Authors' response.

Abstract

To the editor, We thank Stefano Miceli Sopo, Roberta Arena, and Guglielmo Scala for the interest in our recent article “Evaluation and Treatment of Functional Constipation in Infants and Children: Evidence-Based Recommendations From ESPGHAN and NASPGHAN” (1). Miceli Sopo et al conducted a review of the literature (2) and found 6 studies that were, indeed, not included in the guideline (3–8). Based on their review, which has not yet been published, the authors “believe that the available scientific evidence for a causal relation between CMPA (cow's-milk protein allergy) and functional constipation is now sufficient to formulate a grade A recommendation” and “that a 2- to 4-week restricted diet should not be considered only after all of the other options had failed, but should be instead proposed and discussed with patients and their families as a first-line therapeutic strategy.” In the the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition/North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition guideline, question 4 discusses whether children with constipation should be tested for cow's-milk allergy as an underlying disease (1). To answer this clinical question, the association between CMPA and constipation in children should be investigated: Is the association biologically plausible, are children with constipation more often allergic to cow's milk than children without constipation, and does elimination of exposure to the allergen (cow's-milk–free diet) resolve constipation? Another question concerns the accuracy of the CMA tests. The association between CMPA and constipation has been debated since the study by Iacono et al, in which the authors found that 78% of children affected by constipation and CMPA improved after a CMP elimination diet (9). These data were partially confirmed by a subsequent study by the same authors, in which 18 of 44 (41%) children responsive to a CMP elimination diet were found to have positive specific immunoglobulin E antibodies to cow's-milk antigens (10). Both studies were performed in an allergy center that could have led to an overestimation of the strength of this association. More important, a double-blind provocation test, considered to be the criterion standard to diagnose allergy to a food antigen, was not used in these studies. El-Hodhod et al compared children with constipation with healthy children in their response to a cow's-milk–free diet followed by reinstitution of cow's milk. The results confirmed the data of Iacono et al, and the authors concluded that cow's-milk allergy should be considered a significant etiologic factor for constipation in infants and young children and that cow's-milk tolerance is often achieved after at least 12 months of strict elimination of cow's milk (11). As in the Iacono study, a double-blind provocation test was not used to diagnose food allergy. In contrast to these studies, Simeone et al did not confirm this association. In an unselected Italian pediatric population, the prevalence of atopy in constipated children was not different from that in children without constipation (12). Moreover, a 4-week trial of dietary elimination did not result in improvement in any of the 11 constipated children. Finally, a study by Irastorza et al found that 51% patients responded to a CMP-elimination diet, but no significant differences were noted between the group of responders and nonresponders regarding atopic/allergic history and laboratory results (13). Based on these studies, we concluded that evidence for cow's-milk allergy as an underlying disease in children with functional constipation is conflicting, and therefore there is at present no rationale for allergy testing (1). Miceli Sopo et al suggest that we missed several important articles reporting the association between constipation and cow's-milk allergy; however, strict criteria were used to include possible studies for our review: systematic reviews or prospective controlled studies were considered, the study population consists of children ages 0 to 18 years with functional constipation, a definition of constipation should be provided by the authors, and examination should be laboratory testing for CMPA. The studies as mentioned by Miceli Sopo et al were excluded because of the lack of a control group (3), because of not performing laboratory testing (4–6), or because the role of food allergy in general was investigated instead of only CMPA (7). The study by Dehghani et al was published after our search date and will be included in the update of the guideline (8). In conclusion, based on the present literature, we do not recommend a 2- to 4-week restricted diet as a first-line therapeutic strategy for young children with constipation. van den Berg et al clearly showed that early therapeutic intervention with oral laxatives beneficially contributes to the outcome of constipation in young children (14). Further research is necessary to unravel the possible relation between cow's-milk allergy and constipation.