Low vitamin D newborns getting cows milk formula more likely to get allergies – RCT

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

JAMA Pediatr. doi:10.1001/jamapediatrics.2019.3544

Mitsuyoshi Urashima, MD, MPH, PhD1,2; Hidetoshi Mezawa, MD1,2; Mai Okuyama, MD1,2; et alTakashi Urashima, MD2; Daishi Hirano, MD2; Noriko Gocho, MD2; Hiroshi Tachimoto, MD2

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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.

Editorial on the study in the same issue

Cow’s Milk and Vitamin D Supplementation in Infants—Timing Is Everything

JAMA Pediatr. Published online October 21, 2019. doi:10.1001/jamapediatrics.2019.3560

George du Toit, MBBCh, FRCPCH1; Arnon Elizur, MD2; Kari C. Nadeau, MD, PhD3,4,5

In this issue of JAMA Pediatrics, Urashima and colleagues1 ask whether very early (within 3 days of birth) exposure to cow’s milk formula (CMF) ( a common practice in Japan ) and vitamin D supplementation (uncommon in Japan) lowers or increases the risk of developing food allergy (as determined by cow’s milk–specific IgE [CM-IgE] sensitization at 5 months and 2 years of age) in infants at risk of atopy (risk was defined as having ≥1 of the father, mother, and/or siblings with current and/or past atopic diseases [eg, asthma]). In recent years, the approach for primary prevention of food allergy has changed dramatically. Earlier recommendations to delay the introduction of allergenic foods to 1 to 3 years of age have now been replaced by newer recommendations to introduce allergenic foods such as peanut and egg at 4 to 6 months of age, after a period of exclusive breastfeeding (EBF).2 The World Health Organization and the European Academy of Allergy and Clinical Immunology (EEACI) recommend EBF for a minimum of 6 months and 4 months, respectively.3 However, whether introduction of all typically allergic foods before 4 to 6 months can decrease risk of allergy is unclear. In the case of CM, this issue is of special importance because supplementation or replacement with formula, even in the first days of life, is not infrequent. Partially or extensively hydrolyzed formulas have been developed to reduce the allergenicity of CM. There is currently a lack of consensus among national allergy societies with respect to recommendations for the use of hypoallergenic formula for the prevention of food allergy in infants who are unable to EBF. Although the EAACI3 and American Academy of Allergy, Asthma and Immunology (AAAI) currently recommend the use of hypoallergenic formulas in infants at high risk of allergy, the Australian Society of Clinical Immunology and Allergy does not. The EAACI and the AAAI are likely to reconsider their guidelines because results of more recent studies have been contradictory. At the current time, insufficient evidence suggests that hydrolyzed formulas might decrease risk of developing food allergy.4

Timing of introduction of foods plays a role in the development of tolerance and allergy. Microbial composition changes rapidly, soon after birth. During the first few days of life, bacterial composition resembles that found in the mother’s breast milk or vaginal swabs, but, by 4 to 6 months, the gut microbiome of the infant is vastly different from that of the mother.5 The optimal window during which exposure to common food proteins induces tolerance is unclear. In the study by Urashima et al1 on the effects of early CM exposure on food allergy incidence, the authors conclude that sensitization to CM is primarily preventable by avoiding CMF supplementation for the first 3 days of life (their primary outcome). Their post hoc analysis found that switching to CMF after the first 3 days of life showed no difference in food allergy. Furthermore, no difference in food allergy incidence occurred between those fed hydrolyzed CMF vs those fed nonhydrolyzed CMF starting 3 days after birth. This study begins to help our understanding of timing, but further studies and analyses are needed before making broad conclusions or applications to feeding, because this study focused only on the first 3 days of life.

Studies, many of which were observational, have evaluated the role of supplemental formulas soon after birth on the risk of CM allergy (CMA) with contradicting results. Høst et al6 found that breastfed infants with early occasional exposure to CM proteins had greater risk of food allergy. In a large prospective randomized study of more than 6000 healthy full-term infants,7 those who were supplemented with CMF while in the hospital had higher risk of CMA than those who were supplemented with whey hydrolysate formula or pasteurized breast milk. It should be noted that these earlier studies did not quantitate IgE-CM levels, and many of the symptoms that they used for diagnosis would not be considered to represent milk allergy today. In a single-center cohort study from Israel,8 CMF introduction within the first 2 weeks of life was associated with the lowest rate of milk allergy, whereas the highest rate was observed in infants exposed to CMF at 4 to 6 months of age. An observational study (HealthNuts)9 showed that introduction of CM protein before 3 months of age is associated with significantly reduced risk for CM sensitization and CMA at 12 months of age. The Enquiring About Tolerance (EAT) study10 examined the effect of early introduction of several allergenic foods, including CM, after 3 months of EBF, on the development of food allergy. It indicated that early introduction may be effective in reducing the rate of peanut and egg allergies (in the per protocol but not the intention-to-treat analysis) but failed to show statistically significant efficacy for CMA. Further, the EAT results also indicate that milk intake at 3 months was associated with neither a decrease nor an increase in milk allergy. In a recent retrospective study from Ireland,11 the authors found that breastfed infants are at significantly increased risk of CMA by receiving supplemental formula in the first 24 hours of life. However, it is unclear whether CMF supplementation was continued beyond 24 hours. Moreover, infants who were exclusively formula fed were not at increased risk for CMA. These data may suggest that for early (before 3 months of age) introduction of CMF to be potentially protective against CMA, it should be sustained. Intermittent exposure may paradoxically increase the risk of CMA.

Urashima et al1 also examined the role of vitamin D supplementation, because some studies have suggested an association between vitamin D and food allergy; however, these results have not been conclusive.12 A study of infants with eczema supplemented with vitamin D found no significant decrease in the severity of eczema at 3 months; however, food allergy was increased at 2 years.13 Another study found that infants with CMA had lower levels of vitamin D.14 Guidelines for vitamin D supplementation in newborn infants differ. For example, guidelines in the United States and United Kingdom recommend routine vitamin D supplementation in all breastfed infants, whereas guidelines in Australia recommend supplementation only in breastfed infants at high risk of vitamin D deficiency.15 The American Association of Pediatrics and the Institute of Medicine define vitamin D insufficiency as 25-hydroxyvitamin D concentrations of less than 20 ng/mL in children. Urashima et al1 performed a subgroup analysis, prespecified by tertiles of serum 25-OH-D levels at 5 months of age, and found that avoiding CMF in the first 3 days of life was effective in decreasing risk of CMA only in the middle tertile of 25-OH-D levels (21-36 ng/mL).

This study by Urashima et al1 provides valuable data that could assist in determining optimal timing for supplementation and formula type for newborn infants at risk of atopy who cannot receive EBF. However, the evidence provided by the study needs further validation before changes to infant feeding practice guidelines can be considered. Importantly, the study included infants at risk of atopy, and these results may not be applicable for all newborns. The authors reference the importance of gut microbiota in tolerance and allergy; however, it is not clear why only the first 3 days of life are considered the most critical for gut exposures to dairy. Future studies should evaluate the effect of cofounders such as method of birth, emollient use, and maternal/newborn antibiotic use, because these greatly affect infant gut microbiota and potentially food allergy risk. The question regarding vitamin D and other diverse food supplementation in infants and breastfeeding mothers should be further evaluated by randomized studies.

In summary, Urashima and colleagues1 address an important question that has not been adequately answered to date. Further studies are needed to validate and build on these findings. However, studies in this area might be limited or of inferior design because of the ethical restraints around randomizing infants away from EBF. Efforts to optimize the initiation and continuation of breastfeeding need to be encouraged.

Corresponding Author: Kari C. Nadeau, MD, PhD, Sean N. Parker Center for Allergy and Asthma Research, Stanford University, 269 Campus Dr, CCSR Room 3215, Campus Mail Box 5366, Stanford, CA 94305 (knadeau@stanford.edu).

Published Online: October 21, 2019. doi:10.1001/jamapediatrics.2019.3560

Conflict of Interest Disclosures: Dr du Toit reported receiving grant support from National Institute of Allergy and Infectious Diseases (NIAID), Immune Tolerance Network, Food Allergy & Research Education (FARE), Medical Research Council (MRC) & Asthma UK, UK Department of Health through the National Institute for Health Research, Action Medical Research, and the National Peanut Board; serving as a scientific advisory board member for Aimmune Therapeutics, Inc, and on the UK advisory board for DBV Technologies; serving as an investigator for Aimmune Therapeutics, Inc, and DBV Technologies peanut immunotherapy trials; and serving as a lecturer at allergy symposia supported by Mylan NV and Aimmune. Dr Nadeau reported receiving grant support from the NIAID, NHLBI, National Institute of Environmental Health Sciences, Environmental Protection Agency, FARE, End Allergies Together, AllerGenis, and Ukko; personal fees from Regeneron Pharmaceuticals, Inc, AstraZeneca, ImmuneWorks, Inc, and Cour Pharmaceuticals; sponsored research from Novartis International AG, Sanofi, Astellas Pharma, Inc, and Nestle; sponsored research for clinical trials from Genentech, Inc, Aimmune Therapeutics, Inc, DBV Technologies, AnaptysBio, Inc, Stallergenes-Greer, Regeneron Pharmaceuticals, Inc, and Adare Pharmaceuticals, Inc; serving as a data and safety monitoring board member at Novartis International AG and NHLBI; cofounding Before Brands, Alladapt Immunotherapeutics, Inc, and ForTra; and serving as director for FARE and the World Allergy Organization Center of Excellence. No other disclosures were reported.

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