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O R I G I N A L A R T I C L E

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 yearsA. v. Berg1, U. Kramer2, E. Link2, C. Bollrath1, J. Heinrich3, I. Brockow3, S. Koletzko4, A. Grubl5, B. Filipiak-Pittroff1, H.-E. Wichmann3,7,C.-P. Bauer5,6, D. Reinhardt4, D. Berdel1 and the GINIplus study group1Marien-Hospital Wesel, Department of Paediatrics, Wesel, Germany, 2IUF Institut f ur Umweltmedizinische Forschung at the Heinrich-Heine-University, D usseldorf,

Germany, 3Helmholtz Zentrum M unchen, 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 and7IBE, Chair of Epidemiology, Ludwig-Maximilians University, Munich, Germany

Clinical &

ExperimentalAllergy

Correspondence:

A. v. Berg, Marien-Hospital-Wesel,

Department of Paediatrics, Pastor-

Janssen-Str. 8-38, D 46483 Wesel,

Germany. E-mail:

[email protected]

Cite this as: A. v. Berg, U. Kramer,

E. Link, C. Bollrath, J. Heinrich,

I. Brockow, S. Koletzko, A. Grubl,

B. Filipiak-Pittroff, H.-E. Wichmann,

C.-P. Bauer, D. Reinhardt, D. Berdel and

the GINIplus study group, Clinical&

Experimental Allergy, 2010 (40)627636.

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.

MethodThe 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 cows

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. Thecumulative 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) 1.62.7] than children without a familial predisposition.

The risk was smaller with nutritional intervention even levelling out to 1.3 (95% CI 0.91.9) 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, preventionSubmitted 31 July 2009; revised 19 October 2009; accepted 6 November 2009

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 cows milk

allergens, together with a family history of allergy are

major risk factors for allergy development later [13]. For

children with an allergic background, nutritional preven-

tion efforts have focused on avoiding early exposure to

intact milk proteins by reducing the milks antigenicity

Epidemiology of Allergic Disease

ECdoi: 10.1111/j.1365-2222.2009.03444.x Clinical & Experimental Allergy, 40, 627636

c 2010 Blackwell Publishing Ltd
mailto:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]

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through hydrolysis [46]. It has been shown that feeding

hydrolysed infant formulas in the first months of life can

reduce the risk of allergies [716]. 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 thefirst 4 months of life compared with regular cows 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 familyhistory 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 childs

health, nutrition, and living conditions, the parents keptweekly 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 thelocal 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 childs

first, second, third, fourth, and sixth birthdays to collect

information on the childs 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 thechilds first 4 months of life, smoking in the childs 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

c 2010 Blackwell Publishing Ltd, Clinical & Experimental Allergy, 40 : 627636

628 A. v. Berg et al

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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

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 2124children 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

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 cows 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).


Impact of early feeding on childhood eczema 629

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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

Table 1a. Characteristics of children fed formula

Family historyPositive (FH1) Negative (FH)

Intervention Yes (I) No (NI)

Hydrolysed study formula

Formula CMF pHF-W eHF-W eHF-C Non-compliant NA w

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

German nationality,

N(%)

239 (97.9) 217 (95.9) 221 (98.6) 190 (97.4) 188 (97.3) 418 (96.7) 903 (96.2)

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,

N(%)

237 (43.0) 217 (33.2) 219 (41.1) 190 (36.8) 187 (46.5) 444 (56.3) 987 (45.3)

Study region Munich,

N(%)

240 (48.3) 218 (47.7) 221 (50.2) 190 (42.1) 188 (50.5) 445 (49.4) 987 (29.6)

Maternal smoking during

pregnancy, N(%)

238 (22.3) 216 (20.8) 219 (21.5) 187 (14.4) 126 (26.2) 443 (16.9) 975 (20.6)

Maternal smoking during the

childs first 4 months,

N(%)

238 (23.5) 216 (23.6) 219 (23.7) 187 (16.6) 126 (27.8) 444 (19.1) 973 (22.3)

Smoking in the presence of

the child during the childs

first 4 months, N(%)

237 (15.6) 212 (13.2) 216 (14.8) 184 (15.8) 124 (12.1) 428 (11.5) 938 (14.1)

Furry pets in home during

the childs first year of life,

N(%)

236 (24.6) 215 (18.1) 220 (19.1) 189 (21.2) 185 (20.5) 435 (17.7) 972 (21.1)

Age of mother430 at birth,

N(%)

240 (47.1) 218 (47.7) 221 (50.7) 190 (50.0) 187 (41.7) 445 (57.8) 986 (43.8)

Body mass index at birth

[kg/m2], N (M; SD)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)

Children with (FH1) or without (FH) a family history of allergy from the intervention (I) and non-intervention (NI) groups were included.wNot applicable, Formula was parents own decision, no recommendations.zDefined 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, cows 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.



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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 inpredisposed 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) 1.62.7, 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 ofo 2, and even levelled off to 1.3 (95% CI

0.91.9) 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: 0.13.3 and OR 0.8,

95% CI: 0.23.8, 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: 1.08.2).

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):

Table 1b. Characteristics of breastfed children

Family historyPositive (FH1) Negative (FH)

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 childs first 4 months, N(%) 796 (6.9) 455 (5.1) 860 (5.2)

Smoking in the presence of the child during the childs first 4 months, N(%) 781 (6.8) 448 (3.6) 837 (6.0)

Furry pets in the home during the childs first year of life, N(%) 795 (12.3) 451 (15.3) 854 (15.2)

Age of mother430 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.wDefined as asthma, allergic rhinitis. atopic dermatitis, allergic urticaria, or food allergy in the mother, father, or biological siblings at birth.zNumber (N) and arithmetic mean (M) with standard deviation (SD).



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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%).

Discussion

The results clearly show that the partial and extensive

hydrolysed formulas used in this study compensate, upuntil 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

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 fromthe 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 childs first 4 months, smoking in the

presence of the child during the childs first 4 months, furry pets in the

home during the childs first year of life, and age of mother at birth

(430).

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

Family history

Negative

(FH) Positive (FH1)

Intervention No (NI) Yes (I)

Hydrolysed study formula

Formula NA w 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 (1.642.72) 2.65 (2.003.51) 1.69 (1.222.33) 1.98 (1.452.69) 1.34 (0.931.94) 2.78 (1.963.94)

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).wNot applicable (NA), Formula was parents own decision, no recommendations.zDefined as physician diagnosed.Number (N) and percentage (%).zDefined as itchy skin rash.kHR (95% CI), hazardratio with 95% confidenceintervaladjustedfor sex, body mass index at birth,parental education, biological siblings at birth,study

region, maternal smoking duringpregnancy and/orduring the childs first 4 months, smoking in thepresenceof thechild duringthe 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

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 3years [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

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, cows 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 childs first 4 months, smoking in the presence of the child

during the childs first 4 months, furry pets in the home during the childs

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, cows 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.



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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 ourcontext 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 lifestylefactors, 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 [46] 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 childs 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 doctors diagnosis or alternative definitions

of eczema based on physical examination [17, 27] and the

logistic regression analysis of the point prevalence of



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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 naturalcourse 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 cows 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. Grubl; Follow-up of patients at 6 years: A. v.

Berg, C. Bollrath, A. Grubl, I. Brockow; Epidemiology and

statistics: H. -E. Wichmann, J. Heinrich, B. Filipiak-Pittr-off, U. Kramer; Data management: J. Heinrich, U. Kramer,

E. Link; Manuscript writing: A. v. Berg, U. Kramer

The GINIplus study group until 6 years: Helmholtz

Zentrum Munchen, Institute of Epidemiology, Neuherberg

(H. E. Wichmann, J. Heinrich, A. Schoetzau, M. Mosetter,

J. Schindler, A. Hohnke, 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. Buttner, S. Diekamp, I. Gro, T.

Jakob, K. Klemke, S. Kurpiun, M. Mollemann, J. Neususs,

A. Varhelyi); Department of Pediatrics, Ludwig Maximi-

lians University, Munich (S. Koletzko, D. Reinhard, H.

Weigand, I. Antonie, B. Baumler-Merl, C. Tasch, R.

Gohlert, D. Muhlbauer, C. Sonnichsen, T. Sauerwald, A.

Kindermann, M. Waag, M. Koch); Department of Pedia-

trics, Technical University, Munich (C. P. Bauer, A. Grubl,

P. Bartels, I. Brockow, A. Fischer, U. Hoffmann, F.Lotzbeyer, R. Mayrl, K. Negele, E. M. Schill, B. Wolf);

IUF, Institut fur Umweltmedizinische Forschung at the

Heinrich-Heine-University, Dusseldorf (U. Kramer, E.

Link, U. Ranft, R. Schins, D. Sugiri).

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