Effect of Avoiding Cow's Milk Formula at Birth on Prevention of Asthma or Recurrent Wheeze Among Young Children: Extended Follow-up From the ABC Randomized Clinical Trial.

Importance: Children with food allergies may develop asthma or recurrent wheeze. Objective: To evaluate whether asthma or recurrent wheeze among children were changed by avoiding supplementing breastfeeding (BF) with cow's milk formula (CMF) in the first 3 days of life. Design, Setting, and Participants: This randomized, unmasked, clinical trial was conducted at 1 university hospital in Japan beginning October 2013 with follow-up examinations occurring until January 2020. A total of 312 newborns at risk for atopy were randomized and assigned to either BF with or without amino acid-based elemental formula (EF) or BF with CMF, with follow-up examinations for participants showing signs of atopy conducted at 24 months. Follow-up examinations ran through January 2020. Interventions: Immediately after birth, newborns were randomly assigned (1:1 ratio) to either breastfeeding with or without amino acid-based elemental formula for at least the first 3 days of life (no CMF group) or breastfeeding supplemented with CMF (≥5 mL/d) from the first day of life to 5 months of age (CMF group). Main Outcomes and Measures: Asthma or recurrent wheeze diagnosed by the pediatric allergy specialists of this trial; subgroups were stratified by serum levels of 25-hydroxyvitamin D and IgE. Results: Of 312 infants (156 [50.0%] randomized to the no CMF group), 302 (96.8%) were followed up at their second birthday: 77 of 151 (51.0%) in the no CMF group and 81 of 151 (53.6%) in the CMF group underwent extended follow-up because of having atopic conditions. Asthma or recurrent wheeze developed in 15 (9.9%) of the children in the no CMF group, significantly less than the children in the CMF group (27 [17.9%]; risk difference, -0.079; 95% CI, -0.157 to -0.002). In participants with vitamin D levels above the median at 5 months of age, asthma or recurrent wheeze developled in 5 (6.4%) children in the no CMF group, significantly less than in the children in the CMF group (17 [24.6%]; risk difference, -0.182; 95% CI, -0.298 to -0.067; P for interaction = .04). In the highest quartile group of total IgE at age 24 months, asthma or recurrent wheeze developed in 2 children (5.3%) in the no CMF group, significantly less than the children in the CMF group (14 [43.8%]; risk difference, -0.385; 95% CI, -0.571 to -0.199; P for interaction = .004). Conclusions and Relevance: The findings of this study suggest that avoiding CMF supplementation in the first 3 days of life has the potential to reduce the risk of asthma or recurrent wheeze in young children, especially among those with high vitamin D or high IgE levels. Trial Registration: umin.ac.jp/ctr Identifier: UMIN000011577.

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

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.