Materials and Methods
Study Population
The study protocol, part of a large-scale prospective research project studying the development of CMA in children, was approved by the Helsinki Review Board at Assaf Harofeh Medical Center, and informed consent was obtained from all parents. Of a cohort of 13 234 newborns, born over a 2-year period, 13 019 (98.38%) completed the study. Siblings were excluded. Parents were asked to contact the allergy clinic immediately after any adverse reaction (cutaneous, respiratory, gastrointestinal (GI) or systemic) suspected of being related to maternal or infant consumption of CMP. All parents were contacted 3 months after birth and subsequently bimonthly, and infants' feeding patterns were recorded. Any parent noting a possible adverse event related to CMP was invited for further evaluation. In addition, infants whose parents avoided exposing them to CMP despite having discontinued exclusive or almost exclusive breast feeding, because of general beliefs about the risks of this exposure, were also evaluated. Overall, 381 infants were avoiding CMP (figure 1). After the initial evaluation, 66 infants were diagnosed with IgE-mediated CMA (IgE-CMA), 36 were diagnosed with food protein-induced enterocolitis syndrome, 21 were diagnosed with CMP-associated rectal bleeding, and 15 patients had other symptoms for which a causative relationship to CMP could not be excluded. In the remaining 243 infants (1.87%), categorised as mislabelled CMA, a causal relationship between the complaint and the consumption of CMP was ruled out after a detailed history on the temporal association between the infant's symptoms and the consumption of CMP, the nature of the symptoms, and their reproducibility on repeated exposures. In most cases, the symptoms were not compatible with IgE- or non-IgE-mediated CMA. Skin prick tests (SPTs) and OFCs were performed when history alone was inconclusive.
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Figure 1.
Cow's milk protein (CMP)-related syndromes in the study population. A flow chart showing categorisation of the study population into specific syndromes associated with CMP consumption. FPIES, food protein induced enterocolitis syndrome.
Evaluation and Follow-up
Parents of infants categorised as mislabelled CMA were encouraged to resume CMP-based feeding, and the infants were followed for reappearance of symptoms. In general, infants were followed until their cow's milk-related symptoms resolved. In infants with IgE-CMA, the follow-up extended up to 5 years. Infants with mislabelled adverse reactions to CMP were compared with the group of infants diagnosed with IgE-CMA (n=66) and with the whole group of healthy infants with no adverse effects related to CMP (n=12 638). For analyses of variables that were not available for the whole cohort, 232 infants from this group were randomly chosen, using MATLAB's randperm function, to serve as a control group. Of these, 156 families (312 parents) were successfully recruited for evaluation.
Skin Prick Tests
SPTs for CMP and soy were performed in the infants using the volar arm and reading the reaction after 20 min. A negative control and histamine (1 mg/ml; ALK-Abelló, Port Washington, New York, USA) were used. A wheal response ≥3 mm was considered positive.
Oral Challenge
An OFC to cow's milk formula was performed using Materna (Maabarot Products Ltd, Maabarot, Israel) infant formula unless a history of a life-threatening reaction manifested as either anaphylaxis or severe respiratory distress on exposure to milk protein was reported. Increasing doses were given, from a 1:10 diluted formula of 1.0 ml (2.7 mg CMP) up to 120 ml (3.24 g CMP) every 30 min. The challenge was terminated if a cutaneous, respiratory, GI or systemic response was observed. In the case of a negative challenge result, the infants were observed for 3 h, and subsequent contact was made 2 weeks later to enquire about their feeding habits.
Statistical Analysis
Statistical analyses were performed with SPSS software (V.16). Continuous variables were analysed using the Student t test or one-way analysis of variance and are presented as mean±SD. Fisher's exact test was used to analyse differences between groups in categorical variables. All analyses were two-tailed, and a p value <0.05 was considered significant.