Could Ig E Mediated Cow's Milk Protein Allergy Be a Risk Factor in the Development of Functional Gastrointestinal Disease?

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Nur Kevser Özyurt, Merve Kişioğlu, Burcu Güven, Nalan Yıldız, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7092977/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 14 Oct, 2025 Read the published version in European Journal of Pediatrics → Version 1 posted 10 You are reading this latest preprint version Abstract Objectives Numerous factors have been implicated in the development of functional gastrointestinal disorders (FGID). In this study, we aimed to investigate whether a diagnosis of cow’s milk protein allergy (CMPA) in infancy is a risk factor for the development of FGID in the long term and whether there is a difference between patients with IgE-mediated and non-IgE-mediated CMPA with regard to the development of FGID. Methods The study included 250 patients aged 4–18 years who had been diagnosed with CMPA in infancy. The control group consisted of 250 children of a similar age without CMPA. A questionnaire including Rome IV criteria was prepared and administered to the parents of 500 children. Results FGID were observed in 70 (28%) patients with CMPA and in 76 (30.4%) patients without CMPA ( p = 0.623). functional abdominal pain-not otherwise specified (FAP-NOS), irritable bowel syndrome (IBS), and non-retentive fecal incontinence (NRFI) were significantly more common in patients without CMPA ( p = 0.009, p = 0.016, p = 0.034, respectively). FGID were observed in 36 (33.6%) patients with IgE-mediated CMPA as opposed to 34 (23.8%) patients with non-IgE-mediated CMPA ( p = 0.115). functional dyspepsia (FD), FAP-NOS, and IBS were significantly more common in patients with IgE-mediated CMPA ( p ≤ 0.001, p = 0.001, p = 0.002, respectively). Conclusion Although the frequency of FGID development did not increase in the long term in our CMPA patients, FD, FAP-NOS, and IBS were significantly more common in these patients, particularly in those with IgE-mediated CMPA. This suggests that subclinical CMPA may persist in patients with IgE-mediated CMPA. Cow’s milk protein allergy Functional gastrointestinal disorders pediatric INTRODUCTION Cow’s milk protein allergy (CMPA) is the most common food allergy in early childhood, with a reported prevalence of 1-7.5% (1). CMPA is seen in three forms: immunoglobulin E (IgE)-mediated, non-IgE-mediated, and mixed. IgE-mediated food allergies often develop within the first two hours following food intake, while non-IgE-mediated food allergies develop within a few hours or days following food intake. Mixed-type food allergies, on the other hand, typically affect the gastrointestinal tract and skin, with both mechanisms acting together (2). Functional gastrointestinal disorders (FGID) are chronic and frequently seen digestive system disorders manifesting with abdominal pain, bloating, distension and/or altered bowel habits (constipation, diarrhea or both) (3). Numerous factors including nutrition, low socioeconomic status, psychological factors, and genetic factors have been implicated in the development of FGID. In allergic children exposed to cow’s milk proteins, mast cells have been observed to migrate to the enteric nervous system and become active, which is considered to result in gastrointestinal dysmotility (4). Accordingly, it is proposed that CMPA may trigger gastroesophageal reflux and may also be a factor that may predispose to functional gastrointestinal disorders (5). In this study, we aimed to investigate whether a diagnosis of CMPA in infancy is a risk factor for the development of FGID in the long term. In addition, we also aimed to explore whether there is a difference between patients with IgE-mediated and non-IgE-mediated CMPA with regard to the development of FGID. METHODS The study included a total of 310 pediatric patients diagnosed with CMPA between January 1, 2011 and December 30, 2019. Of these, 60 patients were excluded since the families of 50 children could not be contacted, the families of eight children refused to participate in the study, and two children had active CMPA. The remaining 250 patients aged 4-18 years who had been diagnosed with CMPA and had completed their treatment plans were included in the study. The control group consisted of 250 children of a similar age who were not diagnosed with CMPA. Patients with congenital gastrointestinal anomalies and/or known organic gastrointestinal disorders (inflammatory bowel disease, gastritis) were not included in the study. A questionnaire including Rome IV criteria and probing about gastrointestinal symptoms was prepared and administered to the parents of 500 children participating in the study either face-to-face or via phone. Patients were evaluated according to Rome IV criteria for functional dyspepsia (FD), functional abdominal pain-not otherwise specified (FAP-NOS), functional constipation (FC), irritable bowel syndrome (IBS), non-retentive fecal incontinence (NRFI), and cyclic vomiting syndrome (CVS). Patients’ previous clinical and laboratory findings (skin prick test, total IgE, specific IgE, eosinophil count) were retrieved from hospital databases. Patients diagnosed with CMPA were divided into two groups as IgE-mediated and non-IgE-mediated CMPA according to clinical and laboratory findings (skin prick test and specific IgE). Ethical statement Approval for the study was obtained from Karadeniz Technical University Faculty of Medicine Ethics Committee with appropriate data use agreements. The study was conducted in accordance with the principles of the Declaration of Helsinki. The study was approved by Karadeniz Technical University Scientific Research Ethics Committee (Approval No: 24237859-611). Statistical analysis Data were analyzed using SPSS 22.0 (IBM Corp., 2013). Descriptives were expressed as frequencies (n) and percentages (%) for categorical variables and as mean and standard deviation (SD) for continuous variables. Chi-square test was used for the comparison of categorical variables between independent groups. The Mann-Whitney U test was used to compare continuous variables that were not normally distributed between two independent groups. The normality of continuous variables was assessed using the Kolmogorov-Smirnov and Shapiro-Wilk tests. A p level of <0.05 was considered significant. The study was approved by the Ethics Committee of Karadeniz Technical University Farabi Hospital (No: 24237859-611). A written informed consent was obtained from each parent or legal guardian of all children participating in the study. RESULTS The study included a total of 500 patients, comprising 250 patients diagnosed with CMPA who had completed their treatment plans and 250 patients without a CMPA diagnosis. Patients with CMPA included 145 (58%) boys with a mean age of 5.7±2.0 years and the control group consisted of 138 (55.2%) boys with a mean age of 6.8±3.2 years (Table 1). In patients with CMPA, most common presenting symptom was diarrhea (n=117; 46.8%), followed by foamy stool (n=66; 26.4%), atopic dermatitis (n=57; 22.8%), and bloody stool (n=49; 19.6%). Laboratory workup indicated that 79 (31.6%) had an absolute eosinophil count of greater than 500/ml, 98 (39.2%) had positive milk-specific IgE, and 64 (25.6%) had positive skin prick test results. Based on these findings, 143 (57.2%) of the patients were diagnosed with non-IgE-mediated CMPA and 107 (42.8%) with IgE-mediated CMPA (Table 2). Patients with IgE-mediated CMPA included 68 (63.6%) boys with a mean of 6.1±2.3 years and patients with non-IgE-mediated CMPA included 77 (53.8%) boys with a mean of 5.4±1.6 years. In IgE-mediated CMPA patients, food allergies other than CMPA were significantly more common ( p =0.041) and absolute eosinophil and total IgE values were significantly higher ( p ≤0.001 and p≤0.001, respectively) compared to non-IgE-mediated CMPA patients (Table 3). In total, FGID were detected in 146 (29.2%) patients, comprising 70 (28%) patients with CMPA and 76 (30.4%) patients without CMPA. However, no significant difference was found between the two groups ( p =0.623). In addition, FGID were observed in 36 (33.6%) of patients with IgE-mediated CMPA and 34 (23.8%) patients without IgE-mediated CMPA. Similarly, no significant difference was found between these two groups ( p =0.115) (Table 4). It was also revealed that FAP-NOS, IBS, and NRFI were significantly higher in patients without CMPA compared to non-CMPA patients ( p =0.009, p =0.016, and p =0.034, respectively). By contrast, FC more frequently seen in patients with CMPA and this difference was statistically significant ( p ≤0.001). However, no significant difference was observed between the two groups with regard to FD and CVC. On the other hand, FD, FAP-NOS, and IBS were significantly more common in patients with IgE-mediated CMPA patients compared to non-IgE-mediated CMPA patients ( p ≤0.001, p =0.001, and p =0.002, respectively). In contrast, FC was significantly more common in patients with non-IgE-mediated CMPA ( p =0.018). DISCUSSION This study was conducted to investigate whether a diagnosis CMPA in infancy is a risk factor for the development of FGID in the long term. The results indicated that the frequency of FGID were 28% in patients diagnosed with CMPA and no significant difference was observed between patients with patients without CMPA. However, FAP-NOS, IBS, and NRFI were significantly more common in patients without CMPA. On the other hand, the frequency of FGID were significantly higher in patients with IgE-mediated CMPA, while no significant difference was observed. In comparison, FD, FAP-NOS and IBS were significantly more common in patients with IgE-mediated CMPA. Literature indicates that CMPA is a predisposing or accompanying factor for FGID in children (5). In a study conducted in Turkey, FGID were detected in 31.1% of children diagnosed with CMPA (6). A study by Saps et al. evaluated 52 children aged 4-18 years who were diagnosed with CMPA in the first year of their lives and detected gastrointestinal symptoms in 44.2% and FGID in 19.2% of the children (7). In our study, in line with the literature, FGID were detected in 28% of the patients diagnosed with CMPA. However, no significant difference was observed between patients with and without CMPA. A study by Di Nardo et al. reported that the frequency of FGID were significantly higher in patients with CMPA compared to patients without. Given that CMPA and FGID have a common pathophysiology (mucosal inflammation, intestinal microbiota, diet), this finding is not surprising. However, the number of patients with CMPA in that study was relatively small (n=80) (8). On the other hand, the number of case-controlled studies on this subject is not sufficient. In our study, FAP-NOS, IBS, and NRFI were significantly higher in patients without CMPA compared to patients with CMPA. There are contradictory findings in the literature regarding the relationship between CMPA and FAP. While some studies show a relationship between CMPA and FAP (7), other studies propose that there is insufficient evidence to support this relationship (9). There are very few studies in the literature examining the relationship between encopresis and CMPA. In a study conducted by Iacono et al., the incidence of encopresis was determined as 7.4% in 27 children diagnosed with CMPA (10). Another study conducted in Italy determined the incidence of encopresis as 8.3% in CMPA cases aged 30-70 months (11). Studies investigating the relationship between CMPA and IBS have mostly evaluated food allergies together instead of evaluating CMPA in isolation. In a study conducted by Carroccio et al., food allergies including CMPA were detected in 25% of 160 patients diagnosed with IBS (12). In a study conducted in Stockholm in 2014 with 2610 children, it was observed that 9% of children who developed food allergies at the age of 4 or 8 developed IBS at the age of 12 years, and the difference was found to be statistically significant. The authors suggested that this finding could be an independent risk factor for IBS (13). A 2017 study conducted in Taiwan found that 11,242 preschool children with a history of food and other allergic diseases had a 77% increased risk of developing IBS when they reached school age (14). In addition to its traditional association with food, IBS is now linked to anxiety, depression, and other psychiatric conditions, and is considered a psychosomatic disorder (15). Moreover, some studies have shown that genetic factors play a major role in the development of IBS (16). These findings suggest that IBS, in a similar way to FAP and NRFI, can occur due to both CMPA and other factors. We consider that other factors were effective in the higher frequency of these disorders in our non-CMPA patients compared to CMPA patients. In addition, the higher rate in patients without CMPA could be explained by the fact that CMPA patients tend to be more cautious about their diets due to concerns about allergic reactions, often altering their eating habits because of anxiety surrounding this issue. These differences in dietary patterns also lead to variations in the microbiota among patients. In our study, a comparison of the frequency of FGID between IgE-mediated and non-IgE-mediated CMPA patients indicated that although the frequency was higher in IgE-mediated CMPA patients, no significant difference was observed. To our knowledge, there has been no study comparing IgE-mediated and non-IgE-mediated CMPA patients in the literature. In FD patients, however, it has been shown that allergic reactions to food proteins may contribute to symptoms (17). A recent study conducted in 2023 found that eliminating cow’s milk and dairy products in FD patients was more effective in reducing gastrointestinal symptoms than receiving medical treatment (18). In our study, FD, FAP-NOS, and IBS were more commonly observed in patients with IgE-mediated CMPA. This suggests that subclinical CMPA may persist in these patients. Particularly in patients with IgE-mediated CMPA, the prolonged development of tolerance and the frequent occurrence of coexisting allergic diseases necessitate a longer-term healthy diet for the children. The strengths of our study include the large number of patients and its case-control design. Additionally, there is no existing study in the literature comparing patients with IgE-mediated and non-IgE-mediated CMPA. However, considering that the pathophysiology of FGID is multifactorial, factors such as diet and stress were not included in our study. The use of a food diary and depression scale could have provided valuable insights for these patients. CONCLUSION Although the long-term frequency of FGID development did not increase significantly in patients diagnosed with CMPA compared to non-CMPA patients in our study, FD, FAP, and IBS were notably higher, particularly in patients with IgE-mediated CMPA. The development of FGID is multifactorial, and CMPA alone is not sufficient to explain it. However, the risk is higher in IgE-mediated CMPA. Further case-controlled studies with large patient populations are needed to explore this topic more comprehensively. Declarations The author(s) indicated no potential conflicts of interest. No financial or non-financial benefits have been received or will be received from any party related directly or indirectly to the subject of this article. The study was conducted in accordance with the principles of the Declaration of Helsinki. The study was approved by Karadeniz Technical University Scientific Research Ethics Committee (Approval No: 24237859-611). Informed consent was obtained from patients. This is an original article. Author Contribution Nur Kevser Özyurt, Merve Kişioğlu and Burcu Güven wrote the manuscript text and prepared tables. All authors reviewed the manuscript. 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J Pediatr Gastroenterol Nutr 52(2):166–169 Giovanni DINARDO et al (2018) Allergic proctocolitis is a risk factor for functional gastrointestinal disorders in children. J Pediatr 195:128–133e1 Pensabene L, Salvatore S, D’auria E, Parisi F, Concolino D, Borrelli O et al (2018) Cow’sMilk Protein Allergy in Infancy: A Risk Factor for Functional Gastrointestinal Disorders in Children? Nutrients. ;(10): 1716 Iacono G, Carroccio A, Cavataio F, Montalto G, Cantarero MD, Notarbartolo A (1995) Chronic Constipation as a Symptom of Cow Milk Allergy. J Pediatr 126(1):34–39 Carroccio A, Scalici C, Maresi E, DiPrima L, Cavataio F, Noto D et al (2005) Chronic Constipation and Food Intolerance: A Model of Proctitis Causing Constipation. Scand J Gastroenterol 40(1):33–42 Carroccio A, Brusca I, Mansueto P, Soresi M, D’alcamo A, Ambrosiano G et al (2011) Fecal Assays Detect Hypersensitivity to Cow’sMilk Protein and Gluten in Adults with Irritable Bowel Syndrome. Clin Gastroenterol Hepatol 9(11):965–971 Olén O, Neuman A, Koopmann B, Ludvigsson JF, Ballardini N, Westman M et al (2014) Allergy-Related Diseases and Recurrent Abdominal Pain During Childhood – A Birth Cohort Study. Aliment Pharmacol Ther 40(11–12):1349–1358 Tan TK, Chen AC, Lin CL, Shen TC, Li TC, Wei CC (2017) Preschoolers with Allergic Diseases Have an Increased Risk of Irritable Bowel Syndrome When Reaching School Age. J Pediatr Gastroenterol Nutr 64(1):26–30 Henström M, D’Amato M (2016) Genetics of Irritable Bowel Syndrome. Mol Cell Pediatr 3(7):1–5 Saito YA (2011) The Role of Genetics in IBS. Gastroenterol Clin North Am 40(1):45–67 Ravelli AM, Tobanelli P, Volpi S, Ugazio AG (2001) Vomiting and Gastric Motility in Infants with Cow’s Milk Allergy. J Pediatr Gastroenterol Nutr 32(1):59–64 Akpınar A (2021) Fonksiyonel dispepsi hastalarında inek sütü ve ürünlerinin kesilmesinin dispepsiye etkisinin değerlendirilmesi [tez]. Bezm-i Alem Vakıf Üniversitesi, İstanbul Tables Table 1 . Demographic and clinical characteristics All patients CMPA (+) CMPA (-) p n (%) n (%) n (%) Gender Male 283 (56.6) 145 (58.0) 138 (55.2) 0.528 Age Male 283(6.2± 2.7) 145(5.7±2.0) 138(6.8±3.2) <0.001 Mode of delivery NSVD 330 (66.0) 141 (56.4) 189 (75.6) <0.001 Coexisting allergic disease Yes 20 (3.8) 17 (6.8) 3 (1.2) 0.003 Coexisting allergic diseases Atopic dermatitis 4 (0.8) 4 (1.6) 0 (0.0) Allergic rhinitis 2 (0.4) 2 (0.8) 0 (0.0) Asthma 14 (2.8) 11 (5.6) 3 (1.2) Food allergy other than CMPA Yes 62 (12.2) 60 (24.0) 2 (0.8) <0.001 Food allergies other than CMPA Egg 53 (10.6) 52 (20.8) 1 (0.4) Peanut 9 (1.8) 8 (3.2) 1 (0.4) Nuts 21 (4.2) 21 (8.4) 0 (0.0) Dry legumes 15 (3.3) 15 (6.0) 0 (0.0) Seafood 2 (0.4) 2 (0.8) 0 (0.0) Wheat 15 (3.3) 15 (6.0) 0 (0.0) Family history of allergies Yes 127 (25.4) 79 (31.6) 48 (19.2) 0.001 Familial allergic diseases Asthma 44 (8.8) 24 (9.6) 20 (8.0) Eczema 41 (8.2) 29 (11.6) 12 (4.8) Rhinitis 10 (2.0) 4 (1.6) 6 (2.4) Urticaria 13 (2.6) 7 (2.8) 6 (2.4) Medicine 7 (1.4) 0 (0.0) 7 (2.8) Food 16 (3.2) 9 (3.6) 7 (2.8) Cow’s milk 15 (3.0) 13 (5.2) 2 (0.8) Breastfeeding Yes 482 (96.4) 242 (96.8) 240 (96.0) 0.810 * Percentage within column CMPA: Cow’s milk protein allergy Table 2. Demographic and clinical characteristics in CMPA patients n (%) Presenting symptoms Diarrhea 117 (46.8) Foamy mucous stool 66 (26.4) Atopic dermatitis 57 (22.8) Bloody stool 49 (19.6) Constipation 13 (5.2) Colic 4 (1.6) Wheeze 3 (1.2) Angioedema 3 (1.2) Absolute eosinophil count 500 79 (31.6) Milk-specific IgE Positive 98 (39.2) Negative 152 (60.8) Skin prick test Positive 64 (25.6) Negative 154 (61.6) Untested 32 (12.8) IgE mediation IgE-mediated 107 (42.8) Non-IgE-mediated 143 (57.2) Total IgE Normal 203 (81.2) High 47 (18.8) * Percentage within column CMPA: Cow’s milk protein allergy Table 3. Demographic and clinical characteristics in patients with and without IgE-mediated CMPA IgE mediation Yes No p n (%) n (%) Gender Male 68 (63.6) 77 (53.8) 0.124 Age Male 68 (6.1±2.3) 77(5.4±1.6) 0.004 Mode of delivery NSVD 64 (59.8) 77 (53.8) 0.417 Coexisting allergic diseases Yes 11 (10.3) 6 (4.2) 0.102 Food allergy other than CMPA Yes 33 (30.8) 27 (18.9) 0.041 Family history of allergies Yes 30 (28.0) 49 (34.3) 0.295 Breastfeeding Yes 10 (98.1) 137 (95.8) 0.472 Absolute eosinophil count >500 49 (45.8) 30 (21.0) <0.001 Total IgE High 34 (31.8) 13 (9.1) <0.001 * Percentage within column CMPA: Cow’s milk protein allergy, NSVD: Normal spontaneous vaginal delivery Tablo 4. Functional gastrointestinal disorders in patient groups CMPA IgE mediation CMPA - CMPA + p No Yes p n (%) n (%) n (%) n (%) Functional Dyspepsia 26 (10.4) 26 (10.4) 1.000 5 (3.5) 21 (19.6) <0.001 Functional Abdominal pain 40 (16.0) 20 (8.0) 0.009 4 (2.8) 16 (15.0) 0.001 Functional Constipation 3 (1.2) 26 (10.4) 0.001 21 (14.7) 5 (4.7) 0.018 Irritable Bowel Syndrome 37 (14.8) 19 (7.6) 0.016 4 (2.8) 15 (14.0) 0.002 Encopresis 36 (14.4) 16 (6.4) 0.034 11 (10.2) 5 (4.7) 0.334 Cyclic vomiting syndrome 14 (5.6) 6 (2.4) 0.110 5 (3.5) 1 (0.9) 0.244 Total 76 (30.4) 70 (28.0) 0.623 34 (23.8) 36 (33.6) 0.115 CMPA: Cow’s milk protein allergy Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 14 Oct, 2025 Read the published version in European Journal of Pediatrics → Version 1 posted Editorial decision: Revision requested 31 Aug, 2025 Reviews received at journal 30 Aug, 2025 Reviews received at journal 24 Aug, 2025 Reviewers agreed at journal 10 Aug, 2025 Reviewers agreed at journal 10 Aug, 2025 Reviewers agreed at journal 19 Jul, 2025 Reviewers invited by journal 17 Jul, 2025 Editor assigned by journal 17 Jul, 2025 Submission checks completed at journal 16 Jul, 2025 First submitted to journal 10 Jul, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7092977","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":488121966,"identity":"9b49c974-9108-471a-a258-121db6385c82","order_by":0,"name":"Nur Kevser Özyurt","email":"","orcid":"","institution":"Karadeniz Technical University","correspondingAuthor":false,"prefix":"","firstName":"Nur","middleName":"Kevser","lastName":"Özyurt","suffix":""},{"id":488121967,"identity":"006d52c1-73c1-4481-9609-6b5c56ee0527","order_by":1,"name":"Merve Kişioğlu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/ElEQVRIiWNgGAWjYDCCAzAGD4iogHAPPCBOCzOQOHMArPVAAtFaGNsgWhjwaeG7fYB1w8c9h+X4e84f/Phz3h05e7HDD4G22MnpNmDXInkuge3mjGeHjSXONjNL8257ZswjnWYA1JJsbHYAuxaDMwxst3kOpCU2nGdmkGbcdjixRzoBpOVA4jZ8Wv4cSKuff56Z+efPOSAt6R8Ia2E4YJNgcLaZTYK3AaQlB78tkmcY2272HLAx3HjmsJk1z7HDxjy3cwoOJBjg9gvfGeZjN34ckJCXO5P4+OaPmsNy7LPTN3/4UGEnh0sLMC4asDoYl/JRMApGwSgYBcQAANK5Z0I1691WAAAAAElFTkSuQmCC","orcid":"","institution":"Karadeniz Technical University","correspondingAuthor":true,"prefix":"","firstName":"Merve","middleName":"","lastName":"Kişioğlu","suffix":""},{"id":488121970,"identity":"0e994b03-2757-4cc6-8d7c-c3c0f005963f","order_by":2,"name":"Burcu Güven","email":"","orcid":"","institution":"Karadeniz Technical University","correspondingAuthor":false,"prefix":"","firstName":"Burcu","middleName":"","lastName":"Güven","suffix":""},{"id":488121971,"identity":"e86aa75e-cb73-4620-bb60-59a661762c50","order_by":3,"name":"Nalan Yıldız","email":"","orcid":"","institution":"Karadeniz Technical University","correspondingAuthor":false,"prefix":"","firstName":"Nalan","middleName":"","lastName":"Yıldız","suffix":""},{"id":488121974,"identity":"0af54216-f3a2-4452-b1b5-ec3455c301cc","order_by":4,"name":"Fazıl Orhan","email":"","orcid":"","institution":"Karadeniz Technical University","correspondingAuthor":false,"prefix":"","firstName":"Fazıl","middleName":"","lastName":"Orhan","suffix":""}],"badges":[],"createdAt":"2025-07-10 12:23:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7092977/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7092977/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00431-025-06533-7","type":"published","date":"2025-10-14T15:58:02+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":93956150,"identity":"c834979d-42d7-4a29-9e26-7965e2879054","added_by":"auto","created_at":"2025-10-20 16:11:12","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":887907,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7092977/v1/140175ac-35e9-462b-9d72-37c594897c88.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eCould Ig E Mediated Cow's Milk Protein Allergy Be a Risk Factor in the Development of Functional Gastrointestinal Disease?\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eCow’s milk protein allergy (CMPA) is the most common food allergy in early childhood, with a reported prevalence of 1-7.5% (1). CMPA is seen in three forms: immunoglobulin E (IgE)-mediated, non-IgE-mediated, and mixed. IgE-mediated food allergies often develop within the first two hours following food intake, while non-IgE-mediated food allergies develop within a few hours or days following food intake. Mixed-type food allergies, on the other hand, typically affect the gastrointestinal tract and skin, with both mechanisms acting together (2).\u003c/p\u003e\n\u003cp\u003eFunctional gastrointestinal disorders (FGID) are chronic and frequently seen digestive system disorders manifesting with abdominal pain, bloating, distension and/or altered bowel habits (constipation, diarrhea or both) (3). Numerous factors including nutrition, low socioeconomic status, psychological factors, and genetic factors have been implicated in the development of FGID. In allergic children exposed to cow’s milk proteins, mast cells have been observed to migrate to the enteric nervous system and become active, which is considered to result in gastrointestinal dysmotility (4). Accordingly, it is proposed that CMPA may trigger gastroesophageal reflux and may also be a factor that may predispose to functional gastrointestinal disorders (5).\u003c/p\u003e\n\u003cp\u003eIn this study, we aimed to investigate whether a diagnosis of CMPA in infancy is a risk factor for the development of FGID in the long term. In addition, we also aimed to explore whether there is a difference between patients with IgE-mediated and non-IgE-mediated CMPA with regard to the development of FGID.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003eThe study included a total of 310 pediatric patients diagnosed with CMPA between January 1, 2011 and December 30, 2019. Of these, 60 patients were excluded since the families of 50 children could not be contacted, the families of eight children refused to participate in the study, and two children had active CMPA. The remaining 250 patients aged 4-18 years who had been diagnosed with CMPA and had completed their treatment plans\u0026nbsp;were included in the study. The control group consisted of 250 children of a similar age who were not diagnosed with CMPA. Patients with congenital gastrointestinal anomalies and/or known organic gastrointestinal disorders (inflammatory bowel disease, gastritis) were not included in the study.\u003c/p\u003e\n\u003cp\u003eA questionnaire including Rome IV criteria and probing about gastrointestinal symptoms was prepared and administered to the parents of 500 children participating in the study either face-to-face or via phone. Patients were evaluated according to Rome IV criteria for functional dyspepsia (FD), functional abdominal pain-not otherwise specified (FAP-NOS), functional constipation (FC), irritable bowel syndrome (IBS), non-retentive fecal incontinence (NRFI), and cyclic vomiting syndrome (CVS).\u003c/p\u003e\n\u003cp\u003ePatients’ previous clinical and laboratory findings (skin prick test, total IgE, specific IgE, eosinophil count) were retrieved from hospital databases. Patients diagnosed with CMPA were divided into two groups as IgE-mediated and non-IgE-mediated CMPA according to clinical and laboratory findings (skin prick test and specific IgE).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eApproval for the study was obtained from Karadeniz Technical University Faculty of Medicine Ethics Committee with appropriate data use agreements.\u003c/p\u003e\n\u003cp\u003eThe study was conducted in accordance with the principles of the Declaration of Helsinki. The study was approved by Karadeniz Technical University Scientific Research Ethics Committee (Approval No: 24237859-611).\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eData were analyzed using SPSS 22.0 (IBM Corp., 2013). Descriptives were expressed as frequencies (n) and percentages (%) for categorical variables and as mean and standard deviation (SD) for continuous variables. Chi-square test was used for the comparison of categorical variables between independent groups. The Mann-Whitney U test was used to compare continuous variables that were not normally distributed between two independent groups. The normality of continuous variables was assessed using the Kolmogorov-Smirnov and Shapiro-Wilk tests. A \u003cem\u003ep\u003c/em\u003e level of \u0026lt;0.05 was considered significant.\u003c/p\u003e\n\u003cp\u003eThe study was approved by the Ethics Committee of Karadeniz Technical University Farabi Hospital (No: 24237859-611). A written informed consent was obtained from each parent or legal guardian of all children participating in the study.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003eThe study included a total of 500 patients, comprising 250 patients diagnosed with CMPA who had completed their treatment plans and 250 patients without a CMPA diagnosis. Patients with CMPA included 145 (58%) boys with a mean age of 5.7±2.0 years and the control group consisted of 138 (55.2%) boys with a mean age of 6.8±3.2 years (Table 1).\u003c/p\u003e\n\u003cp\u003eIn patients with CMPA, most common presenting symptom was diarrhea (n=117; 46.8%), followed by foamy stool (n=66; 26.4%), atopic dermatitis (n=57; 22.8%), and bloody stool (n=49; 19.6%). Laboratory workup indicated that 79 (31.6%) had an absolute eosinophil count of greater than 500/ml, 98 (39.2%) had positive milk-specific IgE, and 64 (25.6%) had positive skin prick test results. Based on these findings, 143 (57.2%) of the patients were diagnosed with non-IgE-mediated CMPA and 107 (42.8%) with IgE-mediated CMPA (Table 2).\u003c/p\u003e\n\u003cp\u003ePatients with IgE-mediated CMPA included 68 (63.6%) boys with a mean of 6.1±2.3 years and patients with non-IgE-mediated CMPA included 77 (53.8%) boys with a mean of 5.4±1.6 years. In IgE-mediated CMPA patients, food allergies other than CMPA were significantly more common (\u003cem\u003ep\u003c/em\u003e=0.041) and absolute eosinophil and total IgE values were significantly higher (\u003cem\u003ep\u003c/em\u003e≤0.001 and p≤0.001, respectively) compared to non-IgE-mediated CMPA patients (Table 3).\u003c/p\u003e\n\u003cp\u003eIn total, FGID were detected in 146 (29.2%) patients, comprising 70 (28%) patients with CMPA and 76 (30.4%) patients without CMPA. However, no significant difference was found between the two groups (\u003cem\u003ep\u003c/em\u003e=0.623). In addition, FGID were observed in 36 (33.6%) of patients with IgE-mediated CMPA and 34 (23.8%) patients without IgE-mediated CMPA. Similarly, no significant difference was found between these two groups (\u003cem\u003ep\u003c/em\u003e=0.115) (Table 4).\u003c/p\u003e\n\u003cp\u003eIt was also revealed that FAP-NOS, IBS, and NRFI were significantly higher in patients without CMPA compared to non-CMPA patients (\u003cem\u003ep\u003c/em\u003e=0.009, \u003cem\u003ep\u003c/em\u003e=0.016, and \u003cem\u003ep\u003c/em\u003e=0.034, respectively). By contrast, FC more frequently seen in patients with CMPA and this difference was statistically significant (\u003cem\u003ep\u003c/em\u003e≤0.001). However, no significant difference was observed between the two groups with regard to FD and CVC.\u003c/p\u003e\n\u003cp\u003eOn the other hand, FD, FAP-NOS, and IBS were significantly more common in patients with IgE-mediated CMPA patients compared to non-IgE-mediated CMPA patients (\u003cem\u003ep\u003c/em\u003e≤0.001, \u003cem\u003ep\u003c/em\u003e=0.001, and \u003cem\u003ep\u003c/em\u003e=0.002, respectively). In contrast, FC was significantly more common in patients with non-IgE-mediated CMPA (\u003cem\u003ep\u003c/em\u003e=0.018).\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis study was conducted to investigate whether a diagnosis CMPA in infancy is a risk factor for the development of FGID in the long term. The results indicated that the frequency of FGID were 28% in patients diagnosed with CMPA and no significant difference was observed between patients with patients without CMPA. However, FAP-NOS, IBS, and NRFI were significantly more common in patients without CMPA. On the other hand, the frequency of FGID were significantly higher in patients with IgE-mediated CMPA, while no significant difference was observed. In comparison, FD, FAP-NOS and IBS were significantly more common in patients with IgE-mediated CMPA.\u003c/p\u003e\n\u003cp\u003eLiterature indicates that CMPA is a predisposing or accompanying factor for FGID in children (5). In a study conducted in Turkey, FGID were detected in 31.1% of children diagnosed with CMPA (6). A study by Saps et al. evaluated 52 children aged 4-18 years who were diagnosed with CMPA in the first year of their lives and detected gastrointestinal symptoms in 44.2% and FGID in 19.2% of the children (7). In our study, in line with the literature, FGID were detected in 28% of the patients diagnosed with CMPA. However, no significant difference was observed between patients with and without CMPA. A study by Di Nardo et al. reported that the frequency of FGID were significantly higher in patients with CMPA compared to patients without. Given that CMPA and FGID have a common pathophysiology (mucosal inflammation, intestinal microbiota, diet), this finding is not surprising. However, the number of patients with CMPA in that study was relatively small (n=80) (8). On the other hand, the number of case-controlled studies on this subject is not sufficient.\u003c/p\u003e\n\u003cp\u003eIn our study, FAP-NOS, IBS, and NRFI were significantly higher in patients without CMPA compared to patients with CMPA. There are contradictory findings in the literature regarding the relationship between CMPA and FAP. While some studies show a relationship between CMPA and FAP (7), other studies propose that there is insufficient evidence to support this relationship (9).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThere are very few studies in the literature examining the relationship between encopresis and CMPA. In a study conducted by Iacono et al., the incidence of encopresis was determined as 7.4% in 27 children diagnosed with CMPA (10). Another study conducted in Italy determined the incidence of encopresis as 8.3% in CMPA cases aged 30-70 months (11).\u003c/p\u003e\n\u003cp\u003eStudies investigating the relationship between CMPA and IBS have mostly evaluated food allergies together instead of evaluating CMPA in isolation. In a study conducted by Carroccio et al., food allergies including CMPA were detected in 25% of 160 patients diagnosed with IBS (12). In a study conducted in Stockholm in 2014 with 2610 children, it was observed that 9% of children who developed food allergies at the age of 4 or 8 developed IBS at the age of 12 years, and the difference was found to be statistically significant. The authors suggested that this finding could be an independent risk factor for IBS (13). A 2017 study conducted in Taiwan found that 11,242 preschool children with a history of food and other allergic diseases had a 77% increased risk of developing IBS when they reached school age (14).\u003c/p\u003e\n\u003cp\u003eIn addition to its traditional association with food, IBS is now linked to anxiety, depression, and other psychiatric conditions, and is considered a psychosomatic disorder (15). Moreover, some studies have shown that genetic factors play a major role in the development of IBS (16). These findings suggest that IBS, in a similar way to FAP and NRFI, can occur due to both CMPA and other factors. We consider that other factors were effective in the higher frequency of these disorders in our non-CMPA patients compared to CMPA patients. In addition, the higher rate in patients without CMPA could be explained by the fact that CMPA patients tend to be more cautious about their diets due to concerns about allergic reactions, often altering their eating habits because of anxiety surrounding this issue. These differences in dietary patterns also lead to variations in the microbiota among patients.\u003c/p\u003e\n\u003cp\u003eIn our study, a comparison of the frequency of FGID between IgE-mediated and non-IgE-mediated CMPA patients indicated that although the frequency was higher in IgE-mediated CMPA patients, no significant difference was observed. To our knowledge, there has been no study comparing IgE-mediated and non-IgE-mediated CMPA patients in the literature. In FD patients, however, it has been shown that allergic reactions to food proteins may contribute to symptoms (17). A recent study conducted in 2023 found that eliminating cow’s milk and dairy products in FD patients was more effective in reducing gastrointestinal symptoms than receiving medical treatment (18). In our study, FD, FAP-NOS, and IBS were more commonly observed in patients with IgE-mediated CMPA. This suggests that subclinical CMPA may persist in these patients. Particularly in patients with IgE-mediated CMPA, the prolonged development of tolerance and the frequent occurrence of coexisting allergic diseases necessitate a longer-term healthy diet for the children.\u003c/p\u003e\n\u003cp\u003eThe strengths of our study include the large number of patients and its case-control design. Additionally, there is no existing study in the literature comparing patients with IgE-mediated and non-IgE-mediated CMPA. However, considering that the pathophysiology of FGID is multifactorial, factors such as diet and stress were not included in our study. The use of a food diary and depression scale could have provided valuable insights for these patients.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eAlthough the long-term frequency of FGID development did not increase significantly in patients diagnosed with CMPA compared to non-CMPA patients in our study, FD, FAP, and IBS were notably higher, particularly in patients with IgE-mediated CMPA. The development of FGID is multifactorial, and CMPA alone is not sufficient to explain it. However, the risk is higher in IgE-mediated CMPA. Further case-controlled studies with large patient populations are needed to explore this topic more comprehensively.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eThe author(s) indicated no potential conflicts of interest.\u003c/p\u003e\n\u003cp\u003eNo financial or non-financial benefits have been received or will be received from any party related directly or indirectly to the subject of this article.\u003c/p\u003e\n\u003cp\u003eThe study was conducted in accordance with the principles of the Declaration of Helsinki. The study was approved by Karadeniz Technical University Scientific Research Ethics Committee (Approval No: 24237859-611).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eInformed consent was obtained from patients.\u003c/p\u003e\n\u003cp\u003eThis is an original article.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eNur Kevser \u0026Ouml;zyurt, Merve Kişioğlu and Burcu G\u0026uuml;ven wrote the manuscript text and prepared tables. All authors reviewed the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBognanni A, Fiocchi A, Arasi S, Chu DK, Ansotegui I, Assa'ad AH, Bahna SL, Berni Canani R, Bozzola M, Dahdah L, Dupont C, Dziechciarz P, Ebisawa M, Firmino RT, Chu A, Galli E, Horvath A, Kamenwa R, Lack G, Li H, Martelli A, Nowak-Węgrzyn A, Papadopoulos NG, Pawankar R, Roldan Y, Said M, S\u0026aacute;nchez-Borges M, Shamir R, Spergel JM, Szajewska H, Terracciano L, Vandenplas Y, Venter C, Waffenschmidt S, Waserman S, Warner A, Wong GWK, Sch\u0026uuml;nemann HJ, Brozek JL (2024) World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) guideline update - XII - Recommendations on milk formula supplements with and without probiotics for infants and toddlers with CMA. World Allergy Organ J. ;17(4)\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSicherer SH, Sampson HA (2018) Food Allergy: A Review and Update on Epidemiology, Pathogenesis, Diagnosis, Prevention, And Management. J Allergy Clin Immunol 141(1):41\u0026ndash;58\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAllen KJ, Koplin JJ (2012) The Epidemiology of IgE-Mediated Food Allergy and Anaphylaxis. Immunol Allergy Clin North Am 32(1):35\u0026ndash;50\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBorrelli O Neuroimmune interaction and anorectal motility in children with food allergy-related chronic constipation. Official journal of the American College of Gastroenterology, Votto A, D\u0026rsquo;Auria M, Castagnoli E, Caimmi R, Marseglia SME et al (2009) GL. Eosinophilic Gastrointestinal Diseases in Children: A Practical Review. Curr Pediatr Rev. 2020; 16(2):106\u0026ndash;114\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLicari A, Votto M, D\u0026rsquo;Auria E, Castagnoli R, Caimmi SME, Marseglia GL (2020) Eosinophilic Gastrointestinal Diseases in Children: A Practical Review. Curr Pediatr Rev 16(2):106\u0026ndash;114\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eErel O (2022) İnek s\u0026uuml;t\u0026uuml; protein alerjisi tanılı 4\u0026ndash;10 yaş arası \u0026ccedil;ocuklarda gastrointestinal semptomların incelenmesi [tez]. Dokuz Eyl\u0026uuml;l \u0026Uuml;niversitesi, İzmir\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSaps M, Lu P, Bonilla S (2011) Cow\u0026rsquo;s-Milk Allergyis a Risk Factor for the Development of FGIDs in Children. J Pediatr Gastroenterol Nutr 52(2):166\u0026ndash;169\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGiovanni DINARDO et al (2018) Allergic proctocolitis is a risk factor for functional gastrointestinal disorders in children. J Pediatr 195:128\u0026ndash;133e1\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePensabene L, Salvatore S, D\u0026rsquo;auria E, Parisi F, Concolino D, Borrelli O et al (2018) Cow\u0026rsquo;sMilk Protein Allergy in Infancy: A Risk Factor for Functional Gastrointestinal Disorders in Children? Nutrients. ;(10): 1716\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eIacono G, Carroccio A, Cavataio F, Montalto G, Cantarero MD, Notarbartolo A (1995) Chronic Constipation as a Symptom of Cow Milk Allergy. J Pediatr 126(1):34\u0026ndash;39\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCarroccio A, Scalici C, Maresi E, DiPrima L, Cavataio F, Noto D et al (2005) Chronic Constipation and Food Intolerance: A Model of Proctitis Causing Constipation. Scand J Gastroenterol 40(1):33\u0026ndash;42\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCarroccio A, Brusca I, Mansueto P, Soresi M, D\u0026rsquo;alcamo A, Ambrosiano G et al (2011) Fecal Assays Detect Hypersensitivity to Cow\u0026rsquo;sMilk Protein and Gluten in Adults with Irritable Bowel Syndrome. Clin Gastroenterol Hepatol 9(11):965\u0026ndash;971\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eOl\u0026eacute;n O, Neuman A, Koopmann B, Ludvigsson JF, Ballardini N, Westman M et al (2014) Allergy-Related Diseases and Recurrent Abdominal Pain During Childhood \u0026ndash; A Birth Cohort Study. Aliment Pharmacol Ther 40(11\u0026ndash;12):1349\u0026ndash;1358\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTan TK, Chen AC, Lin CL, Shen TC, Li TC, Wei CC (2017) Preschoolers with Allergic Diseases Have an Increased Risk of Irritable Bowel Syndrome When Reaching School Age. J Pediatr Gastroenterol Nutr 64(1):26\u0026ndash;30\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHenstr\u0026ouml;m M, D\u0026rsquo;Amato M (2016) Genetics of Irritable Bowel Syndrome. Mol Cell Pediatr 3(7):1\u0026ndash;5\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSaito YA (2011) The Role of Genetics in IBS. Gastroenterol Clin North Am 40(1):45\u0026ndash;67\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRavelli AM, Tobanelli P, Volpi S, Ugazio AG (2001) Vomiting and Gastric Motility in Infants with Cow\u0026rsquo;s Milk Allergy. J Pediatr Gastroenterol Nutr 32(1):59\u0026ndash;64\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAkpınar A (2021) Fonksiyonel dispepsi hastalarında inek s\u0026uuml;t\u0026uuml; ve \u0026uuml;r\u0026uuml;nlerinin kesilmesinin dispepsiye etkisinin değerlendirilmesi [tez]. Bezm-i Alem Vakıf \u0026Uuml;niversitesi, İstanbul\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1\u003c/strong\u003e. Demographic and clinical characteristics\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"99%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" rowspan=\"2\" style=\"width: 43px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eAll patients\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eCMPA (+)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eCMPA (-)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 12px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ep\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e\u003cstrong\u003en (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u003cstrong\u003en (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u003cstrong\u003en (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGender\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e283 (56.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e145 (58.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e138 (55.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e0.528\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e283(6.2\u0026plusmn; 2.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e145(5.7\u0026plusmn;2.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e138(6.8\u0026plusmn;3.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMode of delivery\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eNSVD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e330 (66.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e141 (56.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e189 (75.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCoexisting allergic disease\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e20 (3.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e17 (6.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e3 (1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.003\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" style=\"width: 28px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCoexisting allergic diseases\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eAtopic dermatitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e4 (0.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e4 (1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eAllergic rhinitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e2 (0.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e2 (0.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eAsthma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e14 (2.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e11 (5.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e3 (1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFood allergy other than CMPA\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e62 (12.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e60 (24.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e2 (0.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"6\" style=\"width: 28px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFood allergies other than CMPA\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eEgg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e53 (10.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e52 (20.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e1 (0.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003ePeanut\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e9 (1.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e8 (3.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e1 (0.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eNuts\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e21 (4.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e21 (8.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eDry legumes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e15 (3.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e15 (6.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eSeafood\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e2 (0.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e2 (0.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eWheat\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e15 (3.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e15 (6.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFamily history of allergies\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e127 (25.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e79 (31.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e48 (19.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"7\" style=\"width: 28px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFamilial allergic diseases\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eAsthma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e44 (8.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e24 (9.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e20 (8.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eEczema\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e41 (8.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e29 (11.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e12 (4.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eRhinitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e10 (2.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e4 (1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e6 (2.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eUrticaria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e13 (2.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e7 (2.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e6 (2.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eMedicine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e7 (1.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e7 (2.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eFood\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e16 (3.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e9 (3.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e7 (2.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eCow\u0026rsquo;s milk\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e15 (3.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e13 (5.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e2 (0.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBreastfeeding\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e482 (96.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e242 (96.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e240 (96.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e0.810\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e* Percentage within column\u003c/p\u003e\n\u003cp\u003eCMPA: Cow\u0026rsquo;s milk protein allergy\u003c/p\u003e\n\u003cp id=\"_Toc178342345\"\u003e\u003cstrong\u003eTable 2.\u003c/strong\u003e Demographic and clinical characteristics in CMPA patients\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 328px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e\u003cstrong\u003en (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"8\" style=\"width: 122px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePresenting symptoms\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 206px;\"\u003e\n \u003cp\u003eDiarrhea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 134px;\"\u003e\n \u003cp\u003e117 (46.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 206px;\"\u003e\n \u003cp\u003eFoamy mucous stool\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 134px;\"\u003e\n \u003cp\u003e66 (26.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 206px;\"\u003e\n \u003cp\u003eAtopic dermatitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 134px;\"\u003e\n \u003cp\u003e57 (22.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 206px;\"\u003e\n \u003cp\u003eBloody stool\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 134px;\"\u003e\n \u003cp\u003e49 (19.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 206px;\"\u003e\n \u003cp\u003eConstipation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 134px;\"\u003e\n \u003cp\u003e13 (5.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 206px;\"\u003e\n \u003cp\u003eColic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 134px;\"\u003e\n \u003cp\u003e4 (1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 206px;\"\u003e\n \u003cp\u003eWheeze\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 134px;\"\u003e\n \u003cp\u003e3 (1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 206px;\"\u003e\n \u003cp\u003eAngioedema\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 134px;\"\u003e\n \u003cp\u003e3 (1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 122px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAbsolute eosinophil count\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 206px;\"\u003e\n \u003cp\u003e\u0026lt;500\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 134px;\"\u003e\n \u003cp\u003e171 (68.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 206px;\"\u003e\n \u003cp\u003e\u0026gt;500\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 134px;\"\u003e\n \u003cp\u003e79 (31.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 122px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMilk-specific IgE\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 206px;\"\u003e\n \u003cp\u003ePositive\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 134px;\"\u003e\n \u003cp\u003e98 (39.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 206px;\"\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 134px;\"\u003e\n \u003cp\u003e152 (60.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" style=\"width: 122px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSkin prick test\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 206px;\"\u003e\n \u003cp\u003ePositive\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 134px;\"\u003e\n \u003cp\u003e64 (25.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 206px;\"\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 134px;\"\u003e\n \u003cp\u003e154 (61.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 206px;\"\u003e\n \u003cp\u003eUntested\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 134px;\"\u003e\n \u003cp\u003e32 (12.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 122px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIgE mediation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 206px;\"\u003e\n \u003cp\u003eIgE-mediated\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 134px;\"\u003e\n \u003cp\u003e107 (42.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 206px;\"\u003e\n \u003cp\u003eNon-IgE-mediated\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 134px;\"\u003e\n \u003cp\u003e143 (57.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 122px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal IgE\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 206px;\"\u003e\n \u003cp\u003eNormal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 134px;\"\u003e\n \u003cp\u003e203 (81.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 206px;\"\u003e\n \u003cp\u003eHigh\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 134px;\"\u003e\n \u003cp\u003e47 (18.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e* Percentage within column\u003c/p\u003e\n\u003cp\u003eCMPA: Cow\u0026rsquo;s milk protein allergy\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3.\u003c/strong\u003e Demographic and clinical characteristics in patients with and without IgE-mediated CMPA\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"82%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" rowspan=\"3\" style=\"width: 47px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" style=\"width: 52px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIgE mediation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eYes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u003cstrong\u003en (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003en (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 27px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGender\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e68 (63.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e77 (53.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.124\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 27px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e68 (6.1\u0026plusmn;2.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e77(5.4\u0026plusmn;1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.004\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 27px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMode of delivery\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eNSVD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e64 (59.8)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e77 (53.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.417\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 27px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCoexisting allergic diseases\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e11 (10.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e6 (4.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.102\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 27px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFood allergy other than CMPA\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e33 (30.8)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e27 (18.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.041\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 27px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFamily history of allergies\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e30 (28.0)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e49 (34.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.295\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 27px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBreastfeeding\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e10 (98.1)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e137 (95.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.472\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 27px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAbsolute eosinophil count\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026gt;500\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e49 (45.8)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e30 (21.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 27px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal IgE\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eHigh\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e34 (31.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e13 (9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e* Percentage within column\u003c/p\u003e\n\u003cp\u003eCMPA: Cow\u0026rsquo;s milk protein allergy, NSVD: Normal spontaneous vaginal delivery\u003c/p\u003e\n\u003cp id=\"_Toc178342348\"\u003e\u003cstrong\u003eTablo 4.\u003c/strong\u003e Functional gastrointestinal disorders in patient groups\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"101%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCMPA\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 38px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIgE mediation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 22px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCMPA -\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCMPA +\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 8px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ep\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eYes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 12px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ep\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003en (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u003cstrong\u003en (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003en (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e\u003cstrong\u003en (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFunctional Dyspepsia\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e26 (10.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e26 (10.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e5 (3.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e21 (19.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFunctional Abdominal pain\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e40 (16.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e20 (8.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.009\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e4 (2.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e16 (15.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFunctional Constipation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e3 (1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e26 (10.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e21 (14.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e5 (4.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.018\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIrritable Bowel Syndrome\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e37 (14.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e19 (7.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.016\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e4 (2.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e15 (14.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.002\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEncopresis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e36 (14.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e16 (6.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.034\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e11 (10.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e5 (4.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e0.334\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCyclic vomiting syndrome\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e14 (5.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e6 (2.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.110\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e5 (3.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e1 (0.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e0.244\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e76 (30.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e70 (28.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.623\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e34 (23.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e36 (33.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e0.115\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eCMPA: Cow\u0026rsquo;s milk protein allergy\u0026nbsp;\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejpe","sideBox":"Learn more about [European Journal of Pediatrics](https://www.springer.com/journal/431)","snPcode":"431","submissionUrl":"https://submission.nature.com/new-submission/431/3","title":"European Journal of Pediatrics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Cow’s milk protein allergy, Functional gastrointestinal disorders, pediatric","lastPublishedDoi":"10.21203/rs.3.rs-7092977/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7092977/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjectives\u003c/h2\u003e\u003cp\u003eNumerous factors have been implicated in the development of functional gastrointestinal disorders (FGID). In this study, we aimed to investigate whether a diagnosis of cow\u0026rsquo;s milk protein allergy (CMPA) in infancy is a risk factor for the development of FGID in the long term and whether there is a difference between patients with IgE-mediated and non-IgE-mediated CMPA with regard to the development of FGID.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eThe study included 250 patients aged 4\u0026ndash;18 years who had been diagnosed with CMPA in infancy. The control group consisted of 250 children of a similar age without CMPA. A questionnaire including Rome IV criteria was prepared and administered to the parents of 500 children.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eFGID were observed in 70 (28%) patients with CMPA and in 76 (30.4%) patients without CMPA (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.623). functional abdominal pain-not otherwise specified (FAP-NOS), irritable bowel syndrome (IBS), and non-retentive fecal incontinence (NRFI) were significantly more common in patients without CMPA (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.009, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.016, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.034, respectively). FGID were observed in 36 (33.6%) patients with IgE-mediated CMPA as opposed to 34 (23.8%) patients with non-IgE-mediated CMPA (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.115). functional dyspepsia (FD), FAP-NOS, and IBS were significantly more common in patients with IgE-mediated CMPA (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026le;\u0026thinsp;0.001, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002, respectively).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eAlthough the frequency of FGID development did not increase in the long term in our CMPA patients, FD, FAP-NOS, and IBS were significantly more common in these patients, particularly in those with IgE-mediated CMPA. This suggests that subclinical CMPA may persist in patients with IgE-mediated CMPA.\u003c/p\u003e","manuscriptTitle":"Could Ig E Mediated Cow's Milk Protein Allergy Be a Risk Factor in the Development of Functional Gastrointestinal Disease?","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-22 18:33:50","doi":"10.21203/rs.3.rs-7092977/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-08-31T06:53:35+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-31T00:59:08+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-24T14:34:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"191705935207140051125016636925511106721","date":"2025-08-10T17:27:32+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"165257421624440838508603092419734830984","date":"2025-08-10T11:33:36+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"214071005390296775066929990541764497835","date":"2025-07-19T15:04:13+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-07-17T14:31:20+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-17T07:11:39+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-07-17T01:09:31+00:00","index":"","fulltext":""},{"type":"submitted","content":"European Journal of Pediatrics","date":"2025-07-10T12:12:32+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejpe","sideBox":"Learn more about [European Journal of Pediatrics](https://www.springer.com/journal/431)","snPcode":"431","submissionUrl":"https://submission.nature.com/new-submission/431/3","title":"European Journal of Pediatrics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"95b9e8a6-b979-4f7b-b60d-59f322b94498","owner":[],"postedDate":"July 22nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-10-20T16:07:18+00:00","versionOfRecord":{"articleIdentity":"rs-7092977","link":"https://doi.org/10.1007/s00431-025-06533-7","journal":{"identity":"european-journal-of-pediatrics","isVorOnly":false,"title":"European Journal of Pediatrics"},"publishedOn":"2025-10-14 15:58:02","publishedOnDateReadable":"October 14th, 2025"},"versionCreatedAt":"2025-07-22 18:33:50","video":"","vorDoi":"10.1007/s00431-025-06533-7","vorDoiUrl":"https://doi.org/10.1007/s00431-025-06533-7","workflowStages":[]},"version":"v1","identity":"rs-7092977","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7092977","identity":"rs-7092977","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}