Timing of introduction of allergenic solids for infants at high risk

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Introduction

Food allergy affects an estimated 2% to 10% of the population ^[1]. In Canada, one nationwide survey noted a self-reported food allergy prevalence of 7.5% ^[2]. As a result, preventing food allergy has become an important public health goal. While any food can theoretically cause an allergic reaction, the most common allergens in children are cow’s milk, egg, peanut, tree nuts, fish, shellfish, wheat and soy ^[3]. In 2013, a Canadian Paediatric Society joint statement with the Canadian Society of Allergy and Clinical Immunology recommended exclusively breastfeeding infants at high risk for food allergy for their first 6 months ^[4], in keeping with World Health Organization recommendations to exclusively breastfeed infants for the first 6 months of life ^[5]. Since 2013, however, more evidence has become available to suggest that introducing allergenic solids before an infant reaches 6 months of age may help prevent food allergy development, particularly for egg and peanut, in infants at high risk ^[6]-[8]. The goals of this practice point are to: 1)  review evidence that introducing commonly allergenic foods early (before 6 months) to high-risk infants with a personal or immediate family history of an allergic condition can help prevent food allergy; and 2) align CPS and Health Canada recommendations going forward ^[9].

Definition of the infant at high risk for food allergy

There is no current international consensus regarding how to define infants at high risk for developing food allergy. The 2013 CPS statement and other international guidelines defined an infant at high risk as having a first-degree relative with an allergic condition ^[4][10]. In contrast, one recent randomized controlled trial defined infants at high risk for peanut allergy as having severe eczema, egg allergy, or both ^[6], because a proof of concept study had identified these markers as the strongest risk factors for peanut allergy ^[11]. Infants with mild to moderate eczema may also be at risk for developing food allergy ^[12]. Therefore, the definition of ‘at-risk’ or ‘high-risk’ infants is becoming increasingly blurred. Some infants, such as those with severe eczema and egg allergy, may be at higher risk than others for food allergy, and peanut allergy in particular. This practice point defines the infant at high risk as having a personal history of atopy, including eczema, or having a first-degree relative with atopy (e.g., eczema, food allergy, allergic rhinitis, or asthma).

Evidence for early introduction of allergenic solids

Since 2013, evidence from randomized trials has increasingly supported the early introduction (before 6 months) of allergenic foods to prevent food allergy, specifically to peanut and egg ^[6]-[8].

One recent systematic review and meta-analysis found evidence of moderate certainty that early egg introduction (between 4 to 6 months of age) reduced the rate of egg allergy (RR=0.56 (95% CI: 0.36 to 0.87)) ^[8]. There was also evidence of moderate certainty (based on two trials) that early peanut introduction (between 4 to 11 months) reduced the rate of peanut allergy (RR=0.29 (95% CI: 0.11 to 0.74))) ^[8].

For peanut, the most striking study to date was the Learning Early About Peanut (LEAP) study, the first randomized controlled trial to provide evidence that early peanut introduction could help prevent peanut allergy in high-risk infants ^[6]. In this study, 640 high-risk infants in the U.K. (defined as having severe eczema, egg allergy, or both) were randomized into early (4 to 11 months) or delayed (avoidance until 5 years) peanut introduction, then stratified based on skin prick test sizes. All infants with skin prick tests of 5 mm in diameter or greater to peanut were excluded. Results showed an overall relative risk reduction in peanut allergy of up to 80% with early peanut introduction. This reduction was seen in both the skin prick test-negative (13.7% versus 1.9%; P<0.001) and skin prick test-positive, i.e, with a wheal of 1 to 4 mm (35.3% versus 10.6%; P=0.004) cohorts.

Several randomized trials have examined the effect of early egg introduction in at-risk infants. The Prevention of Egg allergy with Tiny amount InTake (PETIT) study of 121 Japanese infants demonstrated that ingesting heated egg powder daily, beginning at 6 months of age, drastically lowered the rate of egg allergy when compared with infants who avoided egg completely until one year of age (9% versus 38%; P=0.0012) ^[7]. In contrast, the Starting Time of Egg Protein (STEP) study randomized 820 infants with hereditary risk of allergy who ingested daily pasteurized egg powder at 4 to 6 months of age versus those who avoided ingestion until 10 months of age. Although researchers noted a trend toward lower rates of egg allergy at one year of age in the early introduction group (7% versus 10.3%; P=.20), a high rate of allergic reactions to egg powder in the early introduction group throughout the study period was also observed (6.1% versus 1.5% in the placebo group) ^[13].

Overall, there is little available data to compare introduction of common allergenic foods at 4 months of age with introduction at 6 months. One randomized controlled trial, the Enquiring About Tolerance (EAT) study, examined very early allergenic food introduction ^[14]. This study randomized 1,303 infants from the general population to early (at 3 months) or standard (at 6 months) introduction of six commonly allergenic foods: milk, egg, wheat, peanut, fish and sesame. No difference in the rate of food allergy was seen in the intention to treat analysis. However, in the per protocol analysis, a difference for egg (1.4% versus 5.5%; p=0.009) and peanut (0% versus 2.5%; p=0.003) was found. The limitations of per protocol analysis should be noted, along with the proviso that compliance became a major issue in this study, with only 42.8% of infants in the early introduction group adhering to early introduction for all six allergenic foods.

Ongoing trials include the European Preventing Atopic Dermatitis and ALLergies in Children (PreventADALL) study, which is randomizing infants to early introduction of egg, milk, wheat and peanut by 4 months of age, regular emollient use, or both. Primary outcome is the presence of eczema or food allergy (ClinicalTrials.gov ID NCT02449850).

In conclusion, there is emerging evidence from randomized trials which have included infants younger than 6 months old, that earlier allergenic solid introduction may prevent peanut and egg allergy in infants at high risk. There is an evidence gap for other allergenic foods, although some observational studies have supported the early introduction of wheat and cow’s milk products to prevent allergy ^[15]-[17].

Finally, regardless of the timing for introducing complementary foods, breastfeeding should be protected, promoted and supported up to the age of 2 years and beyond, because of  its unique immunological and developmental benefits ^[18][19]. Further randomized controlled trials are required to determine whether earlier introduction of allergenic foods is also beneficial for preventing allergy in lower-risk infants ^[20].

The following guidance for practice is based on evidence supporting the early introduction of common allergenic foods to high-risk infants:

• Infants considered to be at high risk for allergic disease have either a personal history of atopy or a first-degree relative with atopy.
• For high-risk infants, and based on developmental readiness, consider introducing common allergenic solids at around 6 months of age, but not before an infant is 4 months of age.
• For infants at no or low risk for food allergy, introducing complementary foods at about 6 months is recommended.
• Breastfeeding should be protected, promoted and supported for up to 2 years and beyond.
• Allergenic foods should be introduced one at a time, to gauge reaction, without unnecessary delay between each new food.
• If an infant appears to be tolerating a common allergenic food, advise parents to offer it a few times a week to maintain tolerance. If an adverse reaction is observed, advise parents to consult with a primary care provider about next steps.
• The texture or size of any complementary food should be age-appropriate to prevent choking. For young infants, smooth peanut butter can be diluted with water or mixed with a previously tolerated puréed fruit or vegetable, or with breast milk ^[12][21]. For older infants, smooth peanut butter can be spread lightly on a piece of thin toast crust, or a peanut puff product could be offered ^[12].

Acknowledgements

This practice point was reviewed by the Community Paediatrics and Nutrition and Gastroenterology Committees of the Canadian Paediatric Society.

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CANADIAN PAEDIATRIC SOCIETY ALLERGY SECTION

Executive members: Elissa M. Abrams MD (President), Nestor Cisneros MD (Past President), Edmond S. Chan MD (Secretary Treasurer)

Principal authors: Elissa M. Abrams MD, Kyla Hildebrand MD, Becky Blair (RD, MSc), Edmond S. Chan MD

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References

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Disclaimer: The recommendations in this position statement do not indicate an exclusive course of treatment or procedure to be followed. Variations, taking into account individual circumstances, may be appropriate. Internet addresses are current at time of publication.