The Risk Reduction Effect of a Nutritional Intervention With a Partially Hydrolyzed Whey-Based Formula on Cow's Milk Protein Allergy and Atopic Dermatitis in High-Risk Infants Within the First 6 Months of Life: The Allergy Reduction Trial (A.R.T.), a Multicenter Double-Blinded Randomized Controlled Study

Abstract

Background: The role of partially hydrolyzed formulas (pHF) as part of nutritional interventions to prevent the development of allergic manifestations (AM) is questioned, and efficacy of each specific pHF should be substantiated.

Objective: To investigate the risk-reduction effect of a whey-based pHF on the development of cow's milk protein allergy (CMPA) and atopic dermatitis (AD) in infants at high-risk for allergy within the first 6 months of life.

Materials and methods: In a multicenter double-blinded randomized controlled setting, healthy non-exclusively breastfed full-term infants, received either a specific whey-based pHF or a standard cow's milk-based formula (SF) and were clinically assessed for AM at 2, 4, and 6 months of age, supported by the objective scoring tools SCORAD and CoMiSS. CMPA was confirmed by open food challenge. Intention-to-Treat (ITT) and Per-Protocol (PP) analyses were performed.

Results: Of 331 randomized subjects (ITT analysis set), 160 received the pHF and 171 the SF. Six (3.8%) infants in the pHF and 12 (7%) in the SF group developed CMPA (p = 0.186). AD incidence was significantly lower in those receiving pHF as compared to SF (10.6% vs. 18.7%, p = 0.024) with a relative risk (RR, 95% CI) of 0.54 (0.32, 0.92), in particular when adjusting for family history of AD [6.5% vs. 27.3%, RR 0.24 (0.07, 0.78), p = 0.018] representing a risk reduction of 76%. The PP analysis showed similar results.

Conclusion: This specific whey-based pHF reduced the risk of AD development, particularly in those with a family history of AD, and tended to reduce the development of CMPA in non-exclusively breastfed infants at high-risk for allergy. The A.R.T. study suggests that this particular pHF may contribute to measures aimed at prevention of allergic manifestations. However, further studies are needed to confirm this risk-reduction effect.

Keywords: allergy prevention; atopic dermatitis; cow milk allergy; high-risk infants; nutritional intervention; partially hydrolyzed formula; randomized controlled trial.

Figure 1

Flow diagram of A.R.T. study population. SF, standard formula; pHF, partially hydrolyzed formula; BF, breastfeeding; ITT, intention-to-treat analysis set; PP, per-protocol analysis set.

Figure 2

Incidence of Cow's Milk Protein Allergy within the first six months of life in high-risk mixed-fed infants. The incidence of cow's milk protein allergy (CMPA) in high-risk mixed-fed infants within the first 6 months of life as generated from Poisson generalized estimating equation (GEE) regression analysis (adjusting for study center, gender and type of formula) are presented in the Intention-to-Treat (A) and Per-Protocol (B) Analyses. SF, standard formula (red columns); pHF, partially hydrolyzed formula (blue columns). The incidence of CMPA observed in the SF group compared to the pHF was higher in both analyses (ITT: 7.9 vs. 3.5%, p = 0.11 and PP: 9.4 vs. 4.5%, p = 0.29) although the difference did not reach statistical significance.

Figure 3

Incidence and relative risk of atopic dermatitis within the first 6 months of life in high-risk mixed-fed infants. The incidence and relative risk (RR) of Atopic Dermatitis (AD) in high-risk infants within the first 6 months of life, in the whole mixed-fed population and in subjects mixed-fed with (FHAD+) and without (FHAD-) family history of AD, generated from Poisson generalized estimating equation (GEE) regression analysis are presented in the Intention-to-Treat (ITT) (A) and Per-Protocol (PP) (B) Analysis. SF, standard formula (red columns); pHF, partially hydrolyzed formula (blue columns). A significant relative risk (RR, 95% CI) and risk reduction effect (%) of the pHF on the incidence of AD for the whole mixed-fed population was observed in both the ITT (A1) [RR 0.50 (0.29, 0.88), p = 0.016] and PP (B1) analysis [RR 0.47 (0.24, 0.91), p = 0.024], representing a risk reduction of 50% and 53% respectively. The reduction effect was most significant in those mixed-fed subjects with FHAD+ [RR 0.24 (0.08, 0.79), p = 0.019] receiving the pHF, representing a 76% reduction on the incidence of AD (A2). In the PP analysis (B2) only a trend was shown in this study group (p = 0.10) whereas, no effect was observed for those infants without a family history of AD (A3, B3).