, Holst
JJ, Björck I, et al. The insulinogenic effect of whey
protein is partially mediated by a direct effect of amino
acids and GIP on β-cells. Nutr Metab. 2012;9(1):48.
40. Hummel S, Beyerlein A, Tamura R, Uusitalo U, Andrén
Aronsson C, Yang J, et al. First infant formula type and
risk of islet autoimmunity in the environmental
determinants of diabetes in the young (TEDDY) study.
Diabetes Care. 2017;40(3):398–404.
41. Vandenplas Y, Hauser B, Salvatore S. Functional
Gastrointestinal Disorders in Infancy: Impact on the
Health of the Infant and Family. Pediatr Gastroenterol
Hepatol Nutr. 2019;22(3):207-216.
42. Vandenplas Y, Abkari A, Bellaiche M, Benninga MA,
Chouraqui JP, Çokura FC, et al. Prevalence and health
Outcomes of functional gastrointestinal symptoms in
infants from birth to 12 months of age J Pediatr
Gastroenterol Nutr. 2015;61(5):531-7.
43. Vandenplas Y, Leluyer B, Cazaubiel M, Housez B,
Bocquet A. Double-blind comparative trial with 2
antiregurgitation formulae J Pediatr Gastroenterol Nutr.
2013;57(3):389-93..
44. Oshikoya KA, Senbanjo IO, Njokanma OF. Self-
medication for infants with colic in Lagos, Nigeria.
BMC Pediatr. 2009;9:9.
45. Headley J, Northstone K. Medication administered to
children from 0 to 7.5 years in the Avon Longitudinal
Study of Parents and Children (ALSPAC). Eur J Clin
Pharmacol. 2007;(63):189-95.
46. Vandenplas Y, Gutierrez-Castrellon P, Velasco-Benitez
C, Palacios J, Jaen D, Ribeiro H, et al. Practical
algorithms for managing common gastrointestinal
symptoms in infants. Nutrition. 2013;29:184-94.
47. Xinias I, Analitis A, Mavroudi A, Roilides I,
Lykogeorgou M, Delivoria V, et al. Innovative dietary
intervention answers to baby colic. Pediatr
Gastroenterol Hepatol Nutr. 2017;20:00-6.
