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In nonexclusively breastfed infants at high-risk for allergy, mixed-feeding with a hydrolyzed whey-based formula for the first 6 months appeared to reduce allergy risk in children up to 5 years of age.

This finding emerged from the randomized double-blind Allergy Reduction Trial (ART) reported in Pediatric Allergy and Immunology by Mikaela Sekkidou, MS, a clinical dietitian at the Asthma and Allergy Center in Limassol, Cyprus, and colleagues. Adding a whey-based small-peptide partially hydrolyzed formula (pHF) to breastfeeding significantly lowered the relative risk (RR) compared with standard formula (SF; intact cow’s milk protein) for several conditions, particularly food allergy from age 1 to age 5. 

The pHF mixed-feeding arm saw the following specific reductions compared with SF:

• Food allergy: 10.5% vs 20.4%; RR, 0.53 (95% CI, 0.29-0.95; P = .03)
• Atopic dermatitis: 22.1% vs 38.5%; RR, 0.58 (95% CI, 0.41-0.83; P = .003)
• Any allergic manifestation: 32.7% vs 51.7%; RR, 0.73 (95% CI, 0.57-0.94; P = .02)

No significant difference in asthma or allergic rhinitis risk was observed between the two formula arms or the exclusively breastfed (EBF) observational cohort. 

In the 1990s, pHF was investigated based on the hypothesis that the breakdown of the cow’s milk protein into smaller peptides with lower molecular weight and reduced epitope allergenicity could prevent the development of allergy, Sekkidou and colleagues wrote. “What distinguishes this specific pHF compared to other similar products is more likely the final epitopes formed after hydrolysis procedures in combination with the reduced molecular weight.”

Although pHF had seemingly shown a preventive effect in earlier studies, many scientific bodies, including the American Academy of Pediatrics (AAP) in a 2019 report, have found insufficient evidence to support a pHF recommendation for allergy prevention.

Trial Details

Enrolled in 2017-2019, the original cohort comprised 551 healthy full-term infants who were at risk for allergies (at least one allergic first-degree relative) from Greece, Bulgaria, and Cyprus; 160 were given pHF, 170 given a SF, and 220 EBF in a parallel, nonrandomized observation group.

Participants in the formula groups consumed a minimum of 40 mL/kg body weight per day of pHF or SF up to the age of 1 month, rising to 60 mL/kg body weight per day up to 6 months. Almost 90% of formula-fed babies also received breast milk, with the idea that combination feeding may synergistically lower allergy risk.

With 83% of the total cohort completing 5-year follow-up, SF children had nearly triple the risk of developing a food allergy from age 1 to 5 as their EBF counterparts. But in the pHF arm, the risk was actually lower than in the EBF group, though not significantly so: 1.5% vs 5.6%.

While the ART results look promising, the authors cautioned that “further well designed, large-scale prospective randomized controlled clinical trials are needed to confirm these findings and contribute to the evidence base for future guidelines on the potential role of pHF in allergy prevention.”

In comments on the study to Medscape Medical News, Maria I. Garcia Lloret, MD, of the Division of Pediatric Allergy and Immunology at UCLA School of Medicine in Los Angeles, called the study’s 85% questionnaire response rate for patients from three different countries at 5 years “very impressive.”

She took issue, however, with aspects of the study’s methods. “The formula is described only as partially hydrolyzed whey,” said Garcia Lloret, who was not involved in the trial. “With today’s plethora of infant formulas on the market, that succinct description is insufficient for pediatricians to determine which to recommend.”

She also pointed to unavoidable vagaries in the diagnosis of food allergies. “It is unclear what type of diagnostic approach was used, although it was mentioned in passing that 80% developed an immunoglobulin (Ig)E-mediated food allergy and 20% a non-IgE-mediated food allergy. This is vague and nonspecific, and not strong enough for change in recommendations.”

On the practical side, barring issues of availability and cost, she added, “I see no harm in recommending one of the many partially hydrolyzed whey formulas on the market today.” Without, however, expecting that this will greatly reduce the risk for food allergies. “If the rest of the nutritional content is comparable to that of regular formula, that option could be a consideration.”

She agreed with the authors that more research is needed to address open questions. “Larger, prospective studies, though difficult to do and expensive, with the collection of markers along the way would provide more convincing evidence. The AAP will likely reconsider then.”

Funding for this study was provided by FrieslandCampina Nederland B.V. Sekkidou had no conflicts of interest. Co-authors Nicolaos Nicolaou and Yannis Manios reported receiving speakers’ bureau honoraria from FrieslandCampina. Linde van Lee is employed by FrieslandCampina. Garcia Lloret had no conflicts of interest relevant to her comments.