Food Allergy Prevention: Is Earlier Complementary Food Introduction Really the Optimal Approach?

It is now widely accepted in the allergy community and wider society that the phenomenon of oral tolerance is relevant to the development of Immunoglobulin-E mediated food allergy in humans. However, the optimal application of oral tolerance for preventing food allergy is unclear. Debate about how to implement oral tolerance for food allergy prevention is currently at risk of pitting public health and allergy communities against each other over the timing of complementary food introduction. In this editorial, we review the evidence for using oral tolerance to prevent food allergy. We highlight limitations of the available data in relation to informing public health guidance for the timing of complementary food introduction. We suggest research is needed to establish whether the optimal approach to food allergy prevention might involve allergenic food introduction that is consistent with current public health guidance.

Oral tolerance was first described by Harry Gideon Wells over 100 years ago, while studying the development of hen's egg allergy in guinea pigs [1]. Wells noted that if young guinea pigs were fed hen's egg before he started an egg sensitisation protocol, egg allergy could not be induced. In contrast, if the pups were not fed hen's egg before sensitisation began, egg allergy could be induced. Although oral tolerance is now a well-understood feature of immunology research in a range of animal and in vitro models, it took over 100 years from Wells's original observations before we found a successful human application of oral tolerance. That application is the inclusion of allergenic foods in the human diet during infancy, to prevent the development of IgE-mediated food allergy. Like in Wells's guinea pigs, the strongest evidence for oral tolerance in humans is for the prevention of common forms of IgE-mediated food allergy such as egg or peanut allergy [2]. Infant feeding guidelines in many regions of the world now recommend including common allergenic foods such as egg or peanut in the infant diet, rather than avoiding such foods. But important questions remain about optimising allergy prevention using allergenic food introduction.

In Wells's classic description of oral tolerance, he noted that early, short-term feeding of a food antigen was not sufficient to induce oral tolerance, but prolonged exposure reliably prevented the development of allergy. He stated, ‘Apparently, then, daily absorption of animal protein in the food at first renders guinea-pigs hypersensitive to this protein, but if the feeding is kept up for a long enough period the animals become refractory to the food protein.’ So Wells's work supports the potential relevance of prolonged oral allergen exposure for effective tolerance induction. Timing of allergenic food introduction is also important, because oral tolerance induction is simpler when allergenic foods are introduced before food allergy has developed. However, the relative importance of timing, frequency and duration of allergenic food consumption for preventing food allergy is unclear.

It is often not appreciated that human clinical trials in this field, both published and registered unfinished trials, tend to test a complex intervention that mixes timing of allergenic food introduction, timing of complementary food introduction and intensity (i.e., frequency, quantity and form) of allergenic food consumption all together (Figure 1). Thus, it is difficult to isolate the relative impact of timing of allergenic food introduction from any broader impact of changing complementary feeding pattern overall, or changing the frequency, dose and format of allergenic food exposure during the first year of life. For example, a clinical trial might test the use of egg powder at a specific daily dose from age 4 months and compare this with a control group that consumes a variable and unspecified amount of egg, at a variable frequency, introduced in a range of different formats at a range of different ages, in the context of later complementary food introduction. To ascribe any allergy-preventing effects of such an intervention to timing alone means making assumptions that the other aspects of the intervention were not relevant.

When we look at the clinical trial evidence supporting oral tolerance induction for the prevention of IgE-mediated food allergy in humans, we see a striking disconnect between the complex interventions tested (and often shown to be effective) and the simplistic interpretation of that evidence, focussing exclusively on the timing of allergenic food introduction. While trials are interpreted as showing that earlier introduction of allergenic foods reduces the risk of food allergy development, the clinical trials themselves are generally not set up to test the timing of allergenic food intervention.

One argument put forward for early allergenic food introduction is that food allergy does sometimes develop before age 6 months. However, there is emerging evidence that oral tolerance can be induced in humans, even after food allergy has fully developed. Oral immunotherapy for treating established food allergy appears to be most effective in the preschool age group and may in time become the standard of care for managing IgE-mediated food allergy in young children [3, 4]. So despite some early food allergy developing before age 6 months, allergenic food introduction undertaken at around 6 months may still facilitate the induction of oral tolerance.

There are no published or registered clinical trials which focus on testing timing of allergenic food introduction alone, without changing intensity of allergenic food consumption and/or timing of complementary feeding. This means that for many years to come, there will remain residual uncertainty as to whether early introduction is the critical factor, or whether later introduction in higher dose/frequency might be as effective for preventing food allergy. There are two important consequences of this uncertainty. First, a reduced population impact in terms of food allergy prevention—this has been seen most clearly in Victoria, Australia, where successive cohorts have shown no definite change in peanut allergy despite a marked shift in timing of introduction of peanut between the cohorts [5]. One possible explanation for this discrepancy is that changing timing, without addressing intensity of peanut exposure, may actually have quite a limited impact on population rates of food allergy. The second consequence of our uncertainty about the relative impact of timing versus intensity of allergenic food introduction is confusion in food allergy prevention guidelines.

The World Health Organization (WHO) recommends complementary food introduction should take place at 6 months due to nutritional requirements of the developing infant [6]. Many government health departments, including the UK, support this recommendation. Variation in individual requirements is recognised and sometimes the term ‘around 6 months’ is used in public communications. It has become common for allergy societies and other professional groups to advocate infant feeding advice which runs counter to this recommendation (Figure 2). For example, European professional societies recommend that in populations affected by food allergy, allergenic food (s) (and therefore complementary foods) may be introduced any time from 4 months [7]. Public health authorities such as WHO have concerns beyond allergy, for example, about possible increased risk for obesity and/or infectious disease with earlier introduction of complementary foods. While the evidence for such risks is limited, the relevant health conditions are the greatest threats to children's health globally. A narrative that prioritises food allergy epidemiology and emphasises rare but tragic outcomes is sometimes invoked to support food allergy prevention as something more important than other public health considerations. But for public health authorities, obesity and/or childhood infectious disease are usually higher priorities than food allergy.

A less controversial approach to allergy prevention research might focus on working within, rather than against, government infant feeding guidelines. This would mean undertaking studies which build on current advice encouraging the introduction of allergenic foods at around age 6 months, together with other complementary foods. For example, new clinical trials might focus on exploring interventions to promote greater intensity of allergenic food consumption from age 6 months, rather than changing guidance for the timing of complementary feeding.

The financial dependence of almost all allergy societies worldwide on the formula milk industry provides important context for this debate [8]. Formula companies have a vested interest in advice that encourages early introduction of complementary foods. Although these companies have not participated in the major food allergy prevention trials, formula milk companies are an interested party. A shift towards earlier complementary feeding would create new marketing opportunities for products such as baby pouches and for ‘follow-on formula’. This category of infant milks is marketed in Europe and many other regions for infants who are already consuming complementary foods—currently specified in formula regulations to be infants over 6 months [9]. Follow-on formula is less tightly regulated than standard infant formula, allowing non-lactose carbohydrate content and more aggressive marketing. If public health guidance were revised to recommend complementary foods before 6 months, companies could potentially exploit this. They might promote unhealthy complementary feeding products and follow-on formula to the carers of younger infants, with adverse consequences for child health.

So while the discovery that oral tolerance is relevant to the development of IgE-mediated food allergy in humans is important, our current evidence base is imperfect. As an allergy community, we need to be cautious about over-simplifying evidence derived from complex interventions in ways that could undermine public health.

C.B. prepared first draft and Figure 1. R.S. prepared updated systematic review search and repository Tables. M.R.P. edited and commented on the first and subsequent drafts. R.J.B. conceived and led the project. All authors contributed to editing the manuscript and approved the final version.

R.J.B. declares payment from Wiley and the British Society for Allergy and Clinical Immunology for editorial work, from the UK Department of Health and Social Care for advisory committee work, from Taus, Cebulash and Landau for expert witness work, from the World Health Organization and the Norwegian Directorate of Health for consultancy and from the European Academy of Allergy and Clinical Immunology for conference presentation. The other authors declare no conflicts of interest.