Early Cow's Milk Formula Tied to Subsequent Allergies in Infants

Diana Swift

October 21, 2019

Avoiding infants' exposure to cow's milk for at least the first 3 days of life appears to decrease the risk for cow's milk sensitization and clinical food allergies, a randomized study found.

In the Atopy Induced by Breastfeeding or Cow's Milk Formula (ABC) trial, cow's milk sensitization was present in 32.2% of 2-year-olds in the group exposed to cow's milk formula right after birth compared with 16.8% of their counterparts who were not, for a relative risk (RR) of 0.52 (95% confidence interval [CI], 0.34 - 0.81).

Food allergy was significantly less prevalent in unexposed 2-year-olds for both immediate and anaphylactic types: 2.6% vs 13.2% (RR, 0.20; 95% CI, 0.07 - 0.57) and 0.7% vs 8.6% (RR, 0.08; 95% CI, 0.01 - 0.58), respectively.

"This prevention is easily and immediately applicable to clinical practice throughout the world without the cost and time of therapy," write Mitsuyoshi Urashima, MD, MPH, PhD, a professor of molecular epidemiology at Jikei School of Medicine in Tokyo, Japan, and colleagues.

The ABC Trial

Published online October 21 in JAMA Pediatrics, the unblinded trial recruited 330 neonates starting in October 2013 and completed follow-up in May 2018. Its operating hypothesis was that exposure to high-volume cow's milk protein just after birth when the gut microbiome is sparsely populated may trigger enterocolitis, enhance gut membrane permeability, promote absorption of food allergens, and increase risks of food allergy later in infancy.

The newborns were all at risk for atopy, having at least one parent or sibling with current and/or past atopic diseases such as asthma. They were randomly assigned in a 1:1 ratio immediately after birth to breastfeeding with or without amino acid-based elemental formula (BF/EF) for at least the first 3 days of life or to breastfeeding supplemented with cow's milk formula at ≥ 5 mL/d (BF/CMF) from the first day of life to age 5 months.

The primary outcome was sensitization to cow's milk protein defined by a cow's milk immunoglobulin E (IgE) level of ≥ 0.35 allergen units (UA)/mL) at 24 months.

Secondary outcomes were immediate and anaphylactic types of food allergy, including cow's milk, egg, wheat, and others, as diagnosed by oral food challenge test or triggered by food ingestion, with food-specific IgE levels of ≥0.35 UA/mL.

Immediate-type food allergy presented with a symptom in at least one of the following organ systems: skin (eg, urticaria), respiratory (wheezing), gastrointestinal (vomiting), or circulatory (loss of consciousness).

With follow-up at 1, 2, 3, 4, 5, 7 to 8, 9 to 10, 12, 14 to 15, 18, and 24 months, the total cohort included 312 children (51.3% female), with 96.8% in both groups followed to their second birthday. At that time, 24 of the 143 patients in the BF/EF group were sensitized to cow's milk compared with 46 of the 143 in the BF/CMF arm.

In a subgroup analysis prespecified by tertiles of serum 25(OH)D levels at age 5 months, the middle tertile had significantly less frequent sensitization in the BF/EF group than in the BF/CMF group: 4 of 44 (9.1%) vs 22 of 45 (48.9%) for an RR of 0.19 (95% CI, 0.07 - 0.50; P = .02), but it was not significant in either the low- or high-level subgroup.

Of a total of 67 infants with food allergy, 43 (64.2%) outgrew the allergy. At their second birthday, four infants (2.6%) in the BF/EF group had not yet outgrown the allergy, significantly fewer than the 20 infants (13.2%) in the BF/CMF group (RR, 0.20; 95% CI, 0.07 - 0.57).

The authors note that in a previous large cohort study, exposure to cow's milk protein within 14 days of birth reduced the risk for IgE-mediated allergy, but the study did not monitor exposure to small quantities of cow's milk formula during the first 3 days of life.

As for other food allergens, sensitization to egg white and others did not significantly differ between the two groups, except for the middle tertile of 25(OH)D levels, in which egg white sensitization was significantly lower in the BF/EF group than in the BF/CMF group (RR, 0.51; 95% CI, 0.28 - 0.92).

Questions Remain

In an accompanying editorial, George du Toit, MBBCh, a pediatric allergist at King's College, London, England, and colleagues point to the dramatic change in recent years in the approach to the primary prevention of food allergy.

Whereas earlier thinking recommended withholding allergenic foods until 1 to 3 years of age, newer recommendations advise giving allergenic foods such as peanut and egg at age 4 month to 6 months, after a period of exclusive breastfeeding.

For newborns at risk for atopy who cannot be exclusively breastfed, findings from the ABC trial could help establish optimal timing for supplementation and the best formula type, the researchers conclude, cautioning that the evidence needs validation before infant feeding guidelines are changed. "Importantly, the study included infants at risk of atopy, and these results may not be applicable for all newborns," they write.

The commentators, who did not participate in the ABC trial, also question why only the first 3 days of life should be the most critical for exposure of the gut microbiome to dairy food. "Future studies should evaluate the effect of cofounders [sic] such as method of birth, emollient use, and maternal/newborn antibiotic use, because these greatly affect infant gut microbiota and potentially food allergy risk," they write.

Although the ABC trial addresses an important question not adequately answered to date, ethical concerns about randomly assigning infants away from exclusive breastfeeding might complicate future studies, they add, writing, "Efforts to optimize the initiation and continuation of breastfeeding need to be encouraged."

Whether the very early introduction of cow's milk formula is instrumental in food allergy is a question that remains unanswered "but this work is a good start," Terri F. Brown-Whitehorn, MD, a pediatric allergist at Children's Hospital of Philadelphia, Pennsylvania, told Medscape Medical News. "While I believe the findings of this publication are intriguing, I do think we need more rigid studies to help answer the question," she said. Brown-Whitehorn was not involved in the study.

She also raised some methodological issues such as the exact amounts of cow's milk supplementation given over time and whether some babies stopped receiving formula between day 3 and month 1, which might have affected results. "Is there a crucial window of time or not between 3 days and a month?" she asked. "This study also makes me wonder if there is something about supplementing with cow's milk formula and then stopping the formula for a window of time [that] would also lead to more food allergy."

She wondered if the reactive infants had also developed atopic dermatitis or another atopic condition acting as another potential trigger for food allergy and whether those who were allergic to egg, wheat, or another food had a concomitant allergy to milk.

In her view, the presence of IgE to cow's milk is ultimately not the ideal marker of food allergy, and the authors' conclusion that avoiding cow's milk formula in the first 3 days of life will prevent the development of sensitization of cow's milk and food allergy is premature. "I think there may be more factors involved," she said. At this point, therefore, doctors do not need to recommend withholding cow's milk formula from high-risk breastfed babies requiring supplementation within the first 3 days of life.

Last year Medscape Medical News reported that concerns about cow's milk protein allergy were driving up British healthcare spending on prescriptions for specialized infant formulas.

The ABC study was supported by the Ministry of Education, Culture, Sports, Science, and Technology in the Japan-Supported Program for the Strategic Research Foundation at Private Universities; the Japanese Society for the Promotion of Science; the Practical Research Project for Allergic Disease and Immunology of the Japan Agency for Medical Research and Development; the Dairy Products Health Science Council; the Japan Dairy Association; and the Jikei University School of Medicine. Urashima reported grants from the Dairy Products Health Science Council and Japan Dairy Association, as well as government, university, and research agency grants during the conduct of this study. A complete list is available on the journal's website. Two editorialists reported support from national research agencies and various ties to multiple private-sector entities. Brown-Whitehorn has disclosed no relevant financial relationships.

JAMA Ped. Published online October 21, 2019. Abstract, Editorial

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