The multifactorial nature of food allergy
van Ginkel, Cornelia Doriene
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van Ginkel, C. D. (2018). The multifactorial nature of food allergy. Rijksuniversiteit Groningen.
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RETROSPECTIVE OBSERVATIONAL COHORT
STUDY REGARDING THE EFFECT OF
BREASTFEEDING ON CHALLENGE-PROVEN
FOOD ALLERGY
C. D. VAN GINKEL1 ,2, G. N. VAN DER MEULEN3, E. BAK1 ,2, B. M. J.
FLOKSTRA-DE BLOK2 ,4, B. J. KOLLEN4, G. H. KOPPELMAN1 ,2, A. E. J. DUBOIS1 ,2
1 Department of Pediatric Pulmonology and Pediatric Allergology, University Medical Center
Groningen, University of Groningen, Groningen, The Netherlands, 2 GRIAC Research Institute,
University Medical Center Groningen University of Groningen Groningen, The Netherlands, 3
Department of Pediatrics, Martini Hospital Groningen, Groningen, The Netherlands, 4
Department of General Practice, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
ABSTRACT
BACKGROUND/OBJECTIVES
Human breast milk is generally regarded as the best nutrition for infants in their first months of life. Whether breastfeeding has a protective effect on food allergy is a point of debate and the subject of this study.
SUBJECTS/METHODS
This retrospective study was conducted in 649 children who underwent a double-blind placebo-con-trolled food challenge (DBPCFC) as part of routine care in a tertiary care clinic. Food allergy was defined as having at least one positive DBPCFC to any food. The association between both “any” breastfeeding (yes/no) and its duration in months with food allergy was studied by logistic regression analysis with correction for confounding variables.
RESULTS
The prevalence of food allergy was 58.9% (n = 382). Of all subjects, 75.8% (n = 492) was breastfed and 24.2% (n = 157) bottle-fed. There was no significant association between food allergy and breastfeeding versus bottle-feeding after correction for the confounding effect of increased breastfeeding by atopic parents and a history of asthma in the child (OR = 1.24, 95% CI = 0.85–1.79, p = 0.27). However, in breastfed children, every additional month of breastfeeding lowered the risk for food allergy by ~4% (OR = 0.96, 95% CI = 0.93–0.99, p = 0.02). No confounders were identified in this association.
CONCLUSION
These results show for the first time that in children investigated for possible food allergy, every additional month of breastfeeding is associated with a lower risk of developing clinical food allergy as diagnosed by DBPCFC. However, overall, there was no association between the prevalence of food allergy and breastfeeding versus bottle-feeding in this tertiary care population.
INTRODUCTION
Human breast milk is regarded as conferring health, psychosocial, and developmental benefits on young infants and is recommended as the best food for their first months of life.1 A
preventive effect on the development of atopic diseases such as food allergy has been suggested although the evidence is weak and inconclusive.2-7 Food allergy is a potentially
lethal disease and its prevalence is increasing.8 In addition, it reduces quality of life in patients9
and is strongly heritable.9,10 Although international recommendations advise exclusive
breastfeeding for the first 4–6 months of life,1,11 the preventive effect of breastfeeding on
food allergy is still a point of debate. Two systematic reviews concluded that there is insufficient evidence to draw conclusions about the impact of breastfeeding on the prevention of food allergies in high-risk infants.2,12 A meta-analysis showed no protective effect of
breastfeeding on food allergy due to great heterogeneity of the reported studies.3 This
variability was potentially due to methodological differences including outcome definitions which in most cases did not include oral food challenges.3 Most studies used phenotypes such
as sensitization combined with clinical history,13 parentally reported physician-diagnosed food
allergy14,15 or open food challenges16,17 instead of the more timeconsuming double-blind
placebo-controlled food challenge(DBPCFC), the gold standard. It is widely established that these methods have higher false positive rates than DBPCFCs.
It was shown that “reverse causation” plays an important role in studies investigating the role of breastfeeding in allergic diseases since children with a family history of allergy or early atopic manifestations are more likely to be breastfed because of parental expectation that breastfeeding might reduce the risk of (food) allergy.18 This is a source of bias since these
genetically allergy-prone children will tend to be breastfed more often, causing an under-estimation of the beneficial role of breastfeeding. Additionally, a beneficial dose-response association has been reported for atopic dermatitis.19
Therefore, the aim of this study was to investigate the effect of both breastfeeding (versus bottle-feeding) and its duration on clinical food allergy and sensitization to foods. Food allergy was diagnosed as part of routine care by the gold standard, the double-blind placebo-controlled food challenge (DBPCFC) in a referral center for food allergy. By means of multivariate regression analysis, we corrected for confounders including age, parental atopy and atopic comorbidities reported both in history and specifically before the age of 1 year.
METHODS
STUDY DESIGN & SAMPLING
We retrospectively identified patients from the clinical database of the University Medical Center Groningen, the Netherlands, who underwent a DBPCFC for at least one of the five most frequently suspected allergenic foods (cow’s milk, hen’s egg, peanut, hazelnut or cashew nut) between January 2001 and May 2012 and had a conclusive outcome of this test, either positive or negative. These children were referred to us by primary and secondary healthcare providers
Chap
ter 5
ABSTRACT
BACKGROUND/OBJECTIVES
Human breast milk is generally regarded as the best nutrition for infants in their first months of life. Whether breastfeeding has a protective effect on food allergy is a point of debate and the subject of this study.
SUBJECTS/METHODS
This retrospective study was conducted in 649 children who underwent a double-blind placebo-con-trolled food challenge (DBPCFC) as part of routine care in a tertiary care clinic. Food allergy was defined as having at least one positive DBPCFC to any food. The association between both “any” breastfeeding (yes/no) and its duration in months with food allergy was studied by logistic regression analysis with correction for confounding variables.
RESULTS
The prevalence of food allergy was 58.9% (n = 382). Of all subjects, 75.8% (n = 492) was breastfed and 24.2% (n = 157) bottle-fed. There was no significant association between food allergy and breastfeeding versus bottle-feeding after correction for the confounding effect of increased breastfeeding by atopic parents and a history of asthma in the child (OR = 1.24, 95% CI = 0.85–1.79, p = 0.27). However, in breastfed children, every additional month of breastfeeding lowered the risk for food allergy by ~4% (OR = 0.96, 95% CI = 0.93–0.99, p = 0.02). No confounders were identified in this association.
CONCLUSION
These results show for the first time that in children investigated for possible food allergy, every additional month of breastfeeding is associated with a lower risk of developing clinical food allergy as diagnosed by DBPCFC. However, overall, there was no association between the prevalence of food allergy and breastfeeding versus bottle-feeding in this tertiary care population.
INTRODUCTION
Human breast milk is regarded as conferring health, psychosocial, and developmental benefits on young infants and is recommended as the best food for their first months of life.1 A
preventive effect on the development of atopic diseases such as food allergy has been suggested although the evidence is weak and inconclusive.2-7 Food allergy is a potentially
lethal disease and its prevalence is increasing.8 In addition, it reduces quality of life in patients9
and is strongly heritable.9,10 Although international recommendations advise exclusive
breastfeeding for the first 4–6 months of life,1,11 the preventive effect of breastfeeding on
food allergy is still a point of debate. Two systematic reviews concluded that there is insufficient evidence to draw conclusions about the impact of breastfeeding on the prevention of food allergies in high-risk infants.2,12 A meta-analysis showed no protective effect of
breastfeeding on food allergy due to great heterogeneity of the reported studies.3 This
variability was potentially due to methodological differences including outcome definitions which in most cases did not include oral food challenges.3 Most studies used phenotypes such
as sensitization combined with clinical history,13 parentally reported physician-diagnosed food
allergy14,15 or open food challenges16,17 instead of the more timeconsuming double-blind
placebo-controlled food challenge(DBPCFC), the gold standard. It is widely established that these methods have higher false positive rates than DBPCFCs.
It was shown that “reverse causation” plays an important role in studies investigating the role of breastfeeding in allergic diseases since children with a family history of allergy or early atopic manifestations are more likely to be breastfed because of parental expectation that breastfeeding might reduce the risk of (food) allergy.18 This is a source of bias since these
genetically allergy-prone children will tend to be breastfed more often, causing an under-estimation of the beneficial role of breastfeeding. Additionally, a beneficial dose-response association has been reported for atopic dermatitis.19
Therefore, the aim of this study was to investigate the effect of both breastfeeding (versus bottle-feeding) and its duration on clinical food allergy and sensitization to foods. Food allergy was diagnosed as part of routine care by the gold standard, the double-blind placebo-controlled food challenge (DBPCFC) in a referral center for food allergy. By means of multivariate regression analysis, we corrected for confounders including age, parental atopy and atopic comorbidities reported both in history and specifically before the age of 1 year.
METHODS
STUDY DESIGN & SAMPLING
We retrospectively identified patients from the clinical database of the University Medical Center Groningen, the Netherlands, who underwent a DBPCFC for at least one of the five most frequently suspected allergenic foods (cow’s milk, hen’s egg, peanut, hazelnut or cashew nut) between January 2001 and May 2012 and had a conclusive outcome of this test, either positive or negative. These children were referred to us by primary and secondary healthcare providers
because of suspected food allergy. This study was exempt from medical ethical approval, because DBPCFCs in children were performed as a routine diagnostic test.
DEPENDENT VARIABLES
The DBPCFCs were performed as previously described.20 Placebo and verum challenges were
performed in random order on separate days with at least a one-week interval. The test food was administered in increasing amounts of 6–8 doses at intervals of 30 min. The lowest and top dosages were 0.05–50.0 ml for cow’s milk, 8.0 mg to 23.0 g for hen’s egg, 3.8 mg to 3.8 g for defatted peanut flour and 7.1 mg to 7.1 g for hazelnut and cashew, concordant with the PRACTALL guidelines.21 Tests were assessed as positive when objective or repeated subjective
allergic symptoms occurred during the test on the active test food day but not on the placebo day. Children were classified as being food allergic if they had at least one positive DBPCFC to at least one food. Children were classified as not being food allergic if they had only negative DBPCFCs. In children having negative DBPCFCs, all suspected foods were excluded as a cause of previous reactions. Furthermore, negative DBPCFCs were confirmed by open food challenges and/or introduction of the food into the diet. If foods other than then the five most frequently suspected allergenic foods were tested by DBPCFC, these were taken into account for defining the variable food allergy in general. After an initial positive DBPCFC, repeated challenges were carried out years later to diagnose emergent tolerance to the food. In these cases, only the data on the first conclusive DBPCFC of the child was used. Specific IgE (sIgE) to culprit foods based on clinical suspicion of food allergy was measured as part of the normal clinical routine by CAP-FEIA (ImmunoDiagnostics, Uppsala, Sweden). A value ≥ 0.35 kU/l was considered as positive. Children were defined as sensitized to food(s) when they had at least one positive sIgE test to at least one food.
INDEPENDENT VARIABLES
Characteristics such as atopic (co)morbidities of the child and family were collected as part of the routine history. Parents accompanying their children were interviewed regarding these characteristics by a trained nurse before the start of food challenges to minimize recall bias and variables were directly entered in a clinical database. Among these questions there were two regarding breastfeeding. The first question was “Did you breastfeed your child?”. When the answer was positive, they were asked “For how many months did you breastfeed your child?”. Breastfeeding was studied both as a dichotomous variable (breastfed for any duration versus only bottle-fed) and as a continuous variable (duration of any breastfeeding in months). The latter includes both partial and exclusive breastfeeding and was used to study the dose-response effect of breastfeeding in which the dose was expressed as duration of breastfeeding in months. A parental atopic score was calculated from the number of atopic conditions (food allergy, eczema, rhinoconjunctivitis and asthma) in both parents, yielding a score ranging from 0 to 8, as described previously.22 This role of parental atopy was tested as a continuous and
dichotomous variable (0 versus ≥1 parental atopic condition).
STATISTICAL ANALYSIS
Analyses were performed using SPSS 22 (IBM, Chicago, USA) and a two-tailed significance level of p < 0.05 was used. Associations and dose-response effects were tested by Pearson Chi-square test and logistic regression analysis. The data was checked for the assumptions of logistic regression analysis such as independence of errors and linearity of independent variables. Age of the child during the first DBPCFC, parental atopic conditions and atopic comorbidities of the child (asthma, eczema, rhinoconjunctivitis) were tested for confounding. These atopic comorbidities of the child were tested both before the age of 1 year and “ever in history”, together with the variable “any atopic comorbidity before the age of 1 year”. These variables were considered to be confounders if they met the following criteria; 1. The variable changed the beta coefficient of the effect of breastfeeding on food allergy in the logistic regression by 10% or more23; 2. The variable was associated with the determinant
(breastfeeding); 3. The variable was a predictor of the outcome being measured (food allergy) and 4. The variable was a consequence of the determinant itself (breastfeeding).24
RESULTS
BASELINE CHARACTERISTICS
Of the 754 children who had a conclusive DBPCFC between January 2001 and May 2012, there was no data regarding breastfeeding available for 30 children. Of the remaining 724 we identified 649 (89.6%) children who had at least one DBPCFC for cow’s milk, hen’s egg, peanut, hazelnut or cashew nut. See Table 1 for the descriptive characteristics of the study population. The median age was 61 months (range 5–214, mean 75.6 months). The prevalence of food allergy was 58.9% (n = 382). Only 3 patients (0.4%) did not have any sIgE tests and were excluded from analyses regarding sensitization to foods. The prevalence of sensitization to food(s) was 83.4% (n = 541), based on a mean number of sIgE tests per child of 8.5 (range 1– 95, median 6). The most frequently challenged allergenic food was peanut (n = 334, 51.5%), followed by cow’s milk (n = 270, 41.6%), egg (n = 155, 23.9%), hazelnut (n = 112, 17.3%), and cashew (n = 82, 12.6%). Of these children, 75.8% (n = 492) was breastfed and 24.2 % (n = 157) bottle-fed. The mean duration of breast-feeding was 6.28 months, with a median of 6 months.
As shown in Table 1, a greater number of parental atopic conditions was associated with breastfeeding than with bottle-feeding (OR = 1.23, 95% CI = 1.08–1.41, p < 0.01). Furthermore, a greater number of parental atopic conditions was associated with an increased risk for food allergy in the child (OR = 1.63, 95% CI = 1.11–2.40, p = 0.01).
Of all children, 82.0% (n = 532) reported any atopic comorbidity (eczema, asthma and/or rhinoconjunctivitis) before the age of 1 year. The children with any atopic comorbidity before the age of 1 year were significantly more often food allergic (60.7% versus 50.4% respectively, p = 0.04). However, these children were not more often breastfed than children without any atopic morbidity (75.9% versus 75.2% respectively, p = 0.87).
Chap
ter 5
because of suspected food allergy. This study was exempt from medical ethical approval, because DBPCFCs in children were performed as a routine diagnostic test.
DEPENDENT VARIABLES
The DBPCFCs were performed as previously described.20 Placebo and verum challenges were
performed in random order on separate days with at least a one-week interval. The test food was administered in increasing amounts of 6–8 doses at intervals of 30 min. The lowest and top dosages were 0.05–50.0 ml for cow’s milk, 8.0 mg to 23.0 g for hen’s egg, 3.8 mg to 3.8 g for defatted peanut flour and 7.1 mg to 7.1 g for hazelnut and cashew, concordant with the PRACTALL guidelines.21 Tests were assessed as positive when objective or repeated subjective
allergic symptoms occurred during the test on the active test food day but not on the placebo day. Children were classified as being food allergic if they had at least one positive DBPCFC to at least one food. Children were classified as not being food allergic if they had only negative DBPCFCs. In children having negative DBPCFCs, all suspected foods were excluded as a cause of previous reactions. Furthermore, negative DBPCFCs were confirmed by open food challenges and/or introduction of the food into the diet. If foods other than then the five most frequently suspected allergenic foods were tested by DBPCFC, these were taken into account for defining the variable food allergy in general. After an initial positive DBPCFC, repeated challenges were carried out years later to diagnose emergent tolerance to the food. In these cases, only the data on the first conclusive DBPCFC of the child was used. Specific IgE (sIgE) to culprit foods based on clinical suspicion of food allergy was measured as part of the normal clinical routine by CAP-FEIA (ImmunoDiagnostics, Uppsala, Sweden). A value ≥ 0.35 kU/l was considered as positive. Children were defined as sensitized to food(s) when they had at least one positive sIgE test to at least one food.
INDEPENDENT VARIABLES
Characteristics such as atopic (co)morbidities of the child and family were collected as part of the routine history. Parents accompanying their children were interviewed regarding these characteristics by a trained nurse before the start of food challenges to minimize recall bias and variables were directly entered in a clinical database. Among these questions there were two regarding breastfeeding. The first question was “Did you breastfeed your child?”. When the answer was positive, they were asked “For how many months did you breastfeed your child?”. Breastfeeding was studied both as a dichotomous variable (breastfed for any duration versus only bottle-fed) and as a continuous variable (duration of any breastfeeding in months). The latter includes both partial and exclusive breastfeeding and was used to study the dose-response effect of breastfeeding in which the dose was expressed as duration of breastfeeding in months. A parental atopic score was calculated from the number of atopic conditions (food allergy, eczema, rhinoconjunctivitis and asthma) in both parents, yielding a score ranging from 0 to 8, as described previously.22 This role of parental atopy was tested as a continuous and
dichotomous variable (0 versus ≥1 parental atopic condition).
STATISTICAL ANALYSIS
Analyses were performed using SPSS 22 (IBM, Chicago, USA) and a two-tailed significance level of p < 0.05 was used. Associations and dose-response effects were tested by Pearson Chi-square test and logistic regression analysis. The data was checked for the assumptions of logistic regression analysis such as independence of errors and linearity of independent variables. Age of the child during the first DBPCFC, parental atopic conditions and atopic comorbidities of the child (asthma, eczema, rhinoconjunctivitis) were tested for confounding. These atopic comorbidities of the child were tested both before the age of 1 year and “ever in history”, together with the variable “any atopic comorbidity before the age of 1 year”. These variables were considered to be confounders if they met the following criteria; 1. The variable changed the beta coefficient of the effect of breastfeeding on food allergy in the logistic regression by 10% or more23; 2. The variable was associated with the determinant
(breastfeeding); 3. The variable was a predictor of the outcome being measured (food allergy) and 4. The variable was a consequence of the determinant itself (breastfeeding).24
RESULTS
BASELINE CHARACTERISTICS
Of the 754 children who had a conclusive DBPCFC between January 2001 and May 2012, there was no data regarding breastfeeding available for 30 children. Of the remaining 724 we identified 649 (89.6%) children who had at least one DBPCFC for cow’s milk, hen’s egg, peanut, hazelnut or cashew nut. See Table 1 for the descriptive characteristics of the study population. The median age was 61 months (range 5–214, mean 75.6 months). The prevalence of food allergy was 58.9% (n = 382). Only 3 patients (0.4%) did not have any sIgE tests and were excluded from analyses regarding sensitization to foods. The prevalence of sensitization to food(s) was 83.4% (n = 541), based on a mean number of sIgE tests per child of 8.5 (range 1– 95, median 6). The most frequently challenged allergenic food was peanut (n = 334, 51.5%), followed by cow’s milk (n = 270, 41.6%), egg (n = 155, 23.9%), hazelnut (n = 112, 17.3%), and cashew (n = 82, 12.6%). Of these children, 75.8% (n = 492) was breastfed and 24.2 % (n = 157) bottle-fed. The mean duration of breast-feeding was 6.28 months, with a median of 6 months.
As shown in Table 1, a greater number of parental atopic conditions was associated with breastfeeding than with bottle-feeding (OR = 1.23, 95% CI = 1.08–1.41, p < 0.01). Furthermore, a greater number of parental atopic conditions was associated with an increased risk for food allergy in the child (OR = 1.63, 95% CI = 1.11–2.40, p = 0.01).
Of all children, 82.0% (n = 532) reported any atopic comorbidity (eczema, asthma and/or rhinoconjunctivitis) before the age of 1 year. The children with any atopic comorbidity before the age of 1 year were significantly more often food allergic (60.7% versus 50.4% respectively, p = 0.04). However, these children were not more often breastfed than children without any atopic morbidity (75.9% versus 75.2% respectively, p = 0.87).
BREASTFEEDING VERSUS BOTTLE-FEEDING
There was no significant association between food allergy prevalence in breastfed children compared to bottle-fed children (unadjusted: OR = 1.21, 95% CI = 0.84–1.73, p = 0.31, adjusted for the confounding effect of both the parental atopic score and asthma: OR = 1.24, 95% CI = 0.85–1.79, p = 0.27). Furthermore, the prevalence of sensitization to foods did not differ significantly between breastfed and bottle-fed children (unadjusted: OR = 0.85, 95% CI = 0.52–1.41, p = 0.53, adjusted for the confounding effect of the parental atopic score, asthma reported in the history and in the first year of life and rhinitis and eczema in the first year of life: OR = 0.98, 95% CI = 0.58–1.68, p = 0.95). No other confounders or interactions were identified in both associations.
PROTECTIVE DOSE-RESPONSE RELATIONSHIP OF BREASTFEEDING
The prevalence of food allergy decreased with increasing duration of breastfeeding since 63.3%, 61.2%, 61.1%, and 54.3% of subjects within the 1st, 2nd, 3rd, and 4th quartile of the duration of breastfeeding, respectively, were clinically reactive to any food. In the 492 ever-breastfed children, increasing duration of breastfeeding (ranging from 0 to 42 months) showed a significant protective effect on food allergy, as shown in Fig. 1. Each additional month of breastfeeding was associated with a reduced risk of food allergy to any food by ~4% (n = 492, OR = 0.96, 95% CI 0.93–0.99, p = 0.02). The linear trend as shown in Fig. 1 was confirmed by a linear-by-linear association with a p-value of 0.015. No interactions or confounders were identified in this association. No association was found between the duration of breastfeeding and sensitization to food (unadjusted: OR = 1.01, 95% CI = 0.97– 1.06, p = 0.58, adjusted for the confounding effect of the parental atopic score and a history of asthma: OR = 1.02, 95% CI = 0.97–1.07, p = 0.49).
TABLE 1. DESCRIPTIVE STATISTICS OF THE BREAST-FED AND BOTTLE-FED CHILDREN.
M = missing, DBPCFC = double-blind placebo-controlled food challenge and SD= standard deviation. * Differs significantly between breast-fed and bottle-fed children. * p=0.05, **p<0.01 n=649 Breastfed n=492 (75.8%) Bottle-fed n=157 (24.2%) n (valid%) n (valid%) Food allergic 295 (60.0) 87 (55.4) Gender, male 296 (60.2) 103 (65.6) Age at first DBPCFC - mean (months) - range (months) - 1st quartile (5-28 months), n - 2nd quartile (29-60 months), n - 3rd quartile (61-111 months), n - 4th quartile (≥112 months), n 75.08 5-214 126 117 127 122 77.4 6-199 34 47 34 42 Breastfeeding (months) - mean (SD) - median - range - 1st quartile (1-2 months), n - 2nd quartile (3-5 months), n - 3rd quartile (6-8 months), n - 4th quartile (≥9 months), n 6.28 (5.21) 6.00 <1-42 118 121 126 127 Sensitized to a food 407 (83.2) M: 3 134 (85.4) Diagnosed food allergy,
n positive / n tested in DBPCFC (%) Peanut Cow’s milk Hen’s Egg Hazelnut Cashew 139/248 (56.0) 102/211 (48.3)* 50/118 (42.4) 34/85 (40.0) 48/66 (72.7) 45/86 (52.3) 20/59 (33.9)* 19/37 (51.4) 13/27 (48.1) 12/16 (75.0) Atopic comorbidities,
Asthma (ever in history) - before the age of 12 months Eczema (ever in history) - before the age of 12 months Rhinoconjunctivitis (ever in history) - before the age of 12 months Any of above (ever in history) - before the age of 12 months
213 (43.3) 65 (13.2) 425 (86.4) 398 (80.9) 171 (34.8) 21 (4.3) 434 (91.8) 404 (82.1) 79 (50.3) 26 (16.6) 134 (85.4) 122 (77.7) 53 (33.8) 9 (5.7) 139 (91.4) 128 (81.5) Number of atopic conditions of both parents:
- Mean(SD) - Range
- Parents with any atopic condition
1.89(0,07)** 0-8 405(82.3)** 1.50(0,11)** 0-5 114 (72.6)**
Chap
ter 5
BREASTFEEDING VERSUS BOTTLE-FEEDING
There was no significant association between food allergy prevalence in breastfed children compared to bottle-fed children (unadjusted: OR = 1.21, 95% CI = 0.84–1.73, p = 0.31, adjusted for the confounding effect of both the parental atopic score and asthma: OR = 1.24, 95% CI = 0.85–1.79, p = 0.27). Furthermore, the prevalence of sensitization to foods did not differ significantly between breastfed and bottle-fed children (unadjusted: OR = 0.85, 95% CI = 0.52–1.41, p = 0.53, adjusted for the confounding effect of the parental atopic score, asthma reported in the history and in the first year of life and rhinitis and eczema in the first year of life: OR = 0.98, 95% CI = 0.58–1.68, p = 0.95). No other confounders or interactions were identified in both associations.
PROTECTIVE DOSE-RESPONSE RELATIONSHIP OF BREASTFEEDING
The prevalence of food allergy decreased with increasing duration of breastfeeding since 63.3%, 61.2%, 61.1%, and 54.3% of subjects within the 1st, 2nd, 3rd, and 4th quartile of the duration of breastfeeding, respectively, were clinically reactive to any food. In the 492 ever-breastfed children, increasing duration of breastfeeding (ranging from 0 to 42 months) showed a significant protective effect on food allergy, as shown in Fig. 1. Each additional month of breastfeeding was associated with a reduced risk of food allergy to any food by ~4% (n = 492, OR = 0.96, 95% CI 0.93–0.99, p = 0.02). The linear trend as shown in Fig. 1 was confirmed by a linear-by-linear association with a p-value of 0.015. No interactions or confounders were identified in this association. No association was found between the duration of breastfeeding and sensitization to food (unadjusted: OR = 1.01, 95% CI = 0.97– 1.06, p = 0.58, adjusted for the confounding effect of the parental atopic score and a history of asthma: OR = 1.02, 95% CI = 0.97–1.07, p = 0.49).
TABLE 1. DESCRIPTIVE STATISTICS OF THE BREAST-FED AND BOTTLE-FED CHILDREN.
M = missing, DBPCFC = double-blind placebo-controlled food challenge and SD= standard deviation. * Differs significantly between breast-fed and bottle-fed children. * p=0.05, **p<0.01 n=649 Breastfed n=492 (75.8%) Bottle-fed n=157 (24.2%) n (valid%) n (valid%) Food allergic 295 (60.0) 87 (55.4) Gender, male 296 (60.2) 103 (65.6) Age at first DBPCFC - mean (months) - range (months) - 1st quartile (5-28 months), n - 2nd quartile (29-60 months), n - 3rd quartile (61-111 months), n - 4th quartile (≥112 months), n 75.08 5-214 126 117 127 122 77.4 6-199 34 47 34 42 Breastfeeding (months) - mean (SD) - median - range - 1st quartile (1-2 months), n - 2nd quartile (3-5 months), n - 3rd quartile (6-8 months), n - 4th quartile (≥9 months), n 6.28 (5.21) 6.00 <1-42 118 121 126 127 Sensitized to a food 407 (83.2) M: 3 134 (85.4) Diagnosed food allergy,
n positive / n tested in DBPCFC (%) Peanut Cow’s milk Hen’s Egg Hazelnut Cashew 139/248 (56.0) 102/211 (48.3)* 50/118 (42.4) 34/85 (40.0) 48/66 (72.7) 45/86 (52.3) 20/59 (33.9)* 19/37 (51.4) 13/27 (48.1) 12/16 (75.0) Atopic comorbidities,
Asthma (ever in history) - before the age of 12 months Eczema (ever in history) - before the age of 12 months Rhinoconjunctivitis (ever in history) - before the age of 12 months Any of above (ever in history) - before the age of 12 months
213 (43.3) 65 (13.2) 425 (86.4) 398 (80.9) 171 (34.8) 21 (4.3) 434 (91.8) 404 (82.1) 79 (50.3) 26 (16.6) 134 (85.4) 122 (77.7) 53 (33.8) 9 (5.7) 139 (91.4) 128 (81.5) Number of atopic conditions of both parents:
- Mean(SD) - Range
- Parents with any atopic condition
1.89(0,07)** 0-8 405(82.3)** 1.50(0,11)** 0-5 114 (72.6)**
FIG. 1 THE PREVALENCE OF DBPCFC CONFIRMED FOOD ALLERGY IN BREASTFED CHILDREN BY DURATION OF BREASTFEEDING IN MONTHS.
The X-axis is adapted to improve clarity In logistic regression analysis, each additional month of breastfeeding was associated with a reduced risk of food allergy to any food of ~4% (n = 492, OR = 0.96, 95% CI = 0.93–0.99, p = 0.02). No confounders were identified in this association
BREASTFEEDING AND SPECIFIC ALLERGIES
As shown in Table 1, of the 270 children tested for cow’s milk allergy, 211 were breastfed. Of these, 102 were allergic to cow’s milk, as compared to 20 of the 59 bottle-fed children (48.3% versus 33.9%, p = 0.05). This association was confounded by any parental atopy and asthma reported in the history of the child (unadjusted: OR = 1.83, 95% CI = 1.00–3.34, p = 0.05, adjusted: OR = 1.91, 95% CI = 1.01–3.62, p = 0.05). As indicated in Table 1, there was no significant difference in prevalence of peanut, hen’s egg, hazelnut and cashew allergy between breastfed and bottle-fed children, even after correction for confounding factors (data not shown). There was a significant association between duration of breastfeeding and hen’s egg allergy which was not confounded by any of the tested variables (OR = 0.91, 95% CI = 0.83–0.99, p = 0.03). This was not seen for any of the subanalyses of other foods (data not shown).
DISCUSSION
MAIN FINDINGSThis is the first study showing that in children investigated for possible food allergy, every additional month of breastfeeding is associated with a lower risk of developing food allergy as diagnosed by DBPCFC. Since there were no confounders identified in this association, including parental atopic conditions, this protective effect is relevant for children both with and without a positive family history for atopy.
There was no significant association between breast-feeding (versus bottle-feeding) and food allergy, with and without correction for the confounding effect of increased breastfeeding by atopic parents. However we confirm previous results regarding reverse causation18, since atopic parents indeed breast-fed their children more and their children are
56%66%60%58%70%59%60%61%64%58%67%64%47%70%44%33%54% 100%100% 25% 0% 0% 0% 0% 50% 100% <1, n =9 1, n= 74 2, n= 35 3, n= 62 4, n= 30 5, n= 29 6, n= 73 7, n= 28 8, n= 25 9, n= 36 10, n= 15 11, n= 11 12, n= 17 13, n= 10 14, n= 9 15, n= 3 18, n= 13 19, n= 1 20, n= 1 24, n= 8 25, n= 1 30, n= 1 42, n= 1
Duration of breastfeeding in months
% DBPCFC confirmed food allergy
Trend line (food allergy)
at higher risk for food allergy. Furthermore, no association was found between breastfeeding and sensitization for foods. Other studies are contradictory or inconclusive on this subject, with a decrease25, increase26 and lack of association16 having all been reported. Interestingly,
another study reported a relationship between breastfeeding and food sensitization which varied significantly by individual genotype27. Future studies are indicated to study the
interaction between (duration of) breastfeeding and genetic markers for clinical food allergy. SUBANALYSES
When examining the five most frequently tested allergenic foods in subanalyses, only the prevalence of cow’s milk allergy is significantly higher among breastfed children. This association was confounded by asthma in the child and parental atopic conditions, indicating that reverse causation by parental atopic conditions is at least partially responsible for the higher prevalence of cow’s milk allergy in breastfed children. In the subanalyses, the association between a longer duration of breastfeeding and a lower risk of food allergy was only significantly replicated in children tested for hen’s egg allergy. For some foods, this might be due to power loss. Alternatively, the protective effect of breast milk might be more pronounced with regards to hen’s egg allergy.
COMPARISON WITH LITERATURE
The prevalence of breastfeeding is higher in this study population compared to the prevalence of intention to breastfeed as reported in the KOALA Birth Cohort (75.8% versus 69.6%, respectively)28. This is likely to be due to the higher prevalence or parental atopy in this study
population (79.9% versus 62.1%) and we report that parents with a greater number of atopic conditions breastfed their children more often. Within a Dutch population-based study, 92.1% of the children (n = 5365) was ever breastfed although this was potentially due to selection bias15. The average duration of breastfeeding was long when compared to other studies.15, 25, 26, 29 Furthermore, the age of the children (mean 75.6 months) is higher than that seen in other
cohort studies studying breastfeeding.13, 14, 16, 30 Several studies compared children who were
exclusively breastfed for over 4 months with breastfeeding for a shorter period or bottle-feeding and these studies did not find an association between breastbottle-feeding and food allergy.13, 14, 16 A recent Dutch population-based prospective cohort study found no association
between breastfeeding and allergic sensitization, physician-diagnosed allergy, or a combination of these outcomes at the age of 10 years. They studied the duration of breastfeeding categorized (<2, 2–4, 4–6, and ≥6 months). We now show in children seen at a tertiary care center, that breastfeeding has a protective effect when taking the full range of duration of breastfeeding into account.
STRENGTHS AND LIMITATIONS
To our knowledge, this is the first study on the association between breastfeeding and food allergy in children tested by a DBPCFC, the gold standard to diagnose food allergy.21 This test
Chap
ter 5
FIG. 1 THE PREVALENCE OF DBPCFC CONFIRMED FOOD ALLERGY IN BREASTFED CHILDREN BY DURATION OF BREASTFEEDING IN MONTHS.
The X-axis is adapted to improve clarity In logistic regression analysis, each additional month of breastfeeding was associated with a reduced risk of food allergy to any food of ~4% (n = 492, OR = 0.96, 95% CI = 0.93–0.99, p = 0.02). No confounders were identified in this association
BREASTFEEDING AND SPECIFIC ALLERGIES
As shown in Table 1, of the 270 children tested for cow’s milk allergy, 211 were breastfed. Of these, 102 were allergic to cow’s milk, as compared to 20 of the 59 bottle-fed children (48.3% versus 33.9%, p = 0.05). This association was confounded by any parental atopy and asthma reported in the history of the child (unadjusted: OR = 1.83, 95% CI = 1.00–3.34, p = 0.05, adjusted: OR = 1.91, 95% CI = 1.01–3.62, p = 0.05). As indicated in Table 1, there was no significant difference in prevalence of peanut, hen’s egg, hazelnut and cashew allergy between breastfed and bottle-fed children, even after correction for confounding factors (data not shown). There was a significant association between duration of breastfeeding and hen’s egg allergy which was not confounded by any of the tested variables (OR = 0.91, 95% CI = 0.83–0.99, p = 0.03). This was not seen for any of the subanalyses of other foods (data not shown).
DISCUSSION
MAIN FINDINGSThis is the first study showing that in children investigated for possible food allergy, every additional month of breastfeeding is associated with a lower risk of developing food allergy as diagnosed by DBPCFC. Since there were no confounders identified in this association, including parental atopic conditions, this protective effect is relevant for children both with and without a positive family history for atopy.
There was no significant association between breast-feeding (versus bottle-feeding) and food allergy, with and without correction for the confounding effect of increased breastfeeding by atopic parents. However we confirm previous results regarding reverse causation18, since atopic parents indeed breast-fed their children more and their children are
56%66%60%58%70%59%60%61%64%58%67%64%47%70%44%33%54% 100%100% 25% 0% 0% 0% 0% 50% 100% <1, n =9 1, n= 74 2, n= 35 3, n= 62 4, n= 30 5, n= 29 6, n= 73 7, n= 28 8, n= 25 9, n= 36 10, n= 15 11, n= 11 12, n= 17 13, n= 10 14, n= 9 15, n= 3 18, n= 13 19, n= 1 20, n= 1 24, n= 8 25, n= 1 30, n= 1 42, n= 1
Duration of breastfeeding in months
% DBPCFC confirmed food allergy
Trend line (food allergy)
at higher risk for food allergy. Furthermore, no association was found between breastfeeding and sensitization for foods. Other studies are contradictory or inconclusive on this subject, with a decrease25, increase26 and lack of association16 having all been reported. Interestingly,
another study reported a relationship between breastfeeding and food sensitization which varied significantly by individual genotype27. Future studies are indicated to study the
interaction between (duration of) breastfeeding and genetic markers for clinical food allergy. SUBANALYSES
When examining the five most frequently tested allergenic foods in subanalyses, only the prevalence of cow’s milk allergy is significantly higher among breastfed children. This association was confounded by asthma in the child and parental atopic conditions, indicating that reverse causation by parental atopic conditions is at least partially responsible for the higher prevalence of cow’s milk allergy in breastfed children. In the subanalyses, the association between a longer duration of breastfeeding and a lower risk of food allergy was only significantly replicated in children tested for hen’s egg allergy. For some foods, this might be due to power loss. Alternatively, the protective effect of breast milk might be more pronounced with regards to hen’s egg allergy.
COMPARISON WITH LITERATURE
The prevalence of breastfeeding is higher in this study population compared to the prevalence of intention to breastfeed as reported in the KOALA Birth Cohort (75.8% versus 69.6%, respectively)28. This is likely to be due to the higher prevalence or parental atopy in this study
population (79.9% versus 62.1%) and we report that parents with a greater number of atopic conditions breastfed their children more often. Within a Dutch population-based study, 92.1% of the children (n = 5365) was ever breastfed although this was potentially due to selection bias15. The average duration of breastfeeding was long when compared to other studies.15, 25, 26, 29 Furthermore, the age of the children (mean 75.6 months) is higher than that seen in other
cohort studies studying breastfeeding.13, 14, 16, 30 Several studies compared children who were
exclusively breastfed for over 4 months with breastfeeding for a shorter period or bottle-feeding and these studies did not find an association between breastbottle-feeding and food allergy.13, 14, 16 A recent Dutch population-based prospective cohort study found no association
between breastfeeding and allergic sensitization, physician-diagnosed allergy, or a combination of these outcomes at the age of 10 years. They studied the duration of breastfeeding categorized (<2, 2–4, 4–6, and ≥6 months). We now show in children seen at a tertiary care center, that breastfeeding has a protective effect when taking the full range of duration of breastfeeding into account.
STRENGTHS AND LIMITATIONS
To our knowledge, this is the first study on the association between breastfeeding and food allergy in children tested by a DBPCFC, the gold standard to diagnose food allergy.21 This test
breastfeeding studies either do not make use of oral challenges or make use of open food challenges.16, 17 In young children, false positive rates of the latter may be as high as 70%.31, 32
In this study we minimized recall bias by interviewing parents of patients regarding their breast or bottle-feeding history before undergoing the DBPCFC. Histories were thus obtained before the challenge test outcomes were known. Any incorrect recall of breastfeeding (duration) is therefore likely to be randomly distributed among DBPCFC positive and negative children. Furthermore, it was previously reported that asking a mother 10 years later how long she breast-fed her child is highly reliable.33 Over 75% of the children in our
study were younger than 10 years when having their first DBPCFC. This study population consists of children who were referred to a tertiary care clinic with suspected food allergy and had a DBPCFC as part of routine care. Therefore, the prevalence of food allergy and sensitization to food was high. It is therefore difficult to compare these results with the general population. A limitation of the study is the lack of knowledge on the mode of delivery, social economic status, diet of the mother during breastfeeding, the exclusivity of the breastfeeding, the type of formula used when bottle-feeding and the timing of introduction of solid foods.
Due to ethical and methodological limitations, a study on breastfeeding using a randomized controlled trial is complicated. The well-known center-randomized breastfeeding promotion intervention study by Kramer et al.34,35 did not study the effect of breastfeeding on
food allergy. Therefore, the data presented in this study may well be the best evidence possible for the protective effect of breastfeeding on food allergy in a high risk population such as ours.
CONCLUSIONS
These results indicate for the first time that in children of a tertiary care clinic investigated for possible food allergy, every additional month of breastfeeding is associated with a lower risk of developing clinical food allergy as diagnosed by the gold standard, the double-blind placebo-controlled food challenge. However, overall, there was no association between the prevalence of food allergy and breastfeeding versus bottle-feeding when breastfeeding of all durations was considered. Thus, this study supports the general recommendation of breastfeeding, and specifically suggests that preventive effects with respect to food allergy may be achieved if breastfeeding is prolonged since every additional month of breastfeeding was associated with a lower risk of developing food allergy.
REFERENCES
1. Victora CG, Bahl R, Barros AJD, Franca GVA, Horton S, Kra-sevec J, et al. Breastfeeding in the 21st century: Epidemiology, mechanisms, and lifelong effect. Lancet. 2016;387:475–90. 2. Heinrich J. Modulation of allergy risk by
breast feeding. Curr Opin Clin Nutr Metab Care. 2017;20:217–21.
3. Lodge CJ, Tan DJ, Lau M, Dai X, Tham R, Lowe AJ, et al. Breastfeeding and asthma and allergies: a systematic review and meta-analysis. Acta Paediatr Suppl. 2015;104:38– 53.
4. Greer FR, Sicherer SH, Burks AW. Effects of early nutritional interventions on the development of atopic disease in infants and children: the role of maternal dietary restriction, breastfeeding, timing of introduction of complementary foods, and hydrolyzed formulas. Pediatrics.
2008;121:183–91.
5. Muraro A, Dreborg S, Halken S, Høst A, Niggemann B, Aalberse R. Dietary prevention of allergic diseases in infants and small children Part III: critical review of published peer-reviewed observational and
interventional studies and final recommenda-tions *. Pediatr Allergy Immunol. 2004;15:291–307.
6. van Odijk J, Kull I, Borres MP, Brandtzaeg P, Edberg U, Hanson LA, et al. Breastfeeding and allergic disease: a multidisciplinary review of the literature (1966–2001) on the mode of early feeding in infancy and its impact on later atopic manifestations. Allergy. 2003;58:833–43.
7. Høst A, Halken S, Muraro A, Dreborg S, Niggemann B, Aalberse R, et al. Dietary prevention of allergic diseases in infants and small children. Pediatr Allergy Immunol. 2008;19:1–4.
8. Branum AM, Lukacs SL. Food allergy among children in the United States. Pediatrics. 2009;124:1549–55.
9. Flokstra-de Blok BMJ, Dubois AEJ, Vlieg-Boerstra BJ, Oude Elberink JNG, Raat H,
DunnGalvin A, et al. Health-related quality of life of food allergic patients: comparison with the general population and other diseases. Allergy. 2010;65:238–44.
10. Sicherer SH, Furlong TJ, Maes HH, Desnick RJ, Sampson HA, Gelb BD. Genetics of peanut allergy: a twin study. J Allergy Clin Immunol. 2000;106:53–6. 1 Pt 1
11. Muraro A, Halken S, Arshad SH, Beyer K, AEJ Dubois, du Toit G, et al. EAACI Food Allergy and Anaphylaxis Guidelines. Pri-mary prevention of food allergy. Allergy. 2014;69:590–601.
12. de Silva D, Geromi M, Halken S, Host A, Panesar SS, Muraro A, et al. Primary prevention of food allergy in children and adults: systematic review. Allergy. 2014;69:581–9.
13. McGowan EC, Bloomberg GR, Gergen PJ, Visness CM, Jaffee KF, Sandel M, et al. Influence of early-life exposures on food sensitization and food allergy in an inner-city birth cohort. J Allergy Clin Immunol. 2014;135:178.
14. Luccioli S, Zhang Y, Verrill L, Ramos-Valle M, Kwegyir-Afful E. Infant feeding practices and reported food allergies at 6 years of age. Pediatrics. 2014;134:S21–8.
15. Elbert N, van Meel E, den Dekker H, de Jong N, Nijsten T, Jaddoe V et al. Duration and exclusiveness of breastfeeding and risk of childhood atopic disorders. Allergy Eur J Allergy Clin Immunol. 2017;72:1936–43. 16. Venter C, Pereira B, Voigt K, Grundy J,
Clayton CB, Higgins B, et al. Factors associated with maternal dietary intake, feeding and weaning practices, and the development of food hypersensitivity in the infant. Pediatr Allergy Immunol.
2009;20:320–7.
17. Koplin JJ, Osborne NJ, Wake M, Martin PE, Gurrin LC, Robinson MN, et al. Can early introduction of egg prevent egg allergy in infants? A population-based study. J Allergy Clin Immunol. 2010;126:807–13.
Chap
ter 5
breastfeeding studies either do not make use of oral challenges or make use of open food challenges.16, 17 In young children, false positive rates of the latter may be as high as 70%.31, 32
In this study we minimized recall bias by interviewing parents of patients regarding their breast or bottle-feeding history before undergoing the DBPCFC. Histories were thus obtained before the challenge test outcomes were known. Any incorrect recall of breastfeeding (duration) is therefore likely to be randomly distributed among DBPCFC positive and negative children. Furthermore, it was previously reported that asking a mother 10 years later how long she breast-fed her child is highly reliable.33 Over 75% of the children in our
study were younger than 10 years when having their first DBPCFC. This study population consists of children who were referred to a tertiary care clinic with suspected food allergy and had a DBPCFC as part of routine care. Therefore, the prevalence of food allergy and sensitization to food was high. It is therefore difficult to compare these results with the general population. A limitation of the study is the lack of knowledge on the mode of delivery, social economic status, diet of the mother during breastfeeding, the exclusivity of the breastfeeding, the type of formula used when bottle-feeding and the timing of introduction of solid foods.
Due to ethical and methodological limitations, a study on breastfeeding using a randomized controlled trial is complicated. The well-known center-randomized breastfeeding promotion intervention study by Kramer et al.34,35 did not study the effect of breastfeeding on
food allergy. Therefore, the data presented in this study may well be the best evidence possible for the protective effect of breastfeeding on food allergy in a high risk population such as ours.
CONCLUSIONS
These results indicate for the first time that in children of a tertiary care clinic investigated for possible food allergy, every additional month of breastfeeding is associated with a lower risk of developing clinical food allergy as diagnosed by the gold standard, the double-blind placebo-controlled food challenge. However, overall, there was no association between the prevalence of food allergy and breastfeeding versus bottle-feeding when breastfeeding of all durations was considered. Thus, this study supports the general recommendation of breastfeeding, and specifically suggests that preventive effects with respect to food allergy may be achieved if breastfeeding is prolonged since every additional month of breastfeeding was associated with a lower risk of developing food allergy.
REFERENCES
1. Victora CG, Bahl R, Barros AJD, Franca GVA, Horton S, Kra-sevec J, et al. Breastfeeding in the 21st century: Epidemiology, mechanisms, and lifelong effect. Lancet. 2016;387:475–90. 2. Heinrich J. Modulation of allergy risk by
breast feeding. Curr Opin Clin Nutr Metab Care. 2017;20:217–21.
3. Lodge CJ, Tan DJ, Lau M, Dai X, Tham R, Lowe AJ, et al. Breastfeeding and asthma and allergies: a systematic review and meta-analysis. Acta Paediatr Suppl. 2015;104:38– 53.
4. Greer FR, Sicherer SH, Burks AW. Effects of early nutritional interventions on the development of atopic disease in infants and children: the role of maternal dietary restriction, breastfeeding, timing of introduction of complementary foods, and hydrolyzed formulas. Pediatrics.
2008;121:183–91.
5. Muraro A, Dreborg S, Halken S, Høst A, Niggemann B, Aalberse R. Dietary prevention of allergic diseases in infants and small children Part III: critical review of published peer-reviewed observational and
interventional studies and final recommenda-tions *. Pediatr Allergy Immunol. 2004;15:291–307.
6. van Odijk J, Kull I, Borres MP, Brandtzaeg P, Edberg U, Hanson LA, et al. Breastfeeding and allergic disease: a multidisciplinary review of the literature (1966–2001) on the mode of early feeding in infancy and its impact on later atopic manifestations. Allergy. 2003;58:833–43.
7. Høst A, Halken S, Muraro A, Dreborg S, Niggemann B, Aalberse R, et al. Dietary prevention of allergic diseases in infants and small children. Pediatr Allergy Immunol. 2008;19:1–4.
8. Branum AM, Lukacs SL. Food allergy among children in the United States. Pediatrics. 2009;124:1549–55.
9. Flokstra-de Blok BMJ, Dubois AEJ, Vlieg-Boerstra BJ, Oude Elberink JNG, Raat H,
DunnGalvin A, et al. Health-related quality of life of food allergic patients: comparison with the general population and other diseases. Allergy. 2010;65:238–44.
10. Sicherer SH, Furlong TJ, Maes HH, Desnick RJ, Sampson HA, Gelb BD. Genetics of peanut allergy: a twin study. J Allergy Clin Immunol. 2000;106:53–6. 1 Pt 1
11. Muraro A, Halken S, Arshad SH, Beyer K, AEJ Dubois, du Toit G, et al. EAACI Food Allergy and Anaphylaxis Guidelines. Pri-mary prevention of food allergy. Allergy. 2014;69:590–601.
12. de Silva D, Geromi M, Halken S, Host A, Panesar SS, Muraro A, et al. Primary prevention of food allergy in children and adults: systematic review. Allergy. 2014;69:581–9.
13. McGowan EC, Bloomberg GR, Gergen PJ, Visness CM, Jaffee KF, Sandel M, et al. Influence of early-life exposures on food sensitization and food allergy in an inner-city birth cohort. J Allergy Clin Immunol. 2014;135:178.
14. Luccioli S, Zhang Y, Verrill L, Ramos-Valle M, Kwegyir-Afful E. Infant feeding practices and reported food allergies at 6 years of age. Pediatrics. 2014;134:S21–8.
15. Elbert N, van Meel E, den Dekker H, de Jong N, Nijsten T, Jaddoe V et al. Duration and exclusiveness of breastfeeding and risk of childhood atopic disorders. Allergy Eur J Allergy Clin Immunol. 2017;72:1936–43. 16. Venter C, Pereira B, Voigt K, Grundy J,
Clayton CB, Higgins B, et al. Factors associated with maternal dietary intake, feeding and weaning practices, and the development of food hypersensitivity in the infant. Pediatr Allergy Immunol.
2009;20:320–7.
17. Koplin JJ, Osborne NJ, Wake M, Martin PE, Gurrin LC, Robinson MN, et al. Can early introduction of egg prevent egg allergy in infants? A population-based study. J Allergy Clin Immunol. 2010;126:807–13.
18. Kusunoki T, Morimoto T, Nishikomori R, Yasumi T, Heike T, Mukaida K, et al. Breastfeeding and the prevalence of allergic diseases in schoolchildren: does reverse causation matter? Pediatr Allergy Immunol. 2010;21:60–6.
19. Ito J, Fujiwara T. Breastfeeding and risk of atopic dermatitis up to the age 42 months: a birth cohort study in Japan. Ann Epidemiol. 2014;24:267–72.
20. Vlieg-boerstra BJ, Bijleveld CM, Van Der Heide S, Beusekamp BJ, Wolt-plompen SAA, Kukler J, et al. Development and vali-dation of challenge materials for double-blind, placebo- controlled food challenges in children. J Allergy Clin Immunol. 2004;113:341–6.
21. Sampson Ha, Gerth van Wijk R, Bindslev-Jensen C, Sicherer S, Teuber SS, Burks AW. et al. Standardizing double-blind, placebo- controlled oral food challenges: American Academy of Allergy, Asthma & Immunology-European Academy of Allergy and Clinical Immunology PRACTALL consensus report. J Allergy Clin Immunol. 2012;130:1260–74. 22. van den Berg ME, Flokstra-de Blok BMJ,
Vlieg-Boerstra BJ, Kerkhof M, van der Heide S, Koppelman GH, et al. Parental eczema increases the risk of double-blind, placebo-controlled reactions to milk but not to egg, peanut or hazelnut. Int Arch Allergy Immunol. 2012;158:77–83.
23. Twisk JWR. Applied multilevel analysis: a practical guide.
Cambridge: Cambridge university Press; 2006.
24. Wang D, Bakhai A. Clinical Trials. A practical guide to design, analysis, and reporting. London: Remedica; 2006. p. 480.
25. Kull I, Melen E, Alm J, Hallberg J, Svartengren M, van Hage M, et al. Breast-feeding in relation to asthma, lung function, and sensitization in young school children. J Allergy Clin Immunol. 2010;125:1013–9. 26. Brew BK, Kull I, Garden F, Almqvist C,
Bergström A, Lind T, et al. Breastfeeding,
asthma, and allergy: a tale of two cities. Pediatr Allergy Immunol. 2012;23:75–82. 27. Hong X, Wang G, Liu X, Kumar R, Tsai H-J, Arguelles L, et al. Gene polymorphisms, breast-feeding, and development of food sensitization in early childhood. J Allergy Clin Immunol. 2011;128:374–81.e2.
28. Kummeling I, Thijs C, Penders J, Snijders BEP, Stelma F, Reimerink J, et al. Etiology of atopy in infancy: the KOALA Birth Cohort Study. Pediatr Allergy Immunol. 2005;16:679–84. 29. Sears MR, Greene JM, Willan AR, Taylor DR,
Flannery EM, Cowan JO, et al. Long-term relation between breastfeeding and development of atopy and asthma in children and young adults: a longitudinal study. Lancet. 2002;360:901–7.
30. Saarinen KM, Juntunen-Backman K,
Järvenpää AL, Kuitunen P, Lope L, Renlund M, et al. Supplementary feeding in maternity hospitals and the risk of cow’s milk allergy: a pro-spective study of 6209 infants. J Allergy Clin Immunol. 1999;104:457–61.
31. Venter C, Pereira B, Grundy J, Clayton CB, Roberts G, Higgins B, et al. Incidence of parentally reported and clinically diagnosed food hypersensitivity in the first year of life. J Allergy Clin Immunol. 2006;117:1118–24. 32. Brouwer ML, Wolt-Plompen SA, Dubois AE,
Van Der Heide S, Jansen DF, Hoijer MA, et al. No effects of probiotics on atopic dermatitis in infancy: a randomized clinical and experimental allergy. Clin Exp Allergy. 2006;36:899–906.
33. Van ZZ, Maslin K, Dean T, Blaauw R, Venter C. The accuracy of dietary recall of infant feeding and food allergen data. J Hum Nutr Diet. 2016;29:777–85.
34. Kramer MS, Matush L, Vanilovich I, Platt R, Bogdanovich N, Sevkovskaya Z, et al. Effect of prolonged and exclusive breast feeding on risk of allergy and asthma: cluster randomised trial. Br Med J. 2007;335:815. 35. Kramer MS. Breastfeeding and allergy: the
evidence. Ann Nutr Metab. 2011;59:20–6
CHAPTER 6
EFFECT OF BIRTH ORDER AND FAMILIAL
ATOPY ON FOOD ALLERGY RISK
E. BAK1 *, C.D. VAN GINKEL*1, B.J. KOLLEN2, B.M.J. FLOKSTRA-DE BLOK2, G.H.
KOPPELMAN1, A.E.J. DUBOIS1
1) University of Groningen, University Medical Center Groningen, Department of Paediatric Pulmonology and Paediatric Allergy, GRIAC Research Institute, Groningen, the Netherlands. 2) University of Groningen, University Medical Center Groningen, Department of General
Practice, GRIAC Research Institute, Groningen, The Netherlands
*E. Bak and C.D. van Ginkel contributed equally to this work.
