Cow's milk protein allergy (CMPA) is an immune-mediated hypersensitivity reaction to one or more cow's milk proteins. The typical allergic symptoms involve the skin (rash, eczema, and urticaria), the gastrointestinal tract (diarrhea, mucosal, and bloody stool), and the respiratory tract (wheezing and other breathing difficulties) (1). CMPA is a leading cause of food allergy in infants and children under 3 years of age, with an increasing prevalence in Thailand (2). CMPA was among the top three causes of food-induced anaphylaxis reported in a tertiary care hospital in Bangkok during 2008–2018 (3). Children with CMPA are at an increased risk of developing allergic march. They are five times more likely to have early-onset atopic dermatitis (4), which may lead to allergic rhinoconjunctivitis and asthma (5). They are also at an increased risk of poor growth, as a 2019 international survey demonstrates that cow's milk elimination leads to lower weight-for-height Z-scores than other food eliminations (6).

Based on the international consensus guidelines, the diagnosis of CMPA is based on medical and dietary history and confirmed through diagnostic elimination/oral food challenge. Specific IgE or skin prick tests on cow's milk might be performed when IgE-mediated reactions are suspected (1). The adequate management of CMPA resolves current allergic symptoms and prevents disease progression (5). The fundamental principle in treating CMPA is the dietary elimination of cow's milk protein (7).

As breastfeeding remains the primary recommended source of nutrition for infants with CMPA, cow's milk and dairy products should be restricted in the maternal diet because they may present in breast milk up to 7 days after consumption (8). However, in non-breastfed infants and children younger than 2 years, replacement with a therapeutic infant formula designed for CMPA is mandatory (7). For formula-fed infants, whey- or casein-based extensively hydrolyzed formula (eHF) that have short, cow's milk-derived peptides produced by multiple enzymatic processes has been demonstrated as the first-line management of CMPA (5, 7). Each eHF has peptides with different molecular weights and profiles (5). In children who have no co-allergy to soy, some doctors use the soy protein-based formula (SPF), as it is less expensive and has a better acceptance than eHF and amino acid formula (AAF). However, SPF is not hypoallergenic, contains phytate, aluminum, and phytoestrogens (isoflavones), is not recommended as the first choice for CMPA management (7, 9), and no current data demonstrate the use of SPF results in accelerated oral tolerance. AAF is recommended for a child with IgE-mediated CMPA at high risk of anaphylactic reactions when eHF cannot be used or multiple food intolerances. However, AAF does have numerous limitations, including high cost and the unlikelihood of oral tolerance development (7, 9).

In Thailand, EHCF with added probiotic Lacticaseibacillus rhamnosus (previously Lactobacillus rhamnosus) strain GG (EHCF+LGG) is the current standard for CMPA management practice among pediatricians and allergists. A prospective CMPA cohort study recently published in 2021 investigated the effect of different formulas on the occurrence of other allergic manifestations and the time of immune tolerance acquisition over 36 months. EHCF+LGG was associated with a lower incidence of allergic manifestations and a greater rate of immune tolerance acquisition. Infants with CMPA who received EHCF+LGG achieved early CMPA tolerance and had a higher chance of being symptom-free (10). Thus, EHCF+LGG formula can improve the long-term quality of life for infants with CMPA, as they can start consuming a regular diet, including dairy-containing products, earlier in life than other formulas. These improved clinical outcomes of infants with CMPA can potentially save the payer by decreasing direct medical costs due to faster tolerance acquisition and absence of symptoms, as well as parents' productivity loss due to frequent hospital visits (11).

Therapeutic infant formulas for CMPA management are not included in the country's universal health coverage scheme. The infant formulas are classified as over-the-counter products, and prices vary by the market mechanism. Hence, the parents must pay out of pocket, which limits the opportunities for the management of CMPA for many infants and children in Thailand. A previous cost-effectiveness analysis from the United Kingdom demonstrated that EHCF+LGG was the most cost-effective in reducing National Health Service resource use and improving CMPA tolerance compared with SPF, EHWF, and AAF. The current study aimed to assess the cost-effectiveness of CMPA management between therapeutic infant formulas in Thailand, which may reflect applicability in developing newly industrialized countries from the healthcare payer perspective. For reporting economic evaluations of health interventions, the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) were used as a guide (12).

Similar to the previously reported cost-effectiveness analyses (11, 18), those reported here demonstrated ECHF+LGG as the most cost-effective strategy to manage non-breastfed infants with CMPA in Thailand. A recent study from Indonesia, using the private payers' perspective, also demonstrated that EHCF+LGG was the most cost-effective strategy when compared to EHWF and AAF and to be more effective and saved healthcare resources when compared with SPF (19). EHCF+LGG may provide a higher chance of developing immune tolerance to cow's milk and being symptom-free, thus contributing to the high-cost saving potential. EHCF+LGG is associated with the lowest cost of eczema and asthma management. Furthermore, the short duration of CMPA management by effective therapeutic infant formulas such as EHCF+LGG can help save the consequential expense and especially hospital bed quota for patients experiencing severe symptoms, thus benefiting the public health system through budget saving.

The results of this study show that therapeutic infant formulas and prescribed drugs are the top two high-cost clinical resources for CMPA treatment and the associated conditions, respectively. These findings are consistent with a health economic study on CMPA infants with proctocolitis and eczema in Turkey, which found that clinical nutrition was the primary cost driver, accounting for 89–92% of total direct medical costs over a 2-year period. Management of CMPA infants with eczema and/or exclusively formula-fed infants was associated with higher total direct medical costs from both payer and societal perspectives (20). Unfortunately, there is no universal coverage of eHF and some eczema medications; thus, the caregivers must bear their expenses.

While formula price is not among the top influential factors in determining the most cost-effective strategy for managing CMPA in sensitivity analysis, it is still perceived as crucial by price-sensitive consumers. Formula cost represents an up-front cost that is more immediate, and thus apparent, than the long-term saving potential, along with the fact that therapeutic infant formulas are high cost compared with their non-therapeutic infant counterparts, the general consumer may choose the lower cost alternatives. This current study may improve the consumer perception of the EHCF+LGG formula as a long-term, cost-effective strategy.

The estimated costs used in this study may be lower than depicted. For example, surveyed prices of the therapeutic infant formulas for CMPA may be lower than the actual prices that consumers have to pay, which change over time due to many factors, including inflation, manufacturing, and demand-supply in the market. Similarly, specialist visit costs and drug costs in the present research may be lower than actual costs, as these numbers were sourced from the average MOPH-linked hospitals that mostly used generic drugs and the strategy used for the therapeutic infant formula(s) for managing cases with CMPA. All direct medical costs associated with atopic diseases were adjusted for inflation to reflect prices in 2021. The net monetary benefit threshold of USD 4,800 (as shown and discussed in Table 2) is also the summary statistic reflecting the largest amount of money MOPH is willing to spend on an intervention to improve 3 years of life. The cost-effectiveness analysis of therapeutic infant formulas for managing CMPA in the United Kingdom and Indonesia revealed that, like Thailand, EHCF+LGG was likely the most cost-effective formula option regarding the cost-effectiveness strategy (11, 19). As the results of one-way sensitivity analysis, the cost-effectiveness of the strategy for the ICER with life years with symptom-free or life years with cow's milk tolerance may be changed if the probability of symptom-free and CM tolerance varied.

There are some limitations in this study. First, the model is based on data from a non-randomized cohort study conducted in a single European country, as there is no cohort study in the Asia-Pacific region. The current study did not include the rice hydrolyzed formula group because it either has not been recommended for CMPA management or is available in the country. Thus, we used the input parameters such as formula price, direct medical cost, drug cost, and resources for CMPA management that are locally derived to reflect and benefit countries with similar variables. Second, allergic manifestation diagnosis criteria may differ compared between studies.

EHCF+LGG formula was the most cost-effective strategy for non-breastfed infants and children with CMPA. EHCF+LGG is associated with more children developing immune tolerance to cow's milk and being symptom-free, yielding the most significant cost-saving potential via lower long-term medical costs and subsequent decrease of the associated economic burden of disease on the healthcare system.

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author.

PP, PC, and KP: conceptualization. KP: methodology and project administration. AS and KP: software, formal analysis, and writing—original draft preparation. AS, NS, PT, and PC: validation. AS: investigation. PP: resources and funding acquisition. AS, NS, and PC: data curation. PP, AS, and KP: writing—reviewing and editing. NS and PT: visualization. PP and PC: supervision. All authors have read and agreed to the published version of the manuscript.