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Nuhition Research, Vol. 18. No. 8. pp. 1425-1442.

1998
Copyright Q 1998 Elsevier Science Inc.
Printed in the USA. All rights reserved
0271-5317/98 $19.00 + .OO

ELSEVIER PI1 SO271-5317(98)00120-l

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

M. Baumgartner, MS&*, C.A. Brown, RN, MSN’, B-M Exl, PhD3,


M-C. Secretin PhD4, M. van’t Hof, PhD’, F. Haschke, MD4,6
‘Nestle Research Center, Lausamie, CH; 3NestlC Switzerland, Research Department, Vevey,
CH; 4Nestle Nutrition Strategic Business Division, CH; ‘Medical Statistical Department,
Catholic University Nijmegen, NL; 6Dept. Pediatrics, University Vienna, Austria

ABSTRACT

As much as 30% of the pediatric population is reported to be affected by atopic


symptoms, at least temporarily. Therefore, efforts at prevention at an early age
are of paramount importance. A meta-analysis was undertaken with the aim of
combining the results of 15 prospective, controlled trials which measure the effect
of exclusive feeding (minimum of three months) of a moderately hydrolyzed whey
formula (Nestle HA formula) on the development of atopic symptoms between 3-
6 and 60 months of age in children at high risk for allergy. Odds ratios,
statistical methods of meta-analysis (Mantel-Haenszel, Bayesian approach), and
“the number needed to treat” analysis at specific time intervals are reported. The
me&analysis of clinical data at 3-6 months of age indicates that the proportion
of infants developing atopic symptoms when fed with HA is about one-fourth of
the proportion of those fed with the standard cow milk formula (OR 0.25, 95%
CI 0.18-0.36). For the 12 months data, the proportion with HA is about one-
third of the proportion in the cow milk formula group (OR 0.29, 95% CI 0.19-
0.44). The odds ratios between 12-24 and 60 months of age also showed a
significant influence of the HA formula. No significant differences were found
when the HA group was compared with breastfed infants. Computation of the
“number needed to treat” resulted in an estimate that feeding three to five high
risk infants HA formula rather than cow milk formula, will protect one infant
from atopic symptoms. Breastfeeding or exclusive feeding of a moderately
hydrolyzed formula (Nestle HA formula) for at least three months in infants at
high risk for the development of allergic disease, decreases the incidence of atopic
manifestations until 60 months of age.
0 1998 Ekviea scienss Inc.
KEY WORDS: Atopic symptoms, Pediatrics, Clinical trials, Hypoallergenic
formula, Meta-analysis, Prevention

Corresponding author: M. Baumgartner, Nestle Research Center Lausanne, Vers-chez-


les-Blanc, PO Box 44, 1000 Lausanne 26, Switzerland.
1425
1426 M. BAUMGARTNER et al.

INTRODUCTION

Symptomatic manifestations of allergy are increasing and are now among the most
common signs of disease in industrialized society (l-3). As much as 30% of the pediatric
population is reported to be affected by allergy symptoms, at least temporarily (4-6). The
magnitude of allergies, in prevalence, human discomfort and health care costs, selects it as an
area for intervention.

Dietary manipulation during infancy is an area which is being studied as preventive for
the development of atopic symptoms (7-10). Exclusive breastfeeding for four to six months
reduces atopic symptoms in high risk infants, when comprired to formula feeding with standard
cow milk based formulas (11,12). Researchers (8,9,13-20) have also studied the use of
extensively hydrolyzed formulas as a part of comprehensive allergy prevention programs. These
studies did not provide a clear assessment of the formula effect, due to the incorporation of
breastfeeding and combinations of strict diet and environmental controls. Although
recommended by some (21,22), the use of extensively hydrolyzed formulas has not been
generally accepted in the area of prevention, primarily due to concerns about palatability, cost
and long-term nutrition.

In 1985 the first moderately hydrolyzed whey formula was developed and entered clinical
trials as a less expensive and more palatable alternative, and one which might offer a preventive,
rather than therapeutic, effect. Studies in animal models demonstrate that these moderately
hydrolyzed proteins are well tolerated and actively induce oral tolerance in non-sensitized
animals, without sensitization (23-25). Several published studies in infants (11, 26-28) show a
decrease in atopic symptoms when high risk infants are fed this moderately hydrolyzed whey
formula, compared to standard cow milk formula. No difference in atopic presentation was
found in infants fed HA and infants who were breastfed with maternal diet restrictions (29).
Comments by scientific bodies (22,30-33) also recognize the potential impact of early feeding
with moderately hydrolyzed whey formula. The European Union approved the claim
”hypoallergenic” , if clinical studies confirm the efficacy of the formula to prevent atopic
symptoms (34).

While it is important to validate the results obtained in these studies, clincial research of
this nature is difficult to perform. The study population must be carefully screened to meet the
criteria of high risk for allergy development. The number of subjects in this select population
must be large enough for meaningful statistical evaluation. Because of their epidemiological
character, prevention studies must be conducted over many months or years to measure any
long-term effects. Strict controls and definitions of feeding practices need to be maintained and
monitored throughout the study period. Despite the challenges of long-term compliance to a strict
protocol, the drop out rate must be maintained at a very low level to assure that the results are
interpretable. Difficulties also exist in the approaches utilized in prevention studies for the
diagnosis of allergy. The use of double-blind placebo controlled food challenges is held as a
diagnostic standard by some authors (8,21,22), while issues of safety, necessity and practicality
make it didfficult to implement. Given the complexity of these studies, different strengths and
weaknesses can be identified in each of the prevention studies which have been conducted.
META-ANALYSIS OF PREVENTION STUDIES 1427

To further study the prevention of atopic symptoms in infancy and early childhood, a
me&analysis of clinical studies (35-37) utilizing one partially hydrolyzed whey protein formula
(Nestle HA, referred to as HA)* is presented. The purpose of this meta-analysis is to combine,
in a scientifically sound manner, data from the different prevention studies which have been
conducted, with the objective of increasing power and the assessment of effect over time.

METHODS

Studies To Be Included

A search of the literature in the last 12 years (1985-1997) was conducted, including the
medline database. This time frame encompasses the development and the first introduction of
a moderately hydrolyzed whey infant formula into the European market. All published and
unpublished studies with the formula which addressed dietary attempts at prevention of atopic
symptoms in infancy and childhood during this time period were reviewed.

Studies to be included into the meta-analysis were prospective, controlled clinical


evaluations of infants at high risk for the development of allergy. Elevated allergy risk was
defined as a positive family history in a minimum of one first degree relative. Studies using a
positive family history and cord blood IgE of 10.5 IU/ml were also considered. Studies were
examined for scientific protocol and design, including random assignment to groups, which
supported the results. The research had to be designed to evaluate the effect of feeding in the
first few months of life. Studies were screened for a clear indication of feeding groups and
exclusivity of feeding for a minimum of three months, including introduction of beikost after
three to four months of age. All studies were required to incorporate the Nestle HA moderately
hydrolyzed whey formula as a study group.

All studies evaluated the development of atopic symptoms in infants over time as an
outcome variable. The inclusion criteria required that symptoms assessed be based on specific
patterns and definitions of atopic manifestation in infants, as reported in the literature (skin,
respiratory, gastrointestinal) (22). The studies may or may not have included specific diagnosis,
with controlled oral challenge procedures, of cow milk protein allergy and/or atopic disease.
In the studies, the presence or absence of symptoms was assessed by a pediatrician or health care
practitioner at prearranged time points, generally in intervals of 6 to 12 months. In each case,
symptom data was presented as cumulative incidence and analyzed using appropriate statistical
techniques. For inclusion in the meta-analysis, it was required that the period of subject
monitoring and follow up be a minimum of three months, but could extend to 60 months.

2The Nestle HA formula is known under the following brand names in various countries:
Aletemil HA, Beba HA, Good Start, Lait Guigoz hypoallergtnique, Nan HA, Nativa HA, Nidal
HA, Nidina HA.
1428 M. BAUMGARTNER et al.

Statistical Methods

For all seclected individual studies Odds Ratios (OR) on allergy risk for the involved
feeding groups were calculated (adding 0.5 to each count) with 95% asymptotic confidence
intervals (CI) (38) (see TABLE 3). A value of less than one is in favor of HA, a value close
to one indicates no difference.

Individual trials results are summarized using two types of meta-analysis techniques:
1. Fixed Effect Model (Mantel-Haenszel)
After testing the homogeneity of the treatment effects as proposed in (39), the
individual ORs are combined into one OR (and a 95 %-CI) according to the classic
Mantel-Haenszel technique (40).
2. Random Effect Model (Bayesian)
Berlin et al. (41) point out that among-study variation should not be neglected.
Random effect models take account of such possible variation. A Bayesian
approach treats the studies as being exchangeable (42), that is neither identical
repeats of each other (being more or less the assumption in the fixed effect model)
nor completely unrelated. The model proposed by Smith et al. (43) and
Spiegelhalter et al. (44) was applied, using the software BUGS (44) and CODA
(45). The same prior distribution as in Smith et al. has been used.

There are several ways to summarize statistically two-way tables: the OR has been used,
because it is the classic measure suited for meta-analysis. Recently, other measures, that are
more easy to interpret from a clinical point of view have been advocated, in particular the
“Number Needed to Treat” (NNT) (46). An ad-hoc approach is used to estimate this number
for the trials comparing HA and CMF at six months.

RESULTS

Selected Studies

A total of 24 studies were identified in the internal and external review. All of the
clinical trials identified were conducted in developed countries, in industrialized environments,
where increasing prevalence of allergies plays a major role in infant and child health (47). In
these studies, atopic manifestations in infants fed one moderately hydrolyzed whey formula (HA)
were compared to those in infants who received breastmilk (BF), breastmilk with maternal diet
restrictions (BF/diet) and/or standard cow milk adapted formula (CMF). Of the studies initially
identified, 16 were published or accepted for publication, 6 were presented at scientific meetings
with abstracts and 2 were internal publications or communication with the investigators.

A total of 15 studies met the inclusion criteria; nine studies were excluded from the meta-
analysis. Four (48-51) did not have well defined feeding groups, whereas the data on formula
fed infants were combined with data on breastfed infants. A fifth excluded study (52) did not
define specific atopic symptoms and reported only combined symptomatology. In the sixth
META-ANALYSIS OF PREVENTION STUDIES 1429

excluded study (53), the outcomes are not presented as a cumulative incidence of atopic
manifestations, hence the results were not directly comparable to all other studies. The seventh
clinical trial (54) was excluded from the meta-analysis as parental allergy history could not be
confirmed in l/3 of the infants. Further, the feeding groups were not exclusive, as breastfeeding
continued iu the formula groups for varying intervals up to four months. The two final excluded
studies (55,56) were designed to assess growth and atopic symptoms in a general population, and
subjects were not selected for allergy risk.

TABLE 1 provides a description of all the studies included in the meta-analysis. For
comparison of the outcome of HA vs. CMF feeding, 576 vs. 419 infants were available,
respectively. The median incidence of atopic symptoms at six months of age was 7% and
39.5 % (see TABLE 2). While the 15 studies included in the evaluation present comparable
results based on design, protocol and sample selection, some viariability must be acknowledged.
Within the gruop, 73 % are published, 20% have scientific abstracts and 7% are internal reports.
Because most of the studies (13115) included breastfed controls, assignments could not justifiably
be randomized to all feeding groups. Where HA was compared to another formula type, group
assignments were randomized in 9/l 1 of the included studies. Formula groups in three studies
(57-59) included in the meta-analysis may have limited breastmilk exposure in the first two
weeks of life. In 12 of 15 studies, formula feedings were exclusive from birth. In a high
percentage of studies (80%) the data collection intervals were six months within the first 18
months of life. In cases where the intervals differed, the data are combined with the next higher
interval (see footnotes TABLE 2).

Statistical Outcome

The raw data (number of symptomatic infants/sample size n), the calculated odds ratios
of all clinical trials and the pooled estimates and confidence intervals using both methods of
meta-analysis for the selected age groups are presented in TABLE 2.

The comparison of the HA group with the breastfed infants (with and without maternal
diet restriction) do not distinguish among the diets. All confidence intervals, except two, contain
the value one, and thus do not show a differing effect of any diet. Furthermore, the confidence
intervals for HA and breastmilk are wider than those for HA and CMF, indicating less precision
concerning the comparison of HA and with breastfed infants.

Comparison of HA- with CMF-feeding employing meta-analysis indicates significantly


lower odds ratios for the incidence of atopic symptoms in the HA groups for all age intervals
between 3-6 and 60 months. The comparison of HA and CMF for 6 months is visualized in
FIGURE 1; FIGURE 2 shows the comparison of HA and CMF for 12 months.

For the 6 and 12 months results, the two methods of meta-analysis give similar results.
Figure 3 shows a graphical representation of the Mantel Haenszel meta-analysis CI’s obtained
for all time periods studied. A slight increase of the proportion of infants with allergy symptoms
is noted, but the effect of HA formula on reduction of symptoms remains statistically significant
over time. Thus, the comparison of HA with CMF feeding employing meta-analysis indicates
an effect in favor of HA through five years.
1430 M. BAUMGARTNER et al.

TABLE 1
Sample Sizes and Duration in the 15 Studies Selected for Meta-Analysis
-
T Sample Sizes*

Study/Reference HA CMF BF BF/D Feeding Duration of


Duration” Follow-up
(months)

AljamaGarcia (60) 50 50 21 29 3 6
Chandra (7,11,61,62) 68 67 60 6 60
D’Agata (59) 50 15 30 4 48
de Seta (63) 23 39 46 6 21-24
Kraemer (58) 28 59 9 18-24

Lam (57) 44 48 22 6 6
Macagno (64) 16 20 4 18-24
Marini I” (29) 43 79 6 18-24
Marini II” (28) 48 47 124 5 36
Mautone (65,66) 25 19 12 18-24
Porch (67) 41 17 4-6 18-24
Schmidt (68) 59 71 151 117 6 12
Vandenplas I** (69) 15 15 15 4 6
Vandenplas II” 28 30 6 60
(10,26,70)
Willems (27) 38 37 3 12
B =

* At earliest timepoint (BF/D=Breastfeeding with maternal diet restrictions)


# Duration of exclusive feeding (months)
**/” Different cohorts

In order to compute the “Number Needed to Treat” (NNT) (46) for the HA vs. CMF
comparison at six months, the two most extreme 95 %-CI limits have been taken (0.10 and 0.36),
and the incidence of allergies for HA has been computed, assuming that the incidence in the
CMF group is 0.4 (median of incidences at 6 months from TABLE 2). This results in a
“number needed to treat” ranging from three to five. That is, when between three to five
children are fed HA rather than CMF, it is estimated to prevent one case of atopic
manifestations.
META-ANALYSIS OF PREVENTION STUDIES 1431

TABLE 2
Raw Data [symptomatic infants/n (percentage proportion)] and Odds Ratios (OR) of all
Individual Studies (95%-CI) and the Results of Two Types of Meta-Analysis

Aljama Garcia’ 6/50 (12%) 22/50 (44%) 0.19 (0.07,0.50)


Chandra 5/68 (7%) 24/67 (36%) 0.15 (0.06, 0.42) 12/60 (20%) - 0.34 (0.12,0.98)
de Seta 3/23 (13%) 11/39 (28%) 0.42 (0.11, 1.59)
Lam 16/44 (36%) 28/48 (58%) 0.42 (0.18,0.96) 5/20 (25%) - 1.63 (0.52,5.13)
Schmidt 4/59 (7%) 23171 (32%) 0.17 (0.06,0.49) 25/151 (17%) - 0.40 (0.14, 1.15)
16017 (14%) + 0.50 (0.17, 1.49)
Vandenplas I’ o/15 (0%) 8/15 (53%) 0.03 (0.00,0.56)
Vandenplas II 2128 (7%) 13/30 (43%) 0.12 (0.03,0.54)
Willems l/30 (3%) 3/37 (8%) 0.50 (0.07,3.61)
Meta ** 0.25 (0.18, 0.36)
MetafBaves) 0.19 fO.10. 0.34)

ae aera u.04 (“.LL, 1.61,


Marini I 4/40 (10%) S/76(11%)+ 0.99 (0.30, 3.34)
Marini II 5/42 (12%) 11/40 (28%) 0.38 (0.12, 1.16) 1 l/104 (11%) + 1.19 (0.40,3.53)
Mautone 10125 (40%) 9119 (47%) - 0.75 (0.23,2.43)
Porch 12/34 (35%) 8/17 (47%) - 0.62 (0.20, 1.97)
Vandenplas II 7/28 (25%) 17/30 (57%) 0.27 (0.09,0.80)
Meta 0.45 10.28. 0.70)

Marini II 7/40 ilS%; 1 16/38 i42%; 10.31 iO.11: 0.84i 1 13/98 i13%i + I 1.42 i0.53: 3.77; 1

Chandra 22/68 (32%) 40/67 (60%) 0.33 (0.16, 0.66) 16/60 (27%) - 1.30 (0.61, 2.78)
Vandenplas II S/28 (29%) 18/30 (60%) 0.28 (0.10,0.82)
Meta (MI-I) 0.33 (0.19, 0.57)
* -: without Diet, +: with Diet; ’ 3 or 4 months data ;
** (MH=Maqtel-Haenszel) (Bayes=Bayesian);
‘* 14 mos data ; *** Includes Chandra, 18 months
1432 M. BAUMGARTNER et al.

Vandenplas I I

Vandenplas II I

Schmidt I i

Willems I I

Lam

Aljama Garcia I I

Chandra

de Seta t -l
.-----

Mantel-Haenszel

Bayesian Model

0.01 0.02 0.05 0.1 0.25 0.5 1h


Odds Ratio (log scale)

FIG. 1: Comparison HA vs. CMF, 6 Months: Individual and Meta-Analysis (both


methods) OR (95%-CI)

DISCUSSION

Given the immunological and gastrointestinal immaturity of the newborn human infant,
diet has a primary influence on overall health status. Breastmilk provides the most appropriate
dietary environment to the human newborn. Any consideration of prevention of atopic
symptoms or disease must include efforts to promote the initiation of breastfeeding and to
prolong its duration.
META-ANALYSIS OF PREVENTION STUDIES 1433

The costs of atopic symptoms are important in the human condition and in human
resources. The greatest impact comes from the symptomatic expression of the disease, rather
than from the immunological sensitization. The incidence of atopic manifestations in infancy
is reported to be as high as 30%) while only 2-62 (6,71-73) of infants are diagnosed with cow
milk protein sensitization. Subsequently atopic symptoms are considered as the outcome within
the meta-analysis, rather than the incidence of pure cow milk protein allergy.

Vandenplas II I

Schmidt I I

Willems I I

Marini II I -I

Chandra I I

_--

Mantel-Haenszel I I

Bayesian Model

I I 1 I

0.05 0.1 0.25 0.5

Odds Ratio (log scale)

FIG. 2: Comparison HA vs. CMF, 12 months: Individual and Me&Analysis (both


methods) OR (95%-CI)
1434 M. BAUMGARTNER et al.

0.5
z
73
5:

g 0.25
z-
0
‘E

I?
ul

z
0 0.1

0.05

0 12 24 36 48 60
Time [Months]

FIG. 3: Me&Analysis (Mantel-Haenszel) OR (95 %-CI) vs. Follow-up for Comparison


HA vs. CMF (Results from Chandra at 18 months have been incorporated into
24 Months Results)

Valid and reliable prevention studies are difficult to conduct throughout the lifecycle.
All of the studies incorporated in the me&analysis have undertaken the challenge of evaluating
the effect of a single intervention over time in a subpopulation. Because of the logistical
difficulties encountered, the sample sizes are small. Meta-analytical techniques are useful to
address this type of situation, and to provide a scientifically meaningful way to evaluate the
totality of the data. Because the studies considered in the meta-analysis were designed to assess
the same outcomes, they have samples and results which are comparable. The studies
META-ANALYSIS OF PREVENTION STUDIES 1435

incorporated in this meta-analysis include unpublished data, offering greater assurance that all
available data has been accessed and potential sources of bias minimized.

To further increase the strength of this report and the comparison of HA to standard cow
milk formula, results of the studies were compared trial by trial and using two different methods
of me&analysis. The similarity of the results obtained using a classic fixed effect model and
a Bayesian random effects model, which incorporates the nonhomogeneity of the studies, lends
increased credibility to the data and to the use of these meta-analytical approaches.

Within the majority of clinical trials in this report, exclusive feeding of HA occurred
within the first four to six months of life. The meta-analysis shows a significant reduction in
atopic manifestations of HA fed infants during this time of direct dietary intervention. The
percentage of affected infants is lowest in the first six months, thereafter all feeding groups have
some increase in atopic disease. At 12 months, the results of the meta-analysis again show a
significant reduction in atopic manifestations of HA fed infants. This shows that the effect is
maintained, wherein the benefits are detectable past the period of direct intervention.

At both 6 and 12 months, the meta-analyses suggest that the proportaion of infants who
develop atopic symptoms in the standard cow milk formula group is about three to four times
higher than the proportion in the HA group. The data available at later time intervals of 24,36
and 60 months are also consistent among the trials, and meta-analytical techniques show the
same reduction in the incidence of atopic manifestations in infants fed HA, when compared to
infants fed standard cow milk formula. This suggests that the effect of early feeding on
development of atopic symptoms may extend into early childhood. Further study is required on
the relationships between atopic manifestation in infancy, childhood and beyond.

The number needed to treat calculations estimate that between three and five high risk
infants need to receive HA formula in order to protect one infant from atopic symptoms. This
indicates a favorable cost/benefit ratio for prevention of atopic symptoms with HA for formula
fed infants, if the calculated costs for treatment of atopic disease are considered (7,47,74,75).
Report of atopic symptoms in infants fed HA formula and in breastfed infants were not
differentiated by the trials included in this report.

The mechanisms for an effect of HA formula, both short and long-term, on development
of atopic manifestations is unknown. Some authors (24,25) have postulated an oral tolerance
model, such as has been demonstrated in animal studies. In this model, the protein size in HA
and breastmilk may be large enough to stimulate a normal tolerance to the introduction of
foreign proteins via the diet, but reduced enough in size to avoid stimulating an immune
response, an effect which is not observed with extensively hydrolyzed formulas. Similarly, the
benefits in allergy prevention with extensively hydrolyzed formula seems to lose its effect after
two years (13,15,18). Additional research is needed to fully understand this area of mechanism
and to compare the prevention and tolerance inducing effects between extensively and partially
hydrolyzed formulas.

All studies included in the meta-analysis were conducted on high risk populations;
questions remain about efficacy in the general population and other subpopulations. Methods
M. BAUMGARTNER et al.

of identifying accurately all infants at risk for developing allergies are still imperfect.
Prevention of atopic symptoms on a larger scale may be more realistically obtained by offering
some easily implemented approaches to the general population. There is no evidence of risk in
the use of HA as early feeding in a general population. Data from a study which assessed
prevention benefits of early feeding with HA formula in a non-selected population indicate lower
incidence of skin manifestations until six months of age (56,76). The 1996 revision of the
European Community Directives does not restrict use of the category of HA formulas to specific
populations for the reduction of risk effect (34).

For the time periods considered, the meta-analysis offers evidence to support the use and
efficacy of HA formula. If breastmilk is not available, HA is a valid alternative to reduce the
risk of atopic symptoms in infants at high risk for allergy development.

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Accepted for publication February 25, 1998.