EC
doi: 10.1111/j.1365-2222.2009.03444.x Clinical & Experimental Allergy, 40, 627–636
c 2010
 Blackwell Publishing Ltd
ORIGINAL ARTICLE Epidemiology of Allergic Disease

Impact of early feeding on childhood eczema: development after nutritional

intervention compared with the natural course – the GINIplus study up to the
age of 6 years
A. v. Berg1, U. Krämer2, E. Link2, C. Bollrath1, J. Heinrich3, I. Brockow3, S. Koletzko4, A. Grübl5, B. Filipiak-Pittroff1, H.-E. Wichmann3,7,
C.-P. Bauer5,6, D. Reinhardt4, D. Berdel1 and the GINIplus study group
1
Marien-Hospital Wesel, Department of Paediatrics, Wesel, Germany, 2IUF – Institut für Umweltmedizinische Forschung at the Heinrich-Heine-University, Düsseldorf,
Germany, 3Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Institute of Epidemiology, Neuherberg, Germany, 4Department
of Paediatrics, Ludwig-Maximilians University, Munich, Germany, 5Department of Paediatrics, Technical University of Munich, Munich, Germany, 6LVA Oberbayern,
Munich, Germany and 7IBE, Chair of Epidemiology, Ludwig-Maximilians University, Munich, Germany

Clinical &
Experimental
Allergy
Correspondence:
A. v. Berg, Marien-Hospital-Wesel,
Department of Paediatrics, Pastor-
Janssen-Str. 8-38, D 46483 Wesel,
Germany. E-mail:
vonberg@marien-hospital-wesel.de
Cite this as: A. v. Berg, U. Krämer,
E. Link, C. Bollrath, J. Heinrich,
I. Brockow, S. Koletzko, A. Grübl,
B. Filipiak-Pittroff, H.-E. Wichmann,
C.-P. Bauer, D. Reinhardt, D. Berdel and
the GINIplus study group, Clinical &
Experimental Allergy, 2010 (40)
627–636.
Summary
Background Nutritional intervention with hydrolysed infant formulas has been shown
efficacious in preventing eczema in children predisposed to allergy. However, this
preventive effect has never been related to the natural course of eczema in children with or
without a family history of allergy. The aim of this study therefore was to compare the course
of eczema in predisposed children after nutritional intervention to the natural course of
eczema.
Method The prospective German birth cohort study GINIplus includes a total of 5991 children,
subdivided into interventional and non-interventional groups. Children with a familial
predisposition for allergy whose parents agreed to participate in the prospective, double-blind
intervention trial (N = 2252) were randomly assigned at birth to one of four formulas: partially
or extensively hydrolysed whey, extensively hydrolysed casein (eHF-C) or standard cow’s
milk formula. Children with or without familial predisposition represented the non-interventional
group (N = 3739). Follow-up data were taken from yearly self-administered questionnaires
from 1 up to 6 years. The outcome was physician-diagnosed eczema and its symptoms. The
cumulative incidence of eczema in predisposed children with or without nutritional
intervention was compared with that of non-predisposed children who did not receive
intervention. Cox regression was used to adjust for confounding.
Results Predisposed children without nutritional intervention had a 2.1 times higher risk for
eczema [95% confidence interval (CI) 1.6–2.7] than children without a familial predisposition.
The risk was smaller with nutritional intervention even levelling out to 1.3 (95% CI 0.9–1.9) in
children fed eHF-C formula.
Conclusion Although direct comparability is somewhat restricted, the data demonstrate that
early intervention with hydrolysed infant formulas can substantially compensate up until the
age of 6 years for an enhanced risk of childhood eczema due to familial predisposition to
allergy.
Keywords birth cohort, eczema, hydrolysed infant formulas, natural course, prevention
Submitted 31 July 2009; revised 19 October 2009; accepted 6 November 2009

allergens, together with a family history of allergy are

Introduction
The development of allergies is the result of a complex
interaction between genes and the environment [1]. Post-
natal exposure to food allergens, mainly cow’s milk
major risk factors for allergy development later [1–3]. For
children with an allergic background, nutritional preven-
tion efforts have focused on avoiding early exposure to
intact milk proteins by reducing the milk’s antigenicity
628 A. v. Berg et al
through hydrolysis [4–6]. It has been shown that feeding
hydrolysed infant formulas in the first months of life can
reduce the risk of allergies [7–16]. Recently, data from the
German Infant Nutritional Intervention (GINI) study [17]
have shown that eczema [18] is significantly reduced in
high risk children up to the age of 6 years when they are
fed hydrolysed formula (both partial and extensive) in the
first 4 months of life compared with regular cow’s milk
formula (CMF). However, the development of eczema in
high-risk children receiving fully hydrolysed formula
(intervention group) has never been compared with the
natural course of eczema (no intervention group). We
analysed data from the GINI plus non-intervention (GINI-
plus) study to compare the course of eczema in predis-
posed children after nutritional intervention with the
natural course of eczema.
Methods
Subjects
We analysed the questionnaire data from the ongoing
GINIplus study that comprises the GINI intervention study
(I) and the GINI non-intervention study (NI). Detailed
descriptions of the screening and recruitment process for
the GINIplus study were previously published [19, 20].
Briefly, 5991 healthy term newborns were initially
recruited between September 1995 and June 1998 from
16 maternity wards in two regions of Germany (rural
Wesel and urban Munich).
Group I (N = 2252) included infants with a family
history of allergy (FH1). In this prospective, double-blind
intervention trial, newborns were randomized at birth to
one of three hydrolysed formulas [partially hydrolysed
whey (pHF-W); extensively hydrolysed whey (eHF-W);
extensively hydrolysed casein, (eHF-C)] or a conventional
CMF [19]. The formulas were only provided if the recom-
mended exclusive breastfeeding for the first 4 months was
not feasible or wanted. Written and verbal dietary recom-
mendations to avoid allergenic complementary foods
were provided at birth. In addition to filling out yearly
self-administered questionnaires regarding the child’s
health, nutrition, and living conditions, the parents kept
weekly diaries for the first 6 months and participated in
structured interviews and physical examinations at reg-
ular intervals at the study centre until the age of 3 years.
Non-compliance was defined as not following the milk-
feeding recommendations [21].
Infants with no family history of allergy (FH,
N = 2507) or a positive family history but from parents
who denied participation in the intervention trial
(N = 1232) were allocated to the NI group. This group was
sent the yearly questionnaires only and did not receive
any of the additional intervention procedures.
At the age of 6 years, all children were invited to the
study centres for a physical examination. In cases with
visible signs of eczema, the severity scoring was carried
out using SCORAD [22]. Current eczema was determined
using the ISAAC II protocol [23].
Written informed consent was obtained from the parti-
cipating families. The study protocol was approved by the
local ethics committees.
Questionnaires
Parents completed questionnaires before or shortly after
delivery to determine the parental history of allergy,
parental education, maternal smoking during pregnancy,
maternal age at delivery, siblings, pet ownership, and
other lifestyle factors. Self-administered ISAAC-modified
questionnaires [24] were sent to the parents at their child’s
first, second, third, fourth, and sixth birthdays to collect
information on the child’s health and covariates, such as
nutrition, allergy symptoms, doctor-diagnosed allergies,
environmental tobacco smoke exposure, and pets in the
household.
Definition of outcomes and covariates
Parents were asked whether a physician had diagnosed
atopic eczema since the last follow-up and whether the
child experienced an intermittent itchy skin rash that
lasted at least 2 weeks. The following covariates were
considered as potential confounders: birth weight and
length, parental education (schooling o10, 10, and 410
years), maternal smoking during pregnancy or in the
child’s first 4 months of life, smoking in the child’s home,
age of mother at birth, furry pets in the home, and elder
siblings. These covariates were selected based on the
results of former analyses in the study and were deter-
mined a priori.
Statistics
Cox regression was used to analyse the cumulative in-
cidence of eczema diagnoses and the symptoms associated
with different types of formula feeding in the first months
of life and familial predisposition. The effects are indi-
cated as a hazard ratio (HR). We tested the proportionality
assumption of the Cox model by creating interactions of
all types of nutrition, familial predisposition, and all
covariates with time. Time-dependent covariates were
included in the model when significant (Po0.05). We
used the PHREG procedure of SAS (SAS 9.1.3) and applied
the exact method to account for ties, leading to the
correct smaller variances compared with the conventional
method.
Additionally, we graphically depicted the cumulative
incidence of eczema after log (log) transformation
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against the log of lifetime in the different groups using
different formulas. If the proportionality assumption
holds, and the effects remain the same on a multiplicative
scale, the graph should result in parallel curves.
Logistic regression was used to analyse the prevalence
data at the age of 6 years. The effects are indicated as an
odds ratio (OR).
Results
Study population and participation
The study population for the present analysis were sub-
jects who completed the 1-year questionnaire (4613/5991,
77%, Fig. 1 shows all participating children in each year).
The analysis was divided into children who were fed
formula during the first 4 months (fb, 2489/4613) and
fully breastfed children (fb1, 2124/4613). Seven groups
were distinguished to analyse formula supplementation,
five I groups with familial predisposition (four randomly
assigned study formula groups and the non-compliant
subjects, n = 1057) and two NI groups (with or without
predisposition) who received any parent-chosen formula
during the first 4 months of life (n = 1432). In this analysis,
the NI group without a family history of allergy was used
as reference group (NI FH fb). Up to 6 years, 23% of the
children dropped out: 20% in the five I fb groups and
24% in the two NI fb groups. The drop-out rate in the NI
group was not dependent on family history. The analysis
was restricted to children for which information on
Fig. 1. Flow of the GINIplus cohort. Numbers are based on annual questionnaires from birth (N = 5991) to 6 years. The intervention and non-
intervention groups are separated as children with and without family history of atopic manifestations (FH1/FH) and the kind of feeding [fully breast-
fed (fb1), not fully breast-fed (fb), and supplemented with parental chosen formula]. Supplementation was cow’s milk formula (CMF), partially
hydrolysed whey (pHF-W), extensively hydrolysed whey (eHF-W), or extensively hydrolysed casein formula (eHF-C); non-compliant with the milk
feeding recommendations in the intervention group (non-comp).
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Impact of early feeding on childhood eczema 629
diagnosis and all selected confounders was available from
the questionnaires (n = 2228).
For a separate analysis of children who were fully
breastfed for the first 4 months, three groups were
distinguished: one from the I group (I fb1) and two from
the NI group (with or without allergic predisposition: NI
FH1fb1 and NI FH fb1). Up to 6 years, 16% of the 2124
children dropped out: 12% in the I group and 19% in the
two NI fb1 groups.
All children from the four NI groups were used to
determine the natural course of eczema.
The baseline characteristics of the seven groups of
children fed formula showed some differences (Table 1a).
Compared with children from group I, children from the
NI groups had parents with a lower level of education. In
the NI FH group children were less often from Munich,
and had fewer mothers older than 30 years at delivery,
whereas in the NI FH1 group children had more older
mothers at delivery and more siblings.
We adjusted for these variables. Biparental allergy was
almost twice as high in the I group as the NI FH1 group.
The baseline characteristics of fully breastfed children
differed significantly from the children fed formula,
mainly with regard to education level (higher), smoking
habits (fewer), and age at delivery (older). However, the
differences in the baseline characteristics of the predis-
posed and not predisposed breastfed children (Table 1b)
were similar to the differences between the respective
groups of formula-fed children.
At the age of 6 years, 54% of the children whose parents
answered the questionnaire also accepted the invitation to
630 A. v. Berg et al

Table 1a. Characteristics of children fed formula

Positive (FH1) Negative (FH)

Family history
Yes (I) No (NI)
Intervention
Hydrolysed study formula

Formula CMF pHF-W eHF-W eHF-C Non-compliant NAw NAw

Male sex, N (%) 240 (55.4) 218 (52.3) 221 (54.3) 190 (50.5) 188 (56.4) 445 (53.7) 987 (51.9)
AMz in family
Single, N (%) 240 (72.9) 218 (69.3) 221 (68.3) 190 (69.5) 188 (69.2) 445 (82.9) 987 (0.0)
Biparental, N (%) 240 (27.1) 218 (30.7) 221 (31.7) 190 (30.5) 188 (30.9) 445 (17.1) 987 (0.0)
Eczema in family
Single, N (%) 234 (32.5) 217 (30.0) 218 (39.0) 186 (34.4) 184 (36.4) 433 (22.2) 987 (0.0)
Biparental, N (%) 234 (3.0) 217 (2.8) 218 (1.4) 186 (2.2) 184 (2.2) 433 (1.4) 987 (0.0)
Asthma in family
Single, N (%) 238 (28.6) 216 (31.0) 218 (24.8) 185 (29.2) 187 (30.0) 437 (19.9) 987 (0.0)
Biparental, N (%) 238 (1.3) 216 (1.4) 218 (3.2) 185 (2.2) 187 (1.1) 437 (0.7) 987 (0.0)
Hayfever in family
Single, N (%) 238 (63.9) 214 (62.6) 219 (64.4) 186 (66.7) 186 (58.1) 436 (55.3) 987 (0.0)
Biparental, N (%) 238 (14.3) 214 (15.9) 219 (15.1) 186 (11.8) 186 (17.2) 436 (8.5) 987 (0.0)
At least one parent of 239 (97.9) 217 (95.9) 221 (98.6) 190 (97.4) 188 (97.3) 418 (96.7) 903 (96.2)
German nationality,
N (%)
Parental education, N 240 218 221 190 187 444 984
o10 years, n (%) 31 (12.9) 15 (6.9) 22 (10.0) 15 (7.9) 22 (11.8) 80 (18.0) 199 (20.2)
10 years, n (%) 79 (32.9) 77 (35.3) 67 (30.3) 68 (35.8) 68 (36.4) 137 (30.9) 387 (39.3)
4 10 years, n (%) 130 (54.2) 126 (57.8) 132 (59.7) 107 (56.3) 97 (51.9) 227 (51.1) 398 (40.5)
Biological siblings at birth, 237 (43.0) 217 (33.2) 219 (41.1) 190 (36.8) 187 (46.5) 444 (56.3) 987 (45.3)
N (%)
Study region – Munich, 240 (48.3) 218 (47.7) 221 (50.2) 190 (42.1) 188 (50.5) 445 (49.4) 987 (29.6)
N (%)
Maternal smoking during 238 (22.3) 216 (20.8) 219 (21.5) 187 (14.4) 126 (26.2) 443 (16.9) 975 (20.6)
pregnancy, N (%)
Maternal smoking during the 238 (23.5) 216 (23.6) 219 (23.7) 187 (16.6) 126 (27.8) 444 (19.1) 973 (22.3)
child’s first 4 months,
N (%)
Smoking in the presence of 237 (15.6) 212 (13.2) 216 (14.8) 184 (15.8) 124 (12.1) 428 (11.5) 938 (14.1)
the child during the child’s
first 4 months, N (%)
Furry pets in home during 236 (24.6) 215 (18.1) 220 (19.1) 189 (21.2) 185 (20.5) 435 (17.7) 972 (21.1)
the child’s first year of life,
N (%)
Age of mother 430 at birth, 240 (47.1) 218 (47.7) 221 (50.7) 190 (50.0) 187 (41.7) 445 (57.8) 986 (43.8)
N (%)
Body mass index at birth 236 (12.6; 1.19) 214 (12.7; 1.3) 219 (12.9; 1.3) 189 (12.7; 1.2) 186 (12.6; 1.2) 440 (12.7; 1.3) 975 (12.6; 1.1)
[kg/m2], N (M; SD)‰
Children with (FH1) or without (FH) a family history of allergy from the intervention (I) and non-intervention (NI) groups were included.
w
Not applicable, Formula was parents’ own decision, no recommendations.
z
Defined as asthma, allergic rhinitis. atopic dermatitis, allergic urticaria, or food allergy in the mother, father, or biological sibling at birth.
‰
Number (N) and arithmetic mean (M) with standard deviation (SD).
CMF, cow’s milk formula; pHF-W, partially hydrolysed whey formula; eHF-W, extensively hydrolysed whey formula; eHF-C, extensively hydrolysed
casein formula; non-compliant, non-compliant with the milk feeding recommendations in the I group.

the study centres for a physical examination. The inci-
dence of doctor-diagnosed eczema was 1.3 times higher in
participating children, with differences between the NI
and I groups (1.8 vs. 0.9, respectively), but no differences
between the different NI or I groups.
Effect of additional intervention procedures
Apart from the formula, the intervention procedures
included recommendations for complementary feeding
and regular interviews and physical examinations at the

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 Impact of early feeding on childhood eczema 631

Table 1b. Characteristics of breastfed children

Positive (FH1) Negative (FH)

Family history
Intervention Yes (I) No (NI)
Male sex, N (%) 802 (49.5) 457 (49.5) 865 (50.4)
AMw in family
Single, N (%) 802 (66.6) 457 (81.2) 865 (0.0)
Biparental, N (%) 802 (33.4) 457 (18.8) 865 (0.0)
Eczema in family
Single, N (%) 797 (40.4) 448 (31.3) 865 (0.0)
Biparental, N (%) 797 (1.8) 448 (0.9) 865 (0.0)
Asthma in family
Single, N (%) 796 (25.6) 452 (15.5) 865 (0.0)
Biparental, N (%) 796 (1.1) 452 (0.0) 865 (0.0)
Hayfever in family
Single, N (%) 799 (60.3) 444 (57.9) 865 (0.0)
Biparental, N (%) 799 (19.9) 444 (11.0) 865 (0.0)
At least one parent of German nationality, N (%) 801 (98.3) 439 (97.9) 809 (96.0)
Parental education, N 801 457 863
o 10 years, n (%) 19 (2.4) 17 (3.7) 61 (7.1)
10 years, n (%) 152 (19.0) 113 (24.7) 231 (26.8)
4 10 years, n (%) 630 (78.7) 327 (71.6) 571 (66.2)
Biological siblings at birth, N (%) 801 (44.8) 457 (55.8) 865 (49.1)
Study region – Munich, N (%) 802 (58.2) 457 (71.6) 865 (45.7)
Maternal smoking during pregnancy, N (%) 797 (8.4) 455 (8.4) 859 (10.1)
Maternal smoking during the child’s first 4 months, N (%) 796 (6.9) 455 (5.1) 860 (5.2)
Smoking in the presence of the child during the child’s first 4 months, N (%) 781 (6.8) 448 (3.6) 837 (6.0)
Furry pets in the home during the child’s first year of life, N (%) 795 (12.3) 451 (15.3) 854 (15.2)
Age of mother 430 at birth, N (%) 802 (64.0) 457 (63.7) 865 (59.8)
Body mass index at birth (kg/m2), N(M;SD)z 795 (12.8; 1.2) 450 (12.5; 1.1) 855 (12.7; 1.1)
Children with (FH1) or without (FH) a family history of allergy from the intervention (I) and non-intervention (NI) groups were included.
w
Defined as asthma, allergic rhinitis. atopic dermatitis, allergic urticaria, or food allergy in the mother, father, or biological siblings at birth.
z
Number (N) and arithmetic mean (M) with standard deviation (SD).

study centres. Because the fully breastfed children from
group I participated in the intervention programme except
receiving formula, we determined the sole effect of the
intervention procedures by comparing the predisposed
fully breastfed children in the I and NI groups (I fb1 vs.
NI FH1fb1). The adjusted course of eczema in these two
groups was nearly identical (Fig. 2).
Effect of hydrolysed formulas on eczema
The course of eczema was compared in the formula-fed
children. The raw cumulative incidence of eczema in
predisposed children in the NI group was 31%, compared
with 17% in the reference group of non-predisposed
children (NI FH1fb vs. NI FH-fb, Table 2a). The
adjusted HR for predisposition was 2.1 [95% confidence
interval (CI) 1.6–2.7, Table 2b]. The cumulative incidence
of eczema in the I groups was scattered between (for
hydrolysates) or above (for CMF and non-compliance)
the two NI groups. Intervention with hydrolysates resulted
in eczema HRs of o 2, and even levelled off to 1.3 (95% CI
0.9–1.9) for children fed eHF-C (Table 2b). The cumulative
incidence of eczema symptoms was slightly higher than
the eczema diagnosis, but the relations between the
groups were very similar (Table 2). The course of eczema
from age 1 to 6 years in the seven groups of formula-fed
children is shown in Fig. 3. No deviations from the parallel
course between the groups were detected over time, which
was also confirmed by interaction tests in the Cox regres-
sion analysis.
An analysis of eczema observed on the day of examina-
tion at the age of 6 years largely confirms these results.
The point prevalence of the current eczema in formula-fed
children was 4.0% (N = 1000). In the logistic regression
analysis, using the same covariates as in the Cox regres-
sion analysis above, the eHF-C and pHF-W groups even
showed a reduced (OR 0.7, 95% CI: 0.1–3.3 and OR 0.8,
95% CI: 0.2–3.8, respectively) risk of current eczema
compared with the reference group (NI FH), although it
was not significant; but, it was significantly increased in
the CMF group (OR 2.9, 95% CI: 1.0–8.2).
Effect on different types of eczema
In the formula-fed groups, we distinguished five types of
eczema according to the time of onset and persistence (Fig. 4):

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632 A. v. Berg et al

 Early onset eczema (only in the first 2 years).

 Late onset eczema (only between 2 and 6 years of age).
 Persistent eczema until age 3 or 4 (eczema in the first 2
years and until age 3 or 4).
 Persistent eczema until age 5 or 6 (eczema in the first 2
years and until age 5 or 6).
 Intermittent eczema (all others).

In all groups, the proportion of both early and late onset

eczema was similar, suggesting that these types of eczema
are independent of the kind of formula. In contrast,
persistent eczema until age 5 or 6 was reduced by eHF-C
and pHF-W to the same level as the reference group (eHF-
C 5.0%, pHF-W 6.4%, NI FH 5.0%).

Fig. 2. Adjusted cumulative incidence of physician-diagnosed eczema
in fully breastfed children with its 95% confidence interval (dashed line).
Children with (FH1) and without (FH) a family history of atopy from
the intervention (I) group and the non-intervention (NI) group are
included. Adjusted for sex, body mass index at birth, parental educa-
tion, biological siblings at birth, study region, maternal smoking during
pregnancy and/or during the child’s first 4 months, smoking in the
presence of the child during the child’s first 4 months, furry pets in the
home during the child’s first year of life, and age of mother at birth
(430).
Discussion
The results clearly show that the partial and extensive
hydrolysed formulas used in this study compensate, up
until 6 years of age, to different degree for the enhanced
risk of eczema due to familial predisposition.
Children with a family history of allergy had a twofold
higher risk of eczema than children without a familial
predisposition. In contrast, in predisposed children, feed-
ing the formulas used in this study in the first 4 months of
life reduced, or even levelled, this enhanced risk. This
result prevailed until 6 years of age and was still visible

Table 2. Cumulative incidence of physician-diagnosed eczema and its symptoms

Negative
Family history (FH) Positive (FH1)

Intervention No (NI) Yes (I)

Hydrolysed study formula

Formula NAw NAw CMF pHF-W eHF-W eHF-C Non-compliant

(a) Description
Diagnosisz, N (%)‰ 970 (17.0) 438 (31.2) 238 (38.0) 217 (26.3) 221 (28.9) 188 (21.9) 185 (33.7)
Symptomz, N (%)‰ 970 (22.2) 435 (37.0) 239 (39.6) 218 (37.5) 220 (36.8) 188 (30.8) 186 (41.6)
(b) Results of Cox regression
Diagnosisz (N = 2228),
HR (95% CI)k 1.00 2.11 (1.64–2.72) 2.65 (2.00–3.51) 1.69 (1.22–2.33) 1.98 (1.45–2.69) 1.34 (0.93–1.94) 2.78 (1.96–3.94)
P-value o0.0001 o0.0001 0.002 o0.0001 0.118 o0.0001
Symptomz (N = 2229),
HR (95% CI)k 1.00 1.87 (1.49-2.35) 2.02 (1.55-2.63) 1.94 (1.47-2.55) 1.93 (1.47-2.54) 1.31 (0.95-1.80) 2.26 (1.62-3.13)
P-value o0.0001 o0.0001 o0.0001 o0.0001 0.098 o0.0001
Incidence was determined for the first to sixth year of life in non breast-fed children (a) and the comparison of nutritional intervention and no inter-
vention in children with a positive family history (b).
w
Not applicable (NA), Formula was parents’ own decision, no recommendations.
z
Defined as physician diagnosed.
‰
Number (N) and percentage (%).
z
Defined as itchy skin rash.
k
HR (95% CI), hazard ratio with 95% confidence interval adjusted for sex, body mass index at birth, parental education, biological siblings at birth, study
region, maternal smoking during pregnancy and/or during the child’s first 4 months, smoking in the presence of the child during the first year of life, age
of mother at birth (430), and sexlog (alter).

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for current eczema observed during the physical exam-
ination at 6 years. The latter might be slightly biased
because of selective participation; however, the risk re-
duction by eHF-C and pHF-W would still have been to the
Fig. 3. Adjusted cumulative incidence of physician-diagnosed eczema
in formula fed children. Children from the intervention (I) group and the
non-intervention (NI) group with (FH1) and without (FH) a family
history of allergy were included. CMF, cow’s milk formula; pHF-W,
partially hydrolysed whey formula; eHF-W, extensively hydrolysed whey
formula; eHF-C, extensively hydrolysed casein formula; non-compliant,
non-compliant with the milk feeding recommendations in the I group.
Adjusted for sex, body mass index at birth, parental education, biological
siblings at birth, study region, maternal smoking during pregnancy and/or
during the child’s first 4 months, smoking in the presence of the child
during the child’s first 4 months, furry pets in the home during the child’s
first year of life, and age of mother at birth (430).
Fig. 4. Persistent, early, and late onset eczema in formula-fed children. Children with (FH1) or without (FH) a family history of atopy (complete
participation was required over the entire study period) were included. CMF, cow’s milk formula; pHF-W, partially hydrolysed whey formula; eHF-W,
extensively hydrolysed whey formula; eHF-C, extensively hydrolysed casein formula; non-compliant, non-compliant with the milk feeding
recommendations in the I group; not applicable, formula was parents’ own decision, no recommendations.
c 2010
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Impact of early feeding on childhood eczema 633
level of the reference group, if all children with doctor-
diagnosed eczema, according to the questionnaire, had
participated and been diagnosed with eczema at the time
of examination (worst case, data calculated, not shown). A
similarity of effects between the results of the physical
examination and the questionnaire-based information has
already been shown for these children up to the age of 3
years [17].
Surprisingly, we observed a twofold increased risk of
eczema due to predisposition, irrespective of whether the
children were breastfed (Fig. 2) or supplemented with a
parent-chosen formula (Fig. 3). From previous studies,
including our own, breastfeeding is known to prevent
eczema in children at risk for allergy when performed for
at least 3 months (compared with o3 months of breast-
feeding [25] or when 4 months of breastfeeding was
compared with CMF supplementation [26, 27]). The reason
the present analysis did not find a difference between
breastfeeding and formula supplementation may be ex-
plained by the fact that parent-chosen formula could
include an hydrolysed formula; approximately 9% of the
parents chose an hydrolysate for supplementation. How-
ever, in the formula-supplemented children of the NI
group, we did not differentiate between regular and
hydrolysed formula; instead, we took the ‘parent-chosen
formula’ as an entity to compare the intervention formu-
las with real-life situations in children who need supple-
mentation with a formula for whatever reason.
When planning the study, we considered a difference in
cumulative incidence between 30% (in the CMF group)
and 20% in the groups fed with hydrolysates as relevant
and planned the study to be able to detect such a
634 A. v. Berg et al
difference with 80% power [19]. Compared with this
difference of 10% the difference in cumulative incidence
of doctor-diagnosed eczema between 21.9% in the eHF-C
group and 17.0% in the non-intervention group without
familial predisposition is clearly not relevant (and was not
significant after adjusting for confounding).
Compared with predisposed children without interven-
tion, the reduction of excess risk (HR-1) by eHF-C was
69%, which might be a biased estimate because biparental
allergy was lower in the NI group than the I group.
Recalculating the data after stratification for single or
biparental family history, the risk reduction for eczema by
eHF-C was present in both groups: higher in children with
a single family history and lower in children with bipar-
ental family history (excess risk reduction of 87% and
52%, respectively).
To our knowledge, the incidence of eczema following
an intervention programme with hydrolysates in children
at risk for allergy has never been compared with the
natural course of eczema. One reason may be that a direct
comparison between results from a randomized trial and
those from an observational trial is difficult. We are aware
of this problem in our study; however, comparability
depends on the type of comparison. Comparability within
the randomized trial is very good, and the validity of the
results is high. Non-randomized results can only be
compared epidemiologically, but they are valid if all
relevant covariates have been considered, which was in
fact the case. Families in the NI groups with and without
allergies differed, with regard to certain characteristics,
from families in group I (Table 1). We adjusted for all these
covariates except for predisposition (yes, no), which in our
context was not a confounder because the main aim of the
analysis was to find out whether predisposition can be
overcome by feeding hydrolysates.
We did not adjust for other dietary factors that may
have influenced the development of eczema, such as the
duration of breastfeeding before adding supplementary
formula, the diet of the breastfeeding mother, time and
kind of first solid food introduction, and food variation.
However, we think that not adjusting for these factors did
not introduce major bias because: (1) the time of formula
introduction and duration of breastfeeding was equally
distributed in the intervention study groups [19], (2)
maternal allergen-reduced diet during pregnancy and/or
lactation has not been consistently shown to be effica-
cious in preventing eczema [28, 29], and (3) a detailed
analysis of the use of eight food groups (48 single items)
for the first 12 months as reported by the GINI parents in
special questionnaires revealed a significant effect of
neither the time of first introduction nor the variation of
complementary foods on the incidence of eczema at 4
years [20].
We are aware that the comparison between the inter-
vention and non-intervention groups might yield biased
measures of the effect of the study formulas because the
intervention procedures without formulas might have had
an effect on the development of eczema. However, we did
not see any effect of the additional intervention proce-
dures in the children who were only breastfed (i.e.
complementary feeding). As shown in other studies [10],
breastfed children differ in regards to some lifestyle
factors, such as parental education and smoking. More
importantly, breastfeeding cannot be randomized for
ethical reasons, which also renders a direct comparison
between breastfed and non-breastfed children inappropri-
ate and is the reason for the separate analysis of breastfed
children in this study. The fact that the additional inter-
vention procedures did not have an effect in the fully
breastfed children allows to assume, that the observed effects
in the formula groups are likely related to the study formulas
and not to the additional intervention manoeuvres.
In the I fb groups, eczema persisting from infancy
beyond 3 or 4 years seems to be particularly influenced by
the kind of early feeding, as this type of eczema was
lowest in the eHF-C and pHF-W groups. This observation
is of importance because the persistence of eczema repre-
sents a major risk factor for the later development of
sensitization against inhalant allergens, asthma, and
hayfever [30]. Follow-up data from our study will show
whether the prevention of persistent eczema also prevents
sensitization to inhalant allergens and the development of
asthma and hayfever later in life.
Children from group I who were supplemented with
CMF or non-compliant with the feeding recommendations
had the highest risk for eczema until the age of 6 years.
This association should have consequences for pediatri-
cian recommendations to young mothers of high-risk
children: in the case of insufficient breastfeeding, parents
should follow the general feeding recommendations for
high-risk infants [4–6] and feed only hydrolysed formulas
with a clinically proven effect and, once chosen, stick to
this type of feeding for at least the first 4 months of life.
Although the overall drop-out rate between 1 and 6
years was with 23% not very high, the different drop-out
rates in the I and NI groups (20% and 24%, respectively)
constitute a limitation of this study. Less educated parents
and parents from Wesel participated less often up until the
sixth year of the child’s life. The reasons for non-partici-
pation were equally distributed in all groups. Therefore,
adjusting all HRs for parental education and study region
likely eliminated group-specific drop out. Participation
also did not depend on allergies in the family or the child.
Thus, any bias due to group-selective bias seems unlikely.
Another limitation of the study is the low participation
rate in the physical examination (54%) at 6 years. But
because the overall result was not significantly altered at
3 years by using a doctor’s diagnosis or alternative definitions
of eczema based on physical examination [17, 27] and the
logistic regression analysis of the point prevalence of
c 2010
 Blackwell Publishing Ltd, Clinical & Experimental Allergy, 40 : 627–636

current eczema at 6 years confirmed the results, we regard
our analysis based on the questionnaires to be valid.
The major strength of the GINIplus study, apart from its
large number of subjects and long-term follow-up until
the age of 6 years, is that it offers the unique possibility to
relate the effect of early nutritional intervention strategies
with hydrolysates in predisposed children to the natural
course of eczema.
Conclusion
The results of the study underline that familial risk for
eczema can be overcome by early intervention. Although
direct comparability is somewhat restricted, the data
demonstrate for the first time that the enhanced risk of
eczema in children with a familial predisposition for
allergy is substantially compensated for until the age of 6
years by feeding them certain hydrolysed cow’s milk-
based formulas instead of regular CMF during the first 4
months of life.
Acknowledgements
We thank the children and their families for their contin-
uous participation in the study, the GINIplus study group
for excellent work, and the sponsors for their financial
support. A. v. Berg had full access to all of the data in the
study and takes responsibility for the integrity of the data
and the accuracy of the data analysis. There is no conflict
of interest of all authors including financial interests and
relationships and affiliations relevant to the subject of this
manuscript.
Funding: The GINI Intervention study was funded for 3
years by grants from the Federal Ministry for Education,
Science, Research and Technology (Grant No. 01 EE 9401-
4). The 6-year follow-up of the GINIplus study was partly
funded by the Federal Ministry for Environment (IUF, FKZ
20462296).
Contributors: Principle investigator: D. Berdel; Study
co-ordinator: A. v. Berg; Protocol design: D. Berdel, H. E.
Wichmann, D. Reinhardt, C. P. Bauer, A. v. Berg, S.
Koletzko, A. Grübl; Follow-up of patients at 6 years: A. v.
Berg, C. Bollrath, A. Grübl, I. Brockow; Epidemiology and
statistics: H. -E. Wichmann, J. Heinrich, B. Filipiak-Pittr-
off, U. Krämer; Data management: J. Heinrich, U. Krämer,
E. Link; Manuscript writing: A. v. Berg, U. Krämer
The GINIplus study group until 6 years: Helmholtz
Zentrum München, Institute of Epidemiology, Neuherberg
(H. E. Wichmann, J. Heinrich, A. Schoetzau, M. Mosetter,
J. Schindler, A. Höhnke, K. Franke, B. Laubereau, U.
Gehring, S. Sausenthaler, A. Thaqi, A. Zirngibl, A. Zuta-
vern); Department of Pediatrics, Marien-Hospital, Wesel
(D. Berdel, A. von Berg, B. Filipiak-Pittroff, B. Albrecht, A.
Baumgart, C. Bollrath, S. Büttner, S. Diekamp, I. Groß, T.
Jakob, K. Klemke, S. Kurpiun, M. Möllemann, J. Neusüss,
c 2010
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Impact of early feeding on childhood eczema 635
A. Varhelyi); Department of Pediatrics, Ludwig Maximi-
lians University, Munich (S. Koletzko, D. Reinhard, H.
Weigand, I. Antonie, B. Bäumler-Merl, C. Tasch, R.
Göhlert, D. Mühlbauer, C. Sönnichsen, T. Sauerwald, A.
Kindermann, M. Waag, M. Koch); Department of Pedia-
trics, Technical University, Munich (C. P. Bauer, A. Grübl,
P. Bartels, I. Brockow, A. Fischer, U. Hoffmann, F.
Lötzbeyer, R. Mayrl, K. Negele, E. –M. Schill, B. Wolf);
IUF, Institut für Umweltmedizinische Forschung at the
Heinrich-Heine-University, Düsseldorf (U. Krämer, E.
Link, U. Ranft, R. Schins, D. Sugiri).
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