The Long Search for Evidence Based Nutritional Interventions

ALLERGY PREVENTION – Essential clinical pearls for the early care of every child

In a recent webinar jointly organized by the Nestlé Nutrition Institute under the auspices of the Singapore Paediatric Society and the Malaysian Society of Allergy & Immunology, two eminent experts discussed the latest evidence base and clinical pearls on nutritional interventions to prevent the development of allergy in children.

Globally, the prevalence of food allergy in children vary among countries – from 1% in Thailand, to 10% in Australia,[i] although overall, the prevalence of food allergy in Asia seems comparable to that observed in the West,[ii] and is a source of great concern for children, their parents and among healthcare professionals.

Risk factors for allergy: What’s new?

One of the key factors believed to increase a child’s risk of allergy is family history. It has been reported that about 20-40% of children born to 1 parent with allergies eventually develop allergies; the risk increases to 60-80% among children where both parents have allergies.[iii] However, newer evidence from large retrospective study on children with food-induced allergies showed that 1 in 3 children actually did not have any family history of atopy.[iv]

Emerging evidence on the role of hydrolysed formula in allergy prevention

In 2016, a systematic review and meta-analysis reported that there was no consistent evidence supporting the use of hydrolysed formula for the prevention of allergic disease.[v] However, other experts have commented that the conclusions that could be drawn from the analysis are limited as the authors included studies of different types of hydrolysed formula, for instance, all trials with  partially hydrolysed formula (pHF) and extensively hydrolysed formula (eHF) were included, independent of the study designs used and the outcomes that were measured. This is a critical point, as it is well-known that not all hydrolysed formula provide the same degree of protective benefit; factors, such as the protein source, as well as the method and degree of hydrolysis that often vary across manufacturers contribute to differences among hydrolysates.[vi] To provide evidence that is more meaningful for clinical practice,  the efficacy and safety each hydrolysed formula must be investigated, and the effect on specific outcomes (eczema, asthma, allergic rhinitis or food allergy) must be evaluated separately.

An updated meta-analysis published in 2017 concluded that the use of pHF reduced the risk of eczema and all allergic diseases at some, albeit not all, time points among children at high risk for allergy.[vii] This systematic review included 13 publications reporting on 8 randomised controlled trials. Compared with a 2016 meta-analysis, this review specifically investigated a partially hydrolysed 100% whey formula from a single manufacturer and its effect on eczema and all allergic diseases versus standard cow’s milk formula.  The outcomes were also assessed at time intervals reported by the authors of the original publications. The results showed that the use of pHF conferred a statistically significant reduction of eczema risk in some, but not all time points. One of the studies that contributed the most to the pooled results was the German Infant Nutritional Intervention (GINI) study – a large, well-designed and conducted, randomised, double-blind (until 3 years of age) trial, with a 15-year follow-up period.[viii]The study compared the effect of three interventions – pHF (whey), eHF (whey) and eHF (casein) – versus standard cow’s milk formula on distinct outcomes – atopic dermatitis, allergic urticaria, food allergy with manifestation in the GI tract, allergic rhinitis and asthma – the diagnosis of which were all confirmed by a second, trained allergologist. This study demonstrated that the allergy preventive effect of eHF (casein) and pHF (whey) was evident during the first year of life and persisted until 6 years of age.[ix] The more recently published 15‐year follow‐up study of this cohort also established that the use of certain hydrolysate formulas in high‐risk children is associated with less eczema from birth until the age of 15 years.[x] Taken together, this well-designed study provides robust evidence supporting the use of pHF in reducing the risk of allergic diseases in high-risk children, particularly eczema.

Latest guidelines on the use of hydrolysed formula for allergy prevention

Given the conflicting reports on the value of hydrolysed formula as a preventive measure against allergy development in children at risk, it is no surprise that expert recommendations also vary. The Middle East consensus recommendations support the use of pHF (whey) with documented safety and efficacy for all infants.[xi] The American Academy of Pediatrics, on the other hand, revised their 2008 report to state in 2019 that there is lack of evidence that partially or extensively hydrolysed formula prevents atopic disease in infants and children, even in those at high risk for allergic disease.[xii]

Currently, the European Academy of Allergy and Clinical Immunology (EAACI) is revising  its guidelines following a systematic review that assessed the value of various interventions in preventing immediate-onset/IgE-mediated food allergy.[xiii]

Latest recommendations on the introduction of potentially allergenic foods

Until 2007, experts advocated allergen avoidance for prevention of food allergy, based primarily on data from observational studies. Two recently-published landmark studies, however, resulted in pivotal changes in infant nutrition: the Learning Early about Peanut Allergy (LEAP) and the Enquiring about Tolerance (EAT) trials demonstrated that early introduction of allergenic foods, such as peanut and egg, significantly decreased the risk of allergy among children at high risk.[xiv][xv] Current expert recommendations thus generally agree: allergenic foods, such as peanuts and egg, should be introduced at around 6 months, but not before 4 months, of age.

Early nutritional preventive strategies against food allergy

The latest EAACI systematic review did not find evidence for or against supplementation of pro/pre/synbiotics, fish oil or vitamins for the prevention of food allergy in children.[xvi]

[i] Prescott SL, Pawankar R, Allen KJ, et al. A global survey of changing patterns of food allergy burden in children. World Allergy Organ J. 2013;6(1):21.

[ii] Lee AJ, Thalayasingam M, Lee BW. Food allergy in Asia: how does it compare?. Asia Pac Allergy. 2013;3(1):3-14.

[iii] Bergmann RL, Edenharter G, Bergmann KE, et al. Predictability of early atopy by cord blood-IgE and parental history. Clin Exp Allergy. 1997;27(7):752-760.

[iv] Meyer R, Fleming C, Dominguez-Ortega G, et al. Manifestations of food protein induced gastrointestinal allergies presenting to a single tertiary paediatric gastroenterology unit. World Allergy Organ J. 2013;6(1):13.

[v] Boyle RJ, Ierodiakonou D, Khan T, et al. Hydrolysed formula and risk of allergic or autoimmune disease: systematic review and meta-analysis. BMJ. 2016;352:i974.

[vi] Greer FR, Sicherer SH, Burks AW; American Academy of Pediatrics Committee on Nutrition; American Academy of Pediatrics Section on Allergy and Immunology. Effects of early nutritional interventions on the development of atopic disease in infants and children: the role of maternal dietary restriction, breastfeeding, timing of introduction of complementary foods, and hydrolyzed formulas. Pediatrics. 2008;121(1):183-191.

[vii] Szajewska H, Horvath A. A partially hydrolyzed 100% whey formula and the risk of eczema and any allergy: an updated meta-analysis. World Allergy Organ J. 2017;10(1):27.

[viii] von Berg A, Koletzko S, Grübl A, et al. The effect of hydrolyzed cow's milk formula for allergy prevention in the first year of life: the German Infant Nutritional Intervention Study, a randomized double-blind trial. J Allergy Clin Immunol. 2003;111(3):533-540.

[ix] von Berg A, Filipiak-Pittroff B, Kramer U, Link E, Bollrath C, Brockow I, et al. Preventive effect of hydrolyzed infant formulas persists until age 6 years: longterm results from the German Infant Nutritional Intervention Study (GINI). J Allergy Clin Immunol 2008;121:1442-7.

[x] von Berg A, Filipiak-Pittroff B, Schulz H, et al. Allergic manifestation 15 years after early intervention with hydrolyzed formulas--the GINI Study. Allergy. 2016;71(2):210-219.

[xi] Vandenplas Y, Al-Hussaini B, Al-Mannaei K, et al. Prevention of Allergic Sensitization and Treatment of Cow's Milk Protein Allergy in Early Life: The Middle-East Step-Down Consensus. Nutrients. 2019;11(7):1444.

[xii] Greer FR, Sicherer SH, Burks AW; COMMITTEE ON NUTRITION; SECTION ON ALLERGY AND IMMUNOLOGY. The Effects of Early Nutritional Interventions on the Development of Atopic Disease in Infants and Children: The Role of Maternal Dietary Restriction, Breastfeeding, Hydrolyzed Formulas, and Timing of Introduction of Allergenic Complementary Foods. Pediatrics. 2019;143(4):e20190281.

[xiii] de Silva D, Halken S, Singh C, et al. Preventing food allergy in infancy and childhood: Systematic review of randomised controlled trials [published online ahead of print, 2020 May 12]. Pediatr Allergy Immunol. 2020;10.1111/pai.13273.

[xiv] Du Toit G, Roberts G, Sayre PH, et al. Randomized trial of peanut consumption in infants at risk for peanut allergy [published correction appears in N Engl J Med. 2016 Jul 28;375(4):398]. N Engl J Med. 2015;372(9):803-813.

[xv] Perkin MR, Logan K, Tseng A, et al. Randomized Trial of Introduction of Allergenic Foods in Breast-Fed Infants. N Engl J Med. 2016;374(18):1733-1743.

Click here to watch Prof’s Szajewska’s speech on Allergy Prevention

Click here to read highlights from Dr. Kent Woo's speech on Allergy Prevention

Click here to read Prof. Hugo Van Bever's article - Primary prevention of allergy in infants – What’s new?