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Original Investigation
October 21, 2019

Primary Prevention of Cow’s Milk Sensitization and Food Allergy by Avoiding Supplementation With Cow’s Milk Formula at Birth: A Randomized Clinical Trial

Author Affiliations
  • 1Division of Molecular Epidemiology, Jikei University School of Medicine, Tokyo, Japan
  • 2Department of Pediatrics, Jikei University School of Medicine, Tokyo, Japan
JAMA Pediatr. Published online October 21, 2019. doi:https://doi.org/10.1001/jamapediatrics.2019.3544
Key Points

Question  At birth, are the risks of sensitization to cow’s milk formula and food allergy decreased by avoiding or by supplementing with cow’s milk formula?

Findings  In this randomized clinical trial involving 312 newborns, risks of sensitization to cow’s milk and immediate-type food allergy, including cow’s milk allergy and anaphylaxis, were decreased by avoiding supplementation with cow’s milk formula for at least the first 3 days of life.

Meaning  Results suggest that sensitization to cow’s milk and clinical food allergies may be preventable by avoiding cow’s milk formula supplementation at birth, which is easily and immediately applicable to clinical practice worldwide without the cost and time of therapy.


Importance  Cow’s milk formula (CMF) is used to supplement breastfeeding (BF) at birth without clear clinical evidence to support the practice.

Objective  To determine whether avoiding supplementation with CMF at birth can decrease risks of sensitization to cow’s milk protein and/or clinical food allergy, including cow’s milk allergy (CMA), overall and in subgroups stratified by 25-hydroxyvitamin D (25[OH]D) levels.

Design, Setting, and Participants  The Atopy Induced by Breastfeeding or Cow’s Milk Formula (ABC) trial, a randomized, nonblinded clinical trial, began enrollment October 1, 2013, and completed follow-up May 31, 2018, at a single university hospital in Japan. Participants included 330 newborns at risk for atopy; of these, 312 were included in the analysis. Data were analyzed from September 1 through October 31, 2018.

Interventions  Immediately after birth, newborns were randomized (1:1 ratio) to BF with or without amino acid–based elemental formula (EF) for at least the first 3 days of life (BF/EF group) or BF supplemented with CMF (≥5 mL/d) from the first day of life to 5 months of age (BF plus CMF group).

Main Outcomes and Measures  The primary outcome was sensitization to cow’s milk (IgE level, ≥0.35 allergen units [UA]/mL) at the infant’s second birthday. Secondary outcomes were immediate and anaphylactic types of food allergy, including CMA, diagnosed by oral food challenge test or triggered by food ingestion, with food-specific IgE levels of at least 0.35 UA/mL. Subgroup analysis was prespecified by tertiles of serum 25(OH)D levels at 5 months of age.

Results  Of the 312 infants included in the analysis (160 female [51.3%] and 152 male [48.7%]), 151 of 156 (96.8%) in the BF/EF and BF plus CMF groups were followed up until their second birthday. The primary outcome occurred in 24 infants (16.8%) in the BF/EF group, which was significantly fewer than the 46 infants (32.2%) in the BF plus CMF group (relative risk [RR], 0.52; 95% CI, 0.34-0.81). The middle tertile of the 25(OH)D subgroup, but not the low and high tertiles, had a significant interaction with the intervention (RR, 0.19; 95% CI, 0.07-0.50; P = .02). The prevalence of food allergy at the second birthday was significantly lower in the BF/EF than in the BF plus CMF groups for immediate (4 [2.6%] vs 20 [13.2%]; RR, 0.20; 95% CI, 0.07-0.57) and anaphylactic (1 [0.7%] vs 13 [8.6%]; RR, 0.08; 95% CI, 0.01-0.58) types.

Conclusions and Relevance  The evidence suggests that sensitization to cow’s milk and food allergy, including CMA and anaphylaxis, are primarily preventable by avoiding CMF supplementation for at least the first 3 days of life.

Trial Registration  http://umin.ac.jp Identifier: UMIN000011577

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