Acta Med Kindai Univ Vol.43, No , 2018

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1 Acta Med Kindai Univ Vol.43, No , Preventing development of cow s milk allergies in infants with atopic dermatitis through intake of cow s milk formula before weaning: A cross-sectional study Megumi Nagai 1, Yutaka Takemura 1, Tomoyuki Arima 1, Hiroki Masumi 1, Koji Yamasaki 2, Hitomi Nishi 3, Norihiro Inoue 3, Tsukasa Takemura 1 1 Department of Pediatrics, Faculty of Medicine, University of Kindai, Japan 2 Department of Pediatrics, Kaizuka City Hospital, Japan 3 Department of Pediatrics, National Hospital Organization Osaka Minami Medical Center, Japan Abstract Background: Recent studies demonstrated the effectiveness of the early consumption of specific allergens to prevent food allergies. Although several studies have focused on milk, there has been no intervention study yet. We retrospectively studied infants with atopic dermatitis (AD), a condition associated with a high risk of food allergies, to evaluate the effectiveness of cow s milk formula (CMF) consumed before weaning to prevent the development of cow s milk allergies (CMA). Methods: A questionnaire was sent to parents of infants diagnosed with AD at 2 to 11 months after birth. The timing of nutrition during infancy, development of food allergies, and timing, duration, and frequency of CMF intake were analyzed. Results: We analyzed data from 309 children: 138 receiving CMF and 171 exclusively breastfed. CMA developed significantly less frequently with CMF than with breast milk only: 11.6 vs. 28.1%, respectively (p < 0.001). However, no difference was present in the development of egg and wheat allergies. CMA development in infants given CMF within 1 to 3 months of birth, with intake maintained for at least 4 months, was significantly lower than in infants fed only breast milk or given CMF within 1 to 3 months of birth but with intake for 3 months or less. No difference was noted between subgroups with all-day intake, half-day intake, and intake once or twice daily. Conclusion: Long-term CMF intake reduced the occurrence of CMA among babies with AD even when CMF was consumed only once or twice daily, suggesting that CMF could be beneficial when given concurrently with breast milk. Key words: cow s milk allergies, preventing, cow s milk formula, infants, atopic dermatitis Introduction Approximately 10% of infants and 5% of preschool children in Japan have food allergies; after eggs, cow s milk is the second most common immediate-type food allergy to arise during infancy. Although 50% of infants with cow s milk allergy (CMA) naturally develop tolerance by the time they are 3 years of age and 80 to 90% do so before beginning school, some children may need to exclude cow s milk from their diet indefinitely. 1 For such patients, the main treatment methods include a diet with allergens removed by heat treatment and other processing methods as well as drugs administered for symptoms induced by accidental ingestion; no safe or reliably curative treatment is known. In recent years, oral immunization treatment (OIT) has been used in an attempt to completely cure food allergies; many studies, as well as a systematic review, reported the effectiveness of OIT for various allergens. 2 However, OIT has shown limited effects against established CMA. 3 Received April 10, 2018; Accepted July 13,

2 M. Nagai et al. Moreover, OIT has not been shown to safely promote tolerance in all patients for all allergens, and is not recommended for treatment in the US, Europe, or Japan as part of standard medical care. 4-7 Recent findings suggest the that early intake of foods likely to become allergens when a child starts to wean, at approximately 3 to 6 months after birth, can help prevent the child from developing an allergy to that food; in other words, early intake can help to prevent some food allergies. It has been shown that infant at high risk of food allergy early intake of peanuts and eggs reduces the incidence of each allergy, 8, 9, 10 and a meta-analysis of the introduction of commonly allergenic foods at various times during infancy showed that the early consumption of eggs and peanuts reduced the likelihood of allergy development. 11 This suggested that the early intake of milk protein, particularly cow s milk formula (CMF), might reduce the frequency of CMA development. To date, only a few studies have suggested the effectiveness of early intake in preventing CMA development, while we know of no prospective interventional study conducted to date. In recent years, research has focused on transdermal sensitization to food allergens, whereby the patient is sensitized to allergens in their surrounding environment from their eczema. Clinical studies in Europe and the United States (US) have shown that the presence of eczema during infancy and presence of peanuts in the infant s surroundings can be used to predict the development of peanut allergies A positive correlation has been demonstrated between the severity of an infant s AD and sensitization to allergens, 15 while Langerhans cells have been implicated in the absorption of allergens from the surrounding environment through the epidermis. 16 A strong link between AD and the development of CMA was also identified in a systematic review. 17 In this study we analyzed infants who developed AD during the neonatal period, suggested to be a high risk group for sensitization to cow s milk, to determine the effectiveness of CMF intake before weaning to prevent the development of CMA. Methods Study design, survey subjects, and ethical considerations This was an observational study whereby a questionnaire survey was sent to the parents of patients with AD, and completed surveys were returned using the enclosed envelopes, and collated, analyzed. The contents of the questionnaire are shown in Table 1. Patients to be studied were infants aged 2 to 11 months old who visited Kindai University Hospital Pediatric Department, Kaizuka Hospital Pediatric Department, or National Hospital Organization Osaka South Medical Center Pediatric Department between January 2012 and August 2015 and were diagnosed with AD by doctors. Diagnoses of AD were confirmed based on medical records, according to diagnostic criteria outlined in the Japanese Dermatological Association s 2009 Guidelines for Management of Atopic Dermatitis. 18 For the treatments of AD, we applied alclometasone or similarly potent steroids to the face and betamethasone or similarly potent steroids to the trunk and limbs every day until remission, and performed proactive therapy involving steroid application 2 to 3 times weekly to maintain remission. Some infants were excluded from the study for the following reasons: infants with a serious medical history or developmental problems; largely uncompleted questionnaires; birth weights below 1,500 g; and parental refusal to participate. The first to third reasons were from answers to the questions; the last reason represented failure to return the questionnaire. The study was conducted with the approval of the ethics committees at Kindai University Hospital, Kaizuka Hospital and National Hospital Organization Osaka South Medical Center. Identification of allergies and grouping of infants Food allergy is defined as "a phenomenon in which symptoms that are disadvantageous to the living body are caused by an antigen - specific immunological mechanism caused by food". OFC is the most reliable diagnostic method for food allergy, but in the survey concerning food allergy correspondence in school lunch by the Ministry of Education, Culture, Sports, Science and Technology, diagnosis is carried out only with a questionnaire form. Although there is no diagnostic criteria in the survey using the questionnaire form, since OFC is the most reliable diagnostic method, in this study also judgment of food allergy occurrence was made as follows. Infants with food allergy represented those whose parents answered that their infant had been diagnosed by a doctor 58

3 Preventing development of cow s milk allergies as having a food allergy. Each food allergy was identified as a reaction to either egg, cow s milk, or wheat allergens. The basis for food allergy diagnosis was identified only for infants with confirmation by positive OFC results or a clear history of induced symptoms. Infants with diagnoses of bronchial asthma were identified as those whose parents responded that the infant had developed a wheezing cough at least 3 times, regardless of whether or not they had a cold at the time. Infants whose mothers responded that they gave the infant CMF at least once a day while they were lactating and did so continuously for at least one month were identified as belonging to the CMF group, while others were assigned to an exclusively breastfed group. Evaluation criteria The main evaluation criterion was the development rate of egg, cow s milk, and wheat allergies in the CMF group and in the exclusively breastfed group. Further, we examined development rates separately for specifically confirmed food allergies and for all food allergies, whether specifically confirmed or not. Four ancillary evaluation criteria included the: (1) timing of CMF including months separating the CMF intake period and subsequent development of CMA (1 to 3 months, 4 to 9 months, 10 or more months, or exclusively breastfed), daily CMF intake frequency (once or twice daily, halfday, all day, or exclusively breastfed), and age at the first CMF intake (1 to 3 months, 4 or more months, or exclusively breast fed); (2) impact of various background factors on CMA development; (3) impact of various background factors on development of bronchial asthma; and (4) months between the CMF intake period and development of bronchial asthma (1 to 3 months, 4 to 9 months, 10 or more months, or exclusively breastfed). The background factors in items 2 and 3 included the type of early nutrition where the purely breastfed group and infants receiving CMF for only a short time (3 months or less) were considered together as 1 background factor group. Moreover, the POEM score was used to judge the condition of the infants skin at the time of the initial diagnosis; infants were divided into those with a score of 13 or higher (moderate eczema) and those with a score lower than , 20 Several other background factors were also considered in the context of CMA and bronchial asthma (see Results and Tables). Statistical analysis All statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), 21 which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria). More precisely, it is a modified version of R commander designed to add statistical functions frequently used in biostatistics. A comparison of background factors between the CMF and breastfed groups and a comparison of POEM scores between groups defined by age in months was performed using the Mann-Whitney U test. All other analyses, including the main evaluation criterion, used Fisher s exact test. Ancillary evaluation criteria 1 and 4 were analyzed using multivariate logistic regression. Ancillary evaluation criteria 2 and 3 were analyzed using Fisher s exact test and multivariate logistic regression analysis for each factor. For each test, a p-value below 0.05 was considered to indicate a significant difference. Results Questionnaires were mailed to 655 intended recipients, with 43 returned-to-sender owing to relocation or other reasons, and 612 successfully sent. The latter elicited 349 responses (response rate, 57%). In accordance with the study s exclusion criteria, 40 responses were deemed invalid (39 incomplete surveys and 1 with birth weight reported as below 1,500 g), resulting in 309 valid responses: 139 in the CMF group and 171 in the exclusively breastfed group (Figure 1). No difference was noted between CMF and breastfed groups regarding the proportion of male infants, proportion born in autumn or winter, type of delivery, proportion of infants with birth weight below 2,500 g, proportion with siblings, proportion with smokers in the household, proportion with other family members having an allergy, POEM score, or age in months when weaning was initiated. However, the proportion of households with pets was significantly higher for the CMF group (26.1%) than for the breastfed group (17.4%), and the proportion of children with bronchial asthma was significantly higher in the CMF group (26.8%) than the breastfed group (14.6%, Table 1). 59

4 M. Nagai et al. Fig. 1 Enrollment. Table 1 60

5 Preventing development of cow s milk allergies No difference was noted in the main evaluation criterion, with egg allergy development rates of 62.6% in the breastfed group and 56.5% in the CMF group, and those for wheat allergies at 15.2% in the breastfed group and 13% in the CMF group. However, the CMA development rate was significantly lower (p < 0.001) in the CMF group, at 11.6%, than in the breastfed group, at 28.1%. Further, within the confirmed allergy groups, no difference was noted in the rate of development of egg allergies (35% in the breastfed group and 29% in the CMF group) or that of wheat allergies (7.6% in the breastfed group and 8% in the CMF group). However, the CMA development rate was significantly lower (p < 0.001) in the CMF group (6.5%) than in the breastfed group (17%) (Figure 2). Fig. 2 Association between egg, milk, or wheat allergy, and nutrition. (A) Association between allergy onset and type of nutrition among all respondents who answered Diagnosed with food allergies. (B) Relationship between allergy onset and nutrition for each food among respondents diagnosed with food allergy on the basis of a positive oral food oral challenge test or clearly evoked symptoms. In both analyses, the incidence of cow s milk allergy (CMA) was low in the cow s milk formula (CMF) group. As for ancillary evaluation criterion 1, no significant difference in the rate of CMA development was evident between infants fed CMF for 10 or more months and for 4 to 9 months, although CMA development was significantly more frequent in infants fed CMF for 1 to 3 months or exclusively breastfed. Regarding the daily intake frequency, no differences were noted among the 3 groups (all-day CMF, half-day CMF, and CMF once or twice daily), while CMA development was significantly more frequent in the breastfed group. As for age in months when CMF was introduced, a trend was noted toward more frequent CMA development with introduction at 4 months or later as opposed to 1 to 3 months, although the difference did not reach significance. The group with introduction at 1 to 3 months showed a significantly lower rate of CMA development than the breastfed group. In the group whose CMF intake began at 1 to 3 months, infants with sustained intake for 4 or more months had a significantly lower CMA development rate than those with sustained intake for 3 or fewer months (Table 2). 61

6 M. Nagai et al. Table 2 A significant correlation was noted between CMA development and having an egg allergy or breastfeeding no more than 3 months of sustained CMF intake (ancillary evaluation criterion 2, Table 3). A significant correlation was also noted between bronchial asthma development and the presence of pets or a POEM score of 13 or more points (moderate eczema) (ancillary evaluation criterion 3, Table 4). The groups receiving CMF for only 1 to 3 months and for 4 to 9 months both had a significantly higher rate of bronchial asthma development than the breastfed group, although the group receiving CMF for at least 10 consecutive months showed only a slightly higher tendency to develop asthma than the exclusively breastfed group (ancillary evaluation criteria 4, Table 5). 62

7 Preventing development of cow s milk allergies Table 3 Table 4 63

8 M. Nagai et al. Table 5 Discussion Our results suggest that the sustained intake of CMF for at least 4 consecutive months at least once daily before weaning could prevent the development of CMA in infants with AD. In contrast, the statistical analysis of factors associated with the development of other allergies suggested a link between the development of CMA and exclusively breastfeeding or only short-term intake of CMF. The Learning Early About Peanut Allergy (LEAP) study, which examined the early consumption of peanuts as a way to inhibit the development of allergy to them showed the increase of allergen-specific IgG4 antibodies unaccompanied by a rise in allergen-specific IgE antibodies was associated with the prevention of allergy development. 8 Allergen-specific IgG4 antibodies are considered to block allergen-specific IgE antibodies, and a link has been demonstrated between a decrease in allergen-specific IgE antibodies accompanied by an increase in allergen-specific IgG4 antibodies and the development of early tolerance to CMA. 22 CMF with a standard concentration of 12.4 to 14% contains 1.5 to 1.7 g of protein for every 100 ml, of which approximately 40% is casein and 60% is milk whey protein. 23 The finding that infants in this study with the early sustained intake of CMF exhibited no difference in development rates of egg or wheat allergies but rather exhibited a low development rate of CMA alone suggests that gastrointestinal absorption of the milk-origin casein in the CMF caused an increase in cow s milk-specific IgG4 antibodies, inhibiting the development of CMA, even in these infants with AD (i.e., cutaneous sensitization). However, we did not measure allergen-specific IgE and IgG4 antibodies; this is an important matter for future investigation. A cohort study concluding that CMF intake early in infancy decreases CMA 10-fold 24 and an observational study of infants with egg allergies who were thought to be at high risk of developing CMA, found that those with the sustained intake of CMF within the first 3 months after birth had a lower development rate of CMA than the strictly breastfed group. 25 Another study found that children in a CMA group included fewer who had been given CMF within 1 month after birth and sustained daily intake than a comparison group with egg allergy. 26 Both studies suggested that the sustained daily intake of CMF beginning soon after birth was linked to the prevention of CMA. The results of the present study are consistent with the earlier findings. Furthermore, daily CMF intakes were effective in decreasing CMA development. Thus, infants need not be given CMF exclusively for nutrition during the lactation period; daily intake of CMF once or twice a day concurrently with breastfeeding could help to prevent CMA development. On the other hand, an earlier study found that 64

9 Preventing development of cow s milk allergies an extremely small intake of CMF failed to decrease the risk of developing CMA, even in infants given CMF exclusively in their first postnatal days at the hospital followed by exclusive breastfeeding for the first 2 months of life. 27 Other studies found that long-term exclusion of CMF from the diet can increase the risk of CMA development, even among infants with no previous problems following CMF intake. 28, 29 These findings and our results suggest that limiting CMF intake to a short period immediately after birth can increase the risk of CMA, and that infants at high risk should undergo sustained longterm intake of CMF, although not necessarily to the exclusion of breastfeeding. Cow s milk is important for the growth of children, as indicated by many studies. Cohort studies associated a higher intake of cow s milk with increased stature and weight at age 4, and with increased stature at age 5, 30 while in infants with food allergies the exclusion of cow s milk over long periods has been found to increase the rate of a short stature. 31 This suggests that the prevention of CMA is important for physical development. Breast milk is believed to contribute to the prevention of allergies. Components of breast milk considered beneficial in this respect include immune cells and cytokines including soluble CD14, secretory IgA antibodies, transforming growth factor (TGF)-β, interleukin (IL)-10, and polyamine and contribute to immunologic tolerance. 32, 33, 34 In this study, the proportion of infants in the breastfed group who developed bronchial asthma was smaller than that in the CMF group. However, this might reflect complicating factors such as the presence of pets in the home or severe eczema. Nonetheless, while our results suggest the beneficial effects of CMF on CMA, the effects of CMF on the risk asthma development are less clear. However, our results suggested that 10 months of early CMF intake had little effect on the risk of asthma development. Several meta-analyses have addressed the effect of breastfeeding on the development of bronchial asthma. Some found that exclusive breastfeeding tended to prevent the development of bronchial asthma, 35, 36 while others found no effect, 37, 38 indicating a lack of consensus. In this context, the present results suggest that while CMF intake might not prevent the development of asthma, certain components of breast milk may decrease the risk. Breastfeeding has various benefits that extend beyond allergy prevention, such as in the prevention of respiratory tract infections 39 and infant sudden death syndrome. 40 The results of our study do not question the importance of breastfeeding; rather, they suggest that combining breastfeeding with CMF over the course of the day may help to prevent CMA, particularly in infants at high risk. Limitation of this study is that while it demonstrated a link between CMF intake and the prevention of CMA, the study design precluded determining the direction of causality. Also, analysis was limited to answers to a questionnaire, without consistent documentation of the verification of allergy diagnoses, especially considering that the proportion of children with food allergies in this study was notably high and no data were available on allergen-specific IgG4 and allergenspecific IgE antibodies, or their changes over time. The infants included in the survey were diagnosed with AD by doctors at a limited number of facilities where OFC or clearly induced symptoms constituted the basis for food allergy diagnosis. Importantly, however, few instances of allergy development involved cow s milk as the sole allergen, suggesting that these were high-risk infants who still often avoided CMA after receiving CMF. A prospective randomized controlled trial is needed to clarify the various different cause-and-effect relationships, but randomization to exclusive breastfeeding or exclusive CMF may be unethical. In conclusion, this study, suggested that infants with AD thought to be at high risk of developing food allergies could have their risk of CMA development reduced by means of sustained CMF intake at least once daily for at least 4 months before starting to wean. However, the multiple benefits of breastfeeding cannot be denied. Conflict of interest The authors have no conflict of interest to declare. Acknowledgments The summary of this paper was presented at the 54th Annual Meeting of Japanese Society of Pediatric Allergy and Clinical Immunology in November

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