Cow's milk protein allergy (CMPA) is the most common food allergy in children [1,2]. About 12 % of parents report adverse milk-related reactions [3]. The prevalence is lower when the oral food challenge test (OFC) is performed to diagnose CMPA, as recommended in guidelines, suggesting overdiagnosis [1,2]. CMPA is a public health issue that can hinder growth, micronutrient intake, feeding, and quality of life [1,2,4,5,7,10,17,18,27,30]. CMPA costs medical treatment, diagnostic testing, drugs, and special diets [5,6,14,15,28,29].

CMPA can be IgE-mediated, non-IgE-mediated, or both. Non-IgE CMPA in infants causes nonspecific gastrointestinal symptoms (non-IgE-GI-CMPA). Functional gastrointestinal problems are common in the first six months of life, making differential diagnosis difficult. OFC is the only approved procedure to confirm CMPA diagnosis (D-OFC) [1,2]. At least 50 % of infants on an elimination diet had CMPA ruled out by D-OFC [3,7–9]. D-OFC can reduce healthcare costs, prevent unnecessary continued elimination diets, and lessen the restrictive diet's negative impacts on nutrition and quality of life [10–13] . The OFC should also be used to determine oral tolerance (OT-OFC) in infants on nutritional therapy for at least six months, thereby shortening the elimination diet [1,2].

Two Brazilian studies found that special formulas account for over 90 % of CMPA's expenditures [14,15]. A recent Brazilian survey revealed that 80 % of pediatricians use special formulas according to guidelines for CMPA infants. However, almost 50 % of pediatricians do not endorse D-OFC [16].

D-OFC and OT-OFC have been recommended for suspected non-IgE-GI-CMPA infants, but no study has evaluated their economic impact. This study aimed to analyze the cost-effectiveness and cost-utility of using OFC to manage non-IgE-GI-CMPA in infants within the Brazilian public health system (Sistema Único de Saúde, SUS).

This study demonstrated that the OFC plays a key role in optimizing the use of medical and financial resources for diagnosing and treating non-IgE-GI-CMPA, thereby reducing dietary restrictions and improving quality of life. Recommending OFC for all infants would save USD 241.98, add 0.019 QALYs, and allow 70 extra days without an elimination diet per patient. Even accounting for a 10 % parental refusal rate for OFC, savings would still reach USD 129 million over five years. Furthermore, a positive OFC reduces diagnostic uncertainty, prevents relapses, and supports appropriate long-term management. The effectiveness outcome focused on diet release (negative OFC) captures only one dimension of the overall benefit of OFC.

Two Brazilian studies assessing the cost-effectiveness of CMPA diagnosis and treatment from the SUS perspective used OFC for diagnostic confirmation but did not evaluate different probabilities of performing it [14,15]. As in the current study, formulas accounted for over 95 % of the costs.

Prescription data from the United Kingdom, Norway, and Australia suggest CMPA overdiagnosis. Assuming a 1 % incidence of CMPA, the volume of specialized formula prescribed in 2020 was higher than expected [6]. However, these estimates did not include formula used during diagnostic elimination diets in infants with negative D-OFC results. This omission may be relevant because the diagnostic phase accounted for approximately one-third of formula costs in the present study (Supplementary Material 3b).

Data on the economic impact of OFC are limited. Two U.S. studies found that timely D-OFC would reduce costs and increase QALYs [11,12]. Although consistent with these findings, these studies involved older children with IgE-mediated allergy rather than infants with non-IgE-GI-CMPA. A Dutch study estimated 16 % higher costs if all infants underwent hospital-based double-blind, placebo-controlled OFC rather than open OFC [28]. In the current study, the authors assumed that open OFC would be performed and that only a percentage of patients would undergo the test in a hospital setting, based on frequencies reported in a Brazilian study [16] (Table 1). It should be noted that the most recent guidelines recommend performing open OFC at home for infants with mild-to-moderate non-IgE-GI-CMPA, reserving hospital settings for severe cases [1,2].

The generalizability of the present findings to other healthcare settings should be approached with caution. The magnitude of cost savings may vary depending on local formula pricing, healthcare delivery models, and reimbursement policies.

In March 2022, CONITEC Report No 720 recommended adopting D-OFC and OT-OFC for infants with suspected CMPA within the SUS [23]. This recommendation considered OFC efficacy, safety, cost-effectiveness, and budget impact compared with skin prick and specific IgE tests. The use of D-OFC showed dominance, with lower costs, greater utility, and potential five-year savings of BRL 470–589 million (USD 94–118 million). Although CONITEC also found lower costs and greater benefits, its estimated annual CMPA management cost of BRL 943 (USD 189) was lower than ours, likely due to differences in models and assumptions. Univariate sensitivity analysis (Supplementary Material 4) showed that costs were most sensitive to age at elimination diet initiation, formula-related factors, and severe CMPA frequency. For the same 24-month time horizon, infants entered the CONITEC model at 6 months versus 3.65 months in this study, with infants under 6 months consuming a significantly larger volume of formula. Additionally, the CONITEC study estimated that only 4 % of infants would consume amino acid-based formulas, which have a higher unit cost, while 20 % would consume soy protein-based formulas, which are less costly. Soy protein-based formulas are not recommended for infants with non-IgE-GI-CMPA and were therefore excluded from this study. Finally, the frequency of severe CMPA was not specified in the CONITEC model, a variable that could increase the use of amino acid-based formulas, nor was the OFC parental refusal rate considered.

As the SUS generally provides families with formulas monthly, the model assumes monthly volumes even for use under 30 days. Biweekly dispensing during diagnosis could reduce costs.

The current study did not assess the costs associated with CMPA for families, and no Brazilian studies using this approach were identified. In Bogotá, 17 % of families with infants and children with CMPA spend >15 % of their monthly income on special foods and formulas [5]. In the United States, between 2011 and 2012, families spent an average of US$931 annually on food allergy-related expenses, mainly due to dietary foods [29]. Although in Brazil hypoallergenic formulas are distributed by the SUS for home use, this supply is often delayed [16], which can postpone the start of a nutritionally adequate elimination diet and impact nutritional status. The high prevalence of anthropometric deficits observed in the meta-analysis may partly result from delays in starting an adequate diet, highlighting the importance of prompt diagnosis and access to formulas.

While this study demonstrates economic benefits from the SUS perspective, equity considerations remain important. Delays in formula distribution and limited access to OFC in certain regions may disproportionately affect vulnerable populations, potentially exacerbating health disparities in CMPA management across Brazil. Another source of delay that this study considered is parental refusal of the OFC. Parental refusal, along with events such as acute infections, exacerbations of atopic dermatitis or asthma, and limited appointment availability, are possible delaying factors. It is also important to consider that regional factors, such as food insecurity, difficulties in accessing specialized centers, and geographical and socioeconomic barriers, may raise parental refusal. Policies that ensure equitable assistance must be prioritized.

The authors acknowledge, as a limitation, that anthropometric deficit represents only one of the possible clinical consequences of non-IgE-GI-CMPA and does not fully reflect the severity of the disease itself. Its prevalence was used to define the probability of severe non-IgE-GI-CMPA, which is among the most influential factors on costs, although it did not affect the GUIDELINE-OFC dominance. To address this gap, a meta-analysis estimated the previously unknown rate of any anthropometric deficit among Brazilian infants aged ≤ 6 months with CMPA. Author-provided data were essential for a successful meta-analysis (Supplementary Material 2a). Additionally, the lack of data on the frequency of non-response to the elimination diet is a limitation. Future studies should investigate its prevalence and diagnostic outcomes. The predominant use of Brazilian data strengthens the results’ national relevance.

The projected savings of USD 129 million over five years for the SUS represent a figure of great significance for public policymakers, reinforcing the importance of incorporating OFC into the SUS, in line with the CONITEC recommendation [23]. Moreover, physician adherence may be a barrier as a previous survey revealed that approximately half of Brazilian pediatricians do not routinely recommend D-OFC [16]. The authors recommend continuing medical education programs and the dissemination of these findings to increase adherence to guideline-recommended practices.

In conclusion, the routine use of D-OFC and OT-OFC in infants with non-IgE-GI-CMPA is a dominant strategy, yielding substantial savings for the SUS. The strategy has the potential to improve nutritional status [13] and quality of life, although these outcomes should be considered as potential benefits rather than findings directly demonstrated by this study. Timely access to elimination diets and OFC is necessary, as is the proper inclusion of OFC in the SUS procedure table and its implementation in both outpatient and hospital settings. Physicians should also adhere to OFC recommendations and explain its safety, importance, and benefits to families.

Escola Paulista de Medicina, Universidade Federal de São Paulo.

This work was supported by the Brazilian National Council for Scientific and Technological Development (CNPq) (grant number 142205/2020-6). The CNPq had no role in the design, analysis, or writing of this article.