Elsevier

The Lancet

Volume 399, Issue 10344, 25 June–1 July 2022, Pages 2398-2411
The Lancet

Articles
Early food intervention and skin emollients to prevent food allergy in young children (PreventADALL): a factorial, multicentre, cluster-randomised trial

https://doi.org/10.1016/S0140-6736(22)00687-0Get rights and content

Summary

Background

Primary prevention of food allergy by early introduction of allergenic foods seems promising. We aimed to determine whether early food introduction or the application of regular skin emollients in infants from a general population reduced the risk of food allergy.

Methods

This 2 × 2 factorial, cluster-randomised trial was done at Oslo University Hospital and Østfold Hospital Trust, Oslo, Norway, and Karolinska University Hospital, Stockholm, Sweden. Infants of women recruited antenatally at the routine 18-week ultrasound examination were cluster-randomised at birth to the following groups: (1) no intervention group; (2) the skin intervention group (skin emollients; bath additives and facial cream; from age 2 weeks to <9 months, both at least four times per week); (3) the food intervention group (early complementary feeding of peanut, cow's milk, wheat, and egg from age 3 months); or (4) combined intervention group (skin and food interventions). Participants were randomly assigned (1:1:1:1) using computer-generated randomisation based on clusters of 92 geographical areas and eight 3-month time blocks. Study personnel performing clinical assessments were masked to group allocation. The primary outcome was allergy to any interventional food at 36 months of age. The primary efficacy analysis was done by intention-to-treat analysis, which included all participants who were randomly assigned, apart from three individuals who withdrew their consent. This was a study performed within ORAACLE (the Oslo Research Group of Asthma and Allergy in Childhood; the Lung and Environment). This study is registered as ClinicalTrials.gov, NCT02449850.

Findings

We recruited 2697 women with 2701 pregnancies, from whom 2397 newborn infants were enrolled between April 14, 2015, and April 11, 2017. Of these infants, 597 were randomly assigned to the no intervention group, 575 to the skin intervention group, 642 to the food intervention group, and 583 to the combined intervention group. One participant in each of the no intervention, food intervention, and skin intervention groups withdrew consent and were therefore not included in any analyses. Food allergy was diagnosed in 44 children; 14 (2·3%) of 596 infants in the non-intervention group, 17 (3·0%) of 574 infants in the skin intervention group, six (0·9%) of 641 infants in the food intervention group, and seven (1·2%) of 583 infants in the combined intervention group. Peanut allergy was diagnosed in 32 children, egg allergy in 12 children, and milk allergy in four children. None had allergy to wheat. Prevalence of food allergy was reduced in the food intervention group compared with the no food intervention group (risk difference –1·6% [95% CI –2·7 to –0·5]; odds ratio [OR] 0·4 [95% CI 0·2 to 0·8]), but not compared with the skin intervention group (0·4% [95% CI –0·6 to 1· 5%]; OR 1·3 [0·7 to 2·3]), with no significant interaction effect (p=1·0). Preventing food allergy in one child required early exposure to allergenic foods in 63 children. No serious adverse events were observed.

Interpretation

Exposure to allergenic foods from 3 months of age reduced food allergy at 36 months in a general population. Our results support that early introduction of common allergenic foods is a safe and effective strategy to prevent food allergy.

Funding

Full funding sources listed at end of paper (see Acknowledgments).

Introduction

Food allergy is estimated to affect around 3–7% of children younger than 5 years;1, 2, 3 up to 11% of infants younger than 12 months;1 and 1·4–3·8% of children aged 6–10 years.4 Diagnosis of food allergies can be challenging. Oral food challenge is currently the gold standard to differentiate between reported and confirmed clinical disease.4 IgE-mediated food allergy in early childhood commonly includes cow's milk, hen's egg, peanut, and wheat.2, 4 Most infants with allergy to milk, egg, and wheat develop a natural tolerance to these allergens,1 whereas the development of tolerance is less likely with allergy to peanut and tree nuts.5

Research in context

Evidence before this study

Since allergen avoidance in infancy has failed to prevent food allergy, early complementary introduction of allergenic foods was perceived as a more plausible primary prevention strategy. Allergic sensitisation is observed by age 4–6 months in some infants. Before the start of this study (December, 2014), data on the introduction of allergenic foods before 4 months of age for primary prevention of food allergy were scarce. In a systematic review from 2014, Da Silva and colleagues identified one cohort study by Venter and colleagues, who reported reduced food allergy or sensitisation to food when solids were introduced before age 4 months. Additionally, a Swedish randomised trial reported a reduction in allergy symptoms up to age 18 months in children fed cow's milk during the first few days of life, if both parents were atopic. We searched PubMed on Dec 15, 2020, without date or language restrictions, for clinical trials, randomised controlled trials, systematic reviews, and meta-analyses using the search term “primary prevention and ((atopic dermatitis or eczema) or (food allergy))”. Our search yielded 201 articles, of which 19 were considered relevant. Additionally, two relevant systematic review and meta-analyses from 2016 and 2020, and one randomised controlled trial published in January, 2021, were included in January, 2021. The Learning Early about Peanut Allergy trial done in 2015, showed that the consumption of peanuts in infants with atopic dermatitis or egg allergy, between age 4 months and 10 months, prevented peanut allergy. In the Enquiring About Tolerance trial, in which multiple allergenic foods were introduced in a general cohort of breastfed infants aged 3 months, no significant reduction in food allergy was identified between 1 and 36 months in the intention-to-treat analysis. However, among the 32% of infants who adhered to the food intervention, food allergy was significantly reduced, indicating that primary prevention through early complementary feeding from age 3 months might be possible. On the basis of 15 intervention trials, a 2016 systematic review and meta-analysis by Lerodiakonou and colleagues concluded with moderate-certainty evidence that the introduction of egg between 4 and 6 months of age reduced childhood allergy to egg, and the introduction of peanut between 4 and 11 months of age reduced childhood allergy to peanut. Two studies reported that early exposure to cow's milk had no significant effect on allergy. The 2020 review by Da Silva and colleagues based on the same studies specified that early exposure to cooked hen's egg is likely to reduce the prevalence of egg allergy, whereas raw or pasteurised egg might not. Two of the studies found that most infants with egg allergy were already sensitised and allergic by enrolment at age 4–6 months, indicating the need for earlier application of preventive measures. In a 2021 randomised trial, Sakihara and colleagues concluded that cow's milk allergy at age 6 months was significantly reduced after daily exposure to cow's milk between ages 1 and 2 months.Five randomised controlled trials investigating skin protection as primary prevention of atopic dermatitis were identified, including previous findings from our PreventADALL study. Only one trial reported on food allergy and found no preventive effect of regular emollients applied during the first year of life.

Added value of this study

To our knowledge, no other study has investigated potential additive or synergistic effects of early food allergen introduction and regular emollients to prevent food allergy. The PreventADALL study provides evidence that food allergy at age 36 months might be prevented by the introduction of common foods from age 3 months. The study demonstrated that the food intervention was effective in a general cohort not selected on the basis of atopic risk, suggesting that early feeding of 63 infants might prevent food allergy in one child at age 36 months. In analysis of specific food allergies, the intervention was effective for peanut allergy. There were no safety issues, and breastfeeding rate at 6 months was not affected by early food introduction. Early regular use of skin emollients did not reduce food allergy at 36 months.

Implications of all the available evidence

Collectively, our findings and those of other large randomised controlled trials show that introduction of allergenic foods before age 4 months reduced food allergy in early childhood. Reduced allergy was also observed in the absence of screening for risk of atopic disease. Early complementary feeding seems to be safe and at present is likely to represent a feasible primary prevention strategy to reduce food allergy. We believe that there is sufficient evidence to suggest that food allergy can be prevented by recommending early introduction of allergenic food complementary to regular feeding from age 3 months.

Primary prevention of food allergy would be of major societal and individual benefit. Regular intake of egg6, 7 and peanut8 from age 4 months might reduce food allergy in infants at increased risk;9, 10 however, evidence to support early nutritional interventions before age 4 months in infants from the general population remains scarce.9, 10 In the Enquiring About Tolerance (EAT) study,3 in which 1303 breastfed infants were recruited from the general UK population, no significant reduction in food allergy was observed between 1 and 36 months as a result of the introduction of multiple foods from age 3 months in primary analyses, whereas egg and peanut allergies were significantly less frequent among the 32% of infants who adhered to the intervention.3 Among 504 healthy infants in Japan given cow's milk formula daily between ages 1 and 2 months, allergy to cow's milk was reduced at 6 months compared with those not given cow's milk formula in the study period.11 Further evidence of the effect of foods introduced before age 4 months is urgently needed.9

Atopic dermatitis, a common chronic inflammatory skin disease associated with reduced skin barrier function, is a strong risk factor for subsequent food allergy.12, 13 The first step in primary prevention of food allergy might be to prevent atopic dermatitis.14 However, previous studies have shown that application of regular emollients from the first few weeks of life did not prevent atopic dermatitis up to age 2 years15 in children from a general population,16 nor in children at high risk of atopic dermatitis.17

Preventing food sensitisation by improving the infant skin barrier has been proposed.13 In a randomised controlled pilot trial of 77 infants at high risk of food allergy given ceramide-dominant emollient twice daily, sensitisation to food allergens was reduced at 12 months in the per-protocol analysis only,18 whereas in the Barrier Enhancement for Eczema Prevention (BEEP) study,17 among 1394 infants given daily standard emollients, no reduction in food allergy was identified at age 2 years.17

The dual allergen exposure hypothesis suggests that food allergen exposure through damaged skin before exposure through the alimentary tract might lead to the development of food allergy.19 Combining dietary modifications and improved skin barrier function in early infancy to prevent food allergy has therefore been hypothesised,13, 14, 19 but had not been previously investigated in humans before the Preventing Atopic Dermatitis and ALLergies in children (PreventADALL) study.16 The PreventADALL study is the first large, pragmatic, population-based, randomised clinical trial combing the early introduction of food allergens and regular emollients aiming to prevent atopic dermatitis16 or food allergy in children. The lack of preventive effect of the interventions on atopic dermatitis at 12 months of age was reported in 2020.16

In this study, we aimed to determine whether early food or skin interventions prevented food allergy at age 36 months. We also aimed to assess the effect of the interventions on preventing allergy to specific interventional foods, atopic dermatitis, and allergic sensitisation to the interventional foods at age 36 months.

Section snippets

Study design and participants

The PreventADALL study is an investigator-initiated, 2 × 2, multicentre, cluster-randomised, controlled superiority trial done at Oslo University Hospital and Østfold Hospital Trust, Oslo, Norway, and Karolinska University Hospital, Stockholm, Sweden. The methods of the PreventADALL trial have been published previously.16

Briefly, all healthy newborn babies with a minimum gestational age of 35·0 weeks, born to women enrolled in the PreventADALL study during pregnancy between Dec 9, 2014, and Oct

Results

We recruited 2697 women with 2701 pregnancies from whom 2397 newborn infants were enrolled between April 14, 2015, and April 11, 2017. Of these infants, 597 were randomly assigned to the no intervention group, 575 to the skin intervention group, 642 to the food intervention group, and 583 to the combined intervention group. One participant in each of the no intervention, food intervention, and skin intervention groups withdrew consent and were therefore not included in any of the analyses (

Discussion

In this large, pragmatic, randomised clinical trial, the introduction of peanut, cow's milk, wheat, and egg from 3 months of age, complementary to regular feeding, reduced food allergy at 36 months of age in children from a general population. We were not able to provide evidence that regular emollient baths and facial cream from early infancy reduced food allergy.

This is the first study to demonstrate a significant reduction in risk of documented food allergy in children aged 36 months after

Data sharing

According to Norwegian legislation, identification of individuals stored in public databases by study code is not permitted, when currently stored in the secure Service for Sensitive Data database at the University of Oslo. Furthermore, the PreventADALL study is ongoing, with data currently being collected and analysed by researchers, pertaining to different research questions within the main framework of the study aims. Data storage is currently approved until 2044. Ethical approval and

Declaration of interests

EMR reports honoraria for lectures from Sanofi Genzyme, Leo Pharma, Novartis, Norwegian Psoriasis and Eczema Association, and the Norwegian Asthma and Allergy Association, outside the submitted work. ML reports personal fees for lectures from Merck Sharp & Dohme. AA reports personal fees from Orion Pharma, Novartis, and MEDA Pharmaceuticals, outside the submitted work. CS has received laboratory material and analytical support from Thermo Fisher Scientific in other research projects. KCLC

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