Randomized trial of early infant formula introduction to prevent cow's milk allergy

J Allergy Clin Immunol. 2021 Jan;147(1):224-232.e8. doi: 10.1016/j.jaci.2020.08.021. Epub 2020 Sep 2.


Background: Previous research has produced conflicting evidence on the preventive effects of early introduction of cow's milk protein on cow's milk allergy (CMA).

Objective: Through a randomized controlled trial, we sought to determine whether the early introduction of cow's milk formula (CMF) could serve as an effective strategy in the primary prevention of CMA in a general population.

Methods: We recruited newborns from 4 hospitals in Okinawa, Japan. Participants were randomly allocated to ingest at least10 mL of CMF daily (ingestion group) or avoid CMF (avoidance group) between 1 and 2 months of age. In the avoidance group breast-feeding was supplemented with soy formula as needed. Oral food challenge was performed at 6 months of age to assess CMA development. Continuous breast-feeding was recommended for both groups until 6 months of age.

Results: We identified 504 infants for randomization into the 2 groups. In all, the parents of 12 participants declined to receive the intervention, and the study sample comprised 491 participants (242 in the ingestion group and 249 in the avoidance group) for a modified intention-to-treat analysis. There were 2 CMA cases (0.8%) among the 242 members of the ingestion group and 17 CMA cases (6.8%) among the 249 participants in the avoidance group (risk ratio = 0.12; 95% CI = 0.01-0.50; P < .001). The risk difference was 6.0% (95% CI = 2.7-9.3). Approximately 70% of the participants in both groups were still being breast-fed at 6 months of age.

Conclusions: Daily ingestion of CMF between 1 and 2 months of age prevents CMA development. This strategy does not compete with breast-feeding.

Keywords: Food allergy; birth cohort; cow’s milk; cow’s milk formula; early introduction; infant formula; milk allergy; prevention; randomized controlled trial; soy formula.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Female
  • Humans
  • Infant
  • Infant Formula*
  • Infant, Newborn
  • Male
  • Milk Hypersensitivity / immunology
  • Milk Hypersensitivity / prevention & control*

Associated data

  • UMIN-CTR/UMIN000025402