1 Department of Epidemiology Research, Danish Epidemiology Science Centre, Statens Serum Institut, Copenhagen, Denmark.
2 Department of Dermatology, University of Copenhagen, Bispebjerg Hospital, Copenhagen, Denmark.
3 Department of Human Nutrition, Royal Veterinary and Agricultural University, Frederiksberg, Denmark.
4 Center for Allergy Research and Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Received for publication August 18, 2003; accepted for publication March 1, 2004.
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ABSTRACT |
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breast feeding; child; cohort studies; dermatitis, atopic; hypersensitivity; parents
Abbreviations: Abbreviations: CI, confidence interval; IRR, incidence rate ratio.
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INTRODUCTION |
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The aim of the present study was to examine the association of current breastfeeding and exclusive breastfeeding for 4 months with development of atopic dermatitis in offspring during the period up to 18 months of age for children with and without a parental history of allergy.
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MATERIALS AND METHODS |
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The Danish National Birth Cohort was approved by The Ethics Committees in Denmark and by the Data Protection Board. The steering committee for The Danish National Birth Cohort approved the use of data for the present study.
Breastfeeding
In interview 3, mothers were asked for how long they breastfed exclusively. Besides breast milk, only vitamins and water were allowed; thus, our definition differed slightly from the World Health Organization definition, which allows vitamins only. In addition, the mothers were asked 1) whether they were still breastfeeding and, if not, at what age they stopped; and 2) whether the child had received hydrolyzed formula. In interview 4, they were asked whether they breastfed after the child was 6 months of age and, if so, when they stopped.
Atopic dermatitis
In interview 4, the mothers were asked whether the child had ever had an itchy rash and, if so, about localization and age when affected. They were also asked whether the child had atopic dermatitis and, if so, whether a physician had verified the condition. Eighty-one women who answered that their child suffered from either an itchy rash or atopic dermatitis were invited to participate in a clinical examination by a dermatologist. Of these women, 60 took part in the study. The dermatologist determined whether the child had present atopic dermatitis, previous atopic dermatitis, another skin disease, or no skin disease. The combination of affirmative answers to 1) itchy rash or physician-verified atopic dermatitis and 2) recurrent rash or rash for at least 4 consecutive half-month periods and 3) localization in elbow creases, behind the knees, on the wrists/hands, or on the face or the presence of a generalized rash resulted in the highest sensitivity and specificity for atopic dermatitis as diagnosed by the dermatologist. The combination correctly identified 30 of the 37 children with atopic dermatitis and 21 of the 23 without atopic dermatitis according to the dermatologist, resulting in a positive predictive value of 94 percent (10). This combination of criteria was used in the present paper to define cases of atopic dermatitis. Age at onset was calculated as the middle day of the first half-month period in which the mother reported symptoms.
Background factors
Data on date of birth of the mother and the child, sex of the child, parental allergic diseases (asthma/hay fever/atopic dermatitis), atopic dermatitis in siblings, occupational class, educational level, smoking and consumption of alcohol, cohabitation, household income, pet keeping, living on a farm, number of siblings, use of day care, and clinically apparent infections in the first 6 months of life were obtained from the telephone interviews. The variable "infections" was designed as the sum of colds lasting more than 3 days, diarrhea lasting more than 3 days, and ear infections and pneumonia and was included as a time-varying variable, with age at onset of each infection as the middle day of the half-month period with symptoms. Data on birth characteristics were obtained from The Danish Medical Birth Registry.
Statistical analysis
The effect of breastfeeding, exclusive and nonexclusive, on atopic dermatitis was evaluated by calculating incidence rate ratios. These ratios were estimated by using Cox proportional hazards models with age as the underlying time. The effect of current breastfeeding was evaluated by including breastfeeding as a time-varying variable describing whether or not the child was breastfed. The effect of exclusive breastfeeding on atopic dermatitis was evaluated differently before and after 4 months of age. Until 4 months of age, the effect of exclusive breastfeeding on atopic dermatitis was evaluated as a time-varying covariate describing whether the child currently was being exclusively or not exclusively breastfed (i.e., receiving mixed feeding or not being breastfed at all). After 4 months of age, the effect of being exclusively or not exclusively breastfed at age 4 months on atopic dermatitis occurring between 4 and 18 months of age was evaluated as a time-fixed covariate. To evaluate potential confounders over all age groups, the two variables defining the effect of exclusive breastfeeding before 4 months of age (time-varying variable) and the effect of exclusive breastfeeding after 4 months of age (time-fixed covariate) were included in the same Cox model. In other words, in the model, the effect of exclusive breastfeeding was in relation to the first 4 months represented by the time-varying variable and after 4 months represented by the time-fixed variable. A similar approach was used in an additional analysis, with 6 months of age as the cutpoint instead of 4 months and with the time-fixed exclusive breastfeeding variable further divided according to duration.
For current breastfeeding and exclusive breastfeeding at age 4 months or older, the assumption of proportional hazards was evaluated by including an interaction term with age. No interactions were determined between either measure of breastfeeding and age. For other variables, the assumption was evaluated by using scaled Schoenfeld residuals. If divergence was indicated, the variable was included as a stratifying variable in the Cox regression. There was no indication that the results were biased because of divergence from the assumption of proportional hazards.
We assessed the confounding effect of all background variables on the incidence rate ratio for atopic dermatitis associated with exclusive breastfeeding for at least 4 months. The variables were ranked on the basis of the numerical change in the estimate, and a figure was created showing the impact on the estimate by adding the variables in decreasing order of numerical impact (figure 1). Variables that changed the estimate by more than 5 percent were retained and controlled for in all analyses. Potential effect modification by parental allergy on the effect of a breastfeeding variable on atopic dermatitis was investigated by testing the homogeneity of the effect of the breastfeeding variable for children with no, one, or two parents with allergies.
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RESULTS |
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The association between exclusive breastfeeding and atopic dermatitis in children of nonallergic parents was explored in several ways. When the children were grouped according to duration of exclusive breastfeeding, we found an increasing risk of atopic dermatitis with each month of exclusive breastfeeding (p for trend = 0.003). Dividing the children into those who were exclusively, partially, or not breastfed at 4 months of age revealed that the effects of exclusive breastfeeding (IRR = 1.43, 95 percent CI: 1.15, 1.78) and partial breastfeeding (IRR = 1.31, 95 percent CI: 0.92, 1.86) on atopic dermatitis were of the same magnitude compared with not being breastfed at that age. The estimate for any breastfeeding versus no breastfeeding at 4 months of age was 1.43 (95 percent CI: 1.15, 1.77). Excluding from the analysis all 292 users of hydrolyzed formula who had neither a parental history of allergy nor a sibling with atopic dermatitis did not reduce the associations between exclusive breastfeeding and atopic dermatitis after 4 months of age (IRR = 1.32, 95 percent CI: 1.09, 1.60). Finally, controlling for the number of early infections occurring before 6 months of age did not change the estimate (IRR = 1.33, 95 percent CI: 1.10, 1.62).
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DISCUSSION |
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The strengths of our study include the large sample size and the population-based cohort design. Thorough information on breastfeeding and symptoms of atopic dermatitis was obtained in early infancy by interviewers unaware of the associations to be studied. With no natural cutoff between children with and without atopic dermatitis, the choice of diagnostic criteria will always be a trade-off between sensitivity and specificity. We based the diagnosis of atopic dermatitis on a strict set of criteria to ensure a high positive predictive value, which was found to be 94 percent (10). The criteria are very similar to those used and thoroughly validated by others in clinical situations and, from a clinical perspective, are reasonable.
The observed cumulative prevalence of 11.5 percent tends to be lower than reported in other cohort studies of children in the same age group. However, some cohort studies were allergy-risk-enriched or created with the specific purpose of studying allergic diseases, thus potentially introducing selection bias among participants. Our result is in line with a recent community-based British study applying the United Kingdom working criteria plus a detailed clinical history of children aged 2 years (14 percent, 95 percent CI: 11 percent, 17 percent) (11). In the latter study, the cumulative prevalence of maternally reported physician-diagnosed eczema was much higher (31 percent), and almost half of the mothers (45 percent) reported that their child had ever had eczema. It was concluded that those children with maternally reported eczema or physician-diagnosed eczema are likely to include some with other eczema types or other rashes. When risk factors for disease are studied, a specific diagnosis is particularly important. Because of the large sample size, we were able to control for numerous potential confounders, which reduced the increased risk of atopic dermatitis associated with exclusive breastfeeding observed in the crude analysis. Importantly, we conducted the statistical analyses as survival analyses. Thus, breastfeeding only before the appearance of atopic dermatitis was considered in the analyses.
Weaknesses of the study design include the fact that the genetic predisposition of the children was assessed by self-reported parental allergy obtained from the mother. Mothers of children who develop allergic diseases may be more likely to report allergic diseases in the parents. However, the impact of this bias on the association between breastfeeding and atopic dermatitis is likely to be minor.
A protective effect of exclusive breastfeeding for at least 4 months was observed for children with a very strong family history of allergic diseases, supporting the conclusions of a recent meta-analysis (12) in which a preventive effect of breastfeeding was reported for children with a positive family history of allergic diseases (odds ratio = 0.58, 95 percent CI: 0.41, 0.92). However, the meta-analysis also reported a negative, nonsignificant effect of breastfeeding of 1.43 (95 percent CI: 0.72, 2.86) for children with no family history of allergy. Our findings could support such an increased risk of atopic dermatitis associated with breastfeeding in children of nonallergic parents. The increased risk seemed to be present no matter which type of allergic disease the parents suffered from.
If there was indeed a negative relation between breastfeeding and development of allergic diseases in children of nonallergic parents, one might expect to find a dose-response relation between duration of exclusive breastfeeding and disease. We found an increasing risk of atopic dermatitis with each month of exclusive breastfeeding. However, more than a trend, data indicated that the increased risk was limited to those who were breastfed, exclusively or nonexclusively, for 46 months (table 3). There was no dose-response effect in terms of exclusive breastfeeding for 6 months being worse than exclusive breastfeeding for 4 months or of exclusive breastfeeding being worse than partial breastfeeding compared with not being breastfed at all.
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It has been suggested that as hygienic conditions continue to improve, early infections may be increasingly important for the maturation of the immune system. Thus, breastfeeding may be a risk factor for allergic diseases because it prevents early infections (3). However, on the basis of our study, this possibility is unlikely to explain the increased risk of atopic dermatitis associated with exclusive breastfeeding in children of nonallergic parents, since the findings were similar after we controlled for the number of clinically apparent infections occurring before 6 months of age. Therefore, the effect of exclusive breastfeeding on atopic dermatitis seems unrelated to its well-known protective effects on clinically apparent infections.
While we could think of several reasons why the effect of breastfeeding might be biased in a negative direction, it is difficult to imagine any kind of bias that would lead to an overestimation of the beneficial effect of breastfeeding. Thus, we believe our data are incompatible with a large increased risk of atopic dermatitis associated with breastfeeding, and the beneficial effect of breastfeeding might be underestimated.
Four population-based studies of breastfeeding and atopic dermatitis have been published after the meta-analysis was published (12). Bergmann et al. (6) reported an overall increasing risk of atopic dermatitis with each month of any breastfeeding. In contrast, Kull et al. (13) found a small protective effect of exclusive breastfeeding. To our knowledge, only two studies have investigated the effect according to parental history of allergy. Miyake et al. (7) found an increased risk of atopic dermatitis associated with exclusive breastfeeding for at least 3 months on current atopic dermatitis in Japanese adolescents. In line with our observations, the negative effect was most pronounced in children of nonallergic parents. Because of a retrospective design, their results should be interpreted with caution. Likewise, Siltanen et al. (8) reported a significant increased risk of atopic dermatitis associated with exclusive breastfeeding for 3 months on atopic dermatitis at age 4 years in Finnish children with no parental history, whereas a protective effect was observed for children with a history of parental allergy. Thus, the meta-analysis and the subsequent studies support our findings of an increasingly beneficial effect of breastfeeding on atopic dermatitis associated with an increasingly strong parental history of allergic diseases.
In conclusion, we found no strong overall effect of either exclusive or partial breastfeeding on atopic dermatitis, although family history of allergy appeared to affect the risk. We recommend that future studies take into account the interaction between parental history of allergy and breastfeeding. The available data suggest that breastfeedingclearly worth recommending for many reasonsshould not be recommended as a possible means to protect against atopic dermatitis in the general population. However, a protective effect in children with a strong family history may be possible.
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ACKNOWLEDGMENTS |
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None of the sponsors influenced the design or conduct of the study, the interpretation of the data, or the preparation of the manuscript.
Dr. Lars Åke Hanson, Göteborg, Sweden, is gratefully acknowledged for fruitful discussions during preparation of the manuscript.
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NOTES |
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REFERENCES |
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