The Association between Infant Food Practices and the Increased Risk of Allergic Diseases
- Exposure to a variety of food antigens as early as 4-6 months will be important for the development of immune tolerance and decrease the risk of allergic diseases in children.
- Atopic Disease Overview
- Environmental influences on atopic disease
- Effect of the early introduction of complementary foods on atopic disease
- Infant gut bacterial microbiota and risk of atopic disease
- Epidemiology/Risk Factors
- Clinical Manifestations
- Atopic Dermatitis
- Clinical Manifestations
- Allergic Rhinitis
- Epidemiology/Risk Factors
- Clinical Manifestations
- Food Allergy
- Clinical Manifestations
- Diagnosing Food Allergy
- Gold Standard- Oral food challenge
- Sensitization vs true food allergy
- Gold Standard- Oral food challenge
- Defining High Risk Groups
- Infant Feeding Practices
- Role of human milk and breastfeeding in the development of atopic disease
- Hydrolyzed formula may reduce risk for allergy in high risk group
- Complementary (Solid) Foods
- Previous Recommendations
- Current Recommendation
- Recommendations for Introduction of highly allergenic foods
- Previous recommendations
- Current recommendations
- 2017 Addendum Guidelines
- Highly allergy-inducing food antigens and allergies
- Newest research LEAP study (2015)
- Early infant exposure to peanut protein compared to withholding up to 36 months reveals reduction in peanut allergy
- Addendum guideline 1: In cases of severe eczema, egg allergy or both, strongly consider evaluation by specific IgE (sIgE) measurement and/or skin prick test (SPT) and, if necessary, oral food challenge (OFC). Based on test results, introduce peanut containing foods at the earliest 4-6 months
- Addendum guideline 2: mild-moderate eczema, introduce peanut containing foods at earliest around 6 months
- Addendum guideline 3: no eczema or any food allergy, introduce peanut containing foods as age appropriate and in accordance with family preferences and cultural practices.
- Newest research LEAP study (2015)
- Highly allergy-inducing food antigens and allergies
- Prevention of allergies and asthma in children
Objectives: This paper investigates the relationship between timing of introduction of complementary food and food diversity as early as age 4-6 months and the development of allergic diseases in childhood.
Methods: Information was collected from Salus’ Total Search Article Database, PubMed, Medline, Up-To-Date, and Google Scholar. Terms used in each search included and combined the following: allergies, asthma, atopic disease, food introduction, prevention, allergenic foods and risk of atopy. Abstracts were screened for relevance and references of selected articles were evaluated for importance.
Results: Studies revealed that the introduction of cow’s milk, hen’s egg and peanuts before the age of six months was not significantly associated with atopic dermatitis or asthma in childhood. In high risk groups, complementary food introduced earlier than four months was associated with a reduced risk of peanut sensitization by age two-three years. There is an increased association with sensitization to food allergens when introducing eggs after 10.5 months.
Conclusions: Feeding practices may represent a modifiable risk factor in the prevention of allergic disease. Among children with parental history of asthma or allergy and exposure to complementary food before age four months there is a reduced risk of peanut allergen sensitization. This is supported by the addendum guidelines developed for early introduction of peanut containing foods into diets of infants at various risk levels for peanut allergy. At present, there is need for more research for early introduction of staple foods, such as egg and milk. There is sufficient evidence not to delay introduction of allergenic foods after six months for the prevention of atopic dermatitis and asthma. Modifying feeding practices in infants represent future success in allergy prevention.
The prevalence of allergic disease and asthma are increasing worldwide. Asthma and allergy, defined as immunologically mediated hypersensitivities is the fifth leading chronic disease in the United States.1 It is estimated that over 40% of the population suffers from IgE mediated allergic diseases, such as allergic rhinitis, atopic dermatitis (AD) and anaphylaxis.2 Food allergy is also a growing public health problem, with peanut allergy being the leading cause of death related to food-induced anaphylaxis in the United States.1 Moreover, the complexity of allergic diseases, including asthma, continue to increase in children, who are bearing the greatest burden of these trends. The relationship of food introduction as early as 4-6 months in infant’s life has a large impact on the development of allergic disease. Unfortunately, there is a not a clear answer on how to prevent atopic diseases making this a subject of great concern for parents and clinicians caring for children.
There is often much debate on when to introduce certain foods to children in the prevention of allergic diseases. For many years, the prevailing advice for preventing food allergy in infants at high risk was to delay introduction of potentially allergenic foods (e.g., peanut, cow’s milk and eggs). However, this advice was not based on evidence-based recommendations. It is hypothesized currently that exposure to a variety of food antigens as early as 4-6 months are important for the development of immune tolerance and will decrease the risk of atopic diseases in children.3 This is a case that primary care providers see time and time again. Parents want to prevent their child from having a food allergy or other allergic disease, especially if it runs in the family. It is commonly asked, “When should I introduce foods? Are there foods I should avoid?” It has long been known that allergies tend to run in families so infants may be more likely to develop an allergic condition, such as food allergy or atopic dermatitis (eczema) if parents or siblings have an allergic disease. Although genetic predisposition is a fundamental feature in the susceptibility of allergic disease there are other intrinsic causes and environmental and lifestyle factors that need to be considered. This paper will also discuss specific high risk groups for peanut allergy and the latest 2017 recommendations.
This will lead into a background discussion of this epidemic specifically highlighting a timeline of the various recommendations of infant feeding practices to current recommendations. The hygiene hypothesis, originally formulated by Strachan proposed that allergic diseases were prevented by early infectious exposure introduced by contact with older siblings and the surrounding environment. Therefore meaning that the rise in atopic disorders was due to a reduced exposure to childhood infections and bacterial endotoxins. This hypothesis made many of the allergy pioneers question the role of our own gut microflora and its systemic effects on the body; leading to the thought that allergic disease will be increased with early feeding practices due to the immune immaturity and gut permeability in the post-natal period.4,22 Therefore, it was recommended that mothers exclusively breast feed their infants for the first 4-6 months, and thereafter complementary foods should be introduced.
More recently, the “dual-allergen-exposure hypothesis” proposed by Dr. Gideon Lack suggests that early cutaneous exposure to food protein through a disrupted skin barrier (i.e., eczematous skin) is what leads to allergic sensitization. In support of sensitization via the skin, a recent study has shown that mutations in filaggrin, a gene key to maintenance of the skin barrier, in infants with early-onset food sensitization and AD, are a risk factor for IgE-mediated peanut allergy and increased risk for asthma.9 Furthermore, the author’s hypothesis is that early introduction to a variety of food antigens, including allergenic foods, might actually decrease the risk of allergic disease by promoting immune tolerance.
Undoubtedly, the period of time introducing complementary foods is crucial in an infant’s life. Not only does it involve a great deal of imminent change for the child, but its timing and implementation is also associated with the potential development of allergic diseases. Throughout this paper, the author will highlight the role of early introduction of solid food as well as introduction of highly allergenic food on the development of allergic disease in children. This will allow for a more concrete disposition on how parents of infants at an increased risk for allergic disease should be counseled on food practices. The long-term goal of the review is to provide a roadmap for the future prevention of this epidemic.
This overall study will take a qualitative methodological approach to answer this research problem. Databases including Salus’ Total Search Article Database, PubMed, Medline, Up-To-Date, and Google Scholar were accessed. Terms used in each search included and combined the following: allergies, asthma, atopic disease, food introduction, prevention, allergenic foods and risk of atopy. A total of 594 articles were obtained after being filtered to limit the results to peer reviewed, clinical trials, full text access and published within the last ten years. Among the remaining options, articles were filtered based upon their relevance to the clinical question, specifically to the comparison of outcomes from previous guidelines for the prevention of allergic diseases. A large sample size was also used in the inclusion criteria of searched articles to ensure a good reflection of the entire population. Many studies found evaluated the timing of introduction of complementary food within the first year of life and assessed children up to age five. This inclusion criteria is a limitation because it does not evaluate the long term effect of dietary intervention past childhood and into adulthood. However, the sample sizes in Cohort studies, randomized controlled trials and intervention trials are most appropriate for studying questions regarding quality of life outcomes, and therefore included. Due to ethical concerns of introducing potential allergenic foods that could cause adverse reactions to children, many of the studies were observational trials. Information was gathered mostly through parent questionnaires. The search was useful in gathering current information and therefore would be more relevant to clinical practice. It was necessary to include a search of guidelines from the American Academy of Pediatrics from the previous 10 years to show a trend of what has been studied and changed. The data was analyzed using statistical significance per each article with p<0.05.
Atopic Disease Overview
Atopy refers to the genetic tendency to develop allergic diseases such as allergic rhinitis, asthma and atopic dermatitis.5 Atopy is typically associated with heightened immune responses to common allergens, especially inhaled and food allergens.6 Atopic diseases also result from the genetic predisposition in combination with environmental stimuli such as allergens, smoke, diet and/or infectious agents.6 The epidemiology of atopic diseases is more prominent with age, usually manifesting during the first five years of life. It has long been thought that the allergic manifestations that encompass atopy begin with AD and progress to asthma or allergic rhinitis, a phenomenon referred to as the ‘atopic or allergic march’.6,9 This concept was developed to describe the progression of disorders from AD in infants to asthma and allergic rhinitis in children.
AD is an altered immune reaction in genetically susceptible individuals when exposed to certain triggers leading to T cell mediated immune activation and an increase in IgE production.6,7 Ninety percent of patients with AD experience the onset of disease before age five and is seen in infants as early as two-six months of age. AD is one of the most common inflammatory allergic diseases characterized by erythematous and pruritic lesions most common in the flexor creases in children.1 The Tucson Children’s respiratory study found that eczema during the first year of life is an independent risk factor for persistent wheezing and 18% of children with wheezing at six years of age had experienced eczema before two years of age.8 Thus, AD is a major risk factor for the development of asthma. The most significant risk factors for progression of the atopic march are IgE sensitization and early onset and severity of AD.4 Children with AD with specific IgE antibodies to common environmental allergens who present by 2 to 4 years of age are at a higher risk for progressing to asthma and allergic rhinitis than those with AD without IgE sensitization.6
Atopy is the strongest predisposing factor for asthma, affecting an estimated 7 million children in the U.S. alone and is currently the most common chronic childhood disease.1 Asthma is a reversible hyperirritability of the tracheobronchial trees leading to airway inflammation and bronchoconstriction.1 Children with asthma typically exhibit the triad of dyspnea, cough and wheezing. Asthma disproportionately affects more black children compared to Hispanic or non-Hispanic white children and more boys than girls.1
The atopic march then observed that over half of the children with AD developed respiratory allergy such as allergic rhinitis during late childhood.8 Allergic rhinitis involves inflammation of the mucous membranes characterized by an IgE mediated response to an extrinsic protein.6 In susceptible individuals, exposure to certain foreign proteins leads to allergic sensitization, which is characterized by the production of specific IgE directed against these proteins.6 Allergic rhinitis is reported as high as 40% in children in the U.S. and the mean age of onset is 8 to 11 years old.1 Symptoms may include nasal congestion, sneezing, rhinorrhea and pruritic nose, palate, pharynx and eyes. On physical examination, these patients have bluish boggy nasal turbinates, cobblestoning of the posterior pharynx, a nasal crease and allergic shiners.
Role of Food Allergy in Atopic March
AD and food allergy commonly co-exist and is higher among those with earlier onset AD. In most patients, food allergies began early in life and carry throughout one’s lifetime. Food allergy affects approximately 8% of young children and there is a higher prevalence in children with moderate to severe AD.9,10 Specifically, peanut allergy is the leading cause of death related to food-induced anaphylaxis in the U.S.11 The prevalence of IgE-mediated food allergy is about 35% in children affected with AD.6 Diagnosis of food allergies is initially made through skin prick test (SPT), which utilizes the presence and degree of cutaneous reactivity as a surrogate marker to confirm sensitization in IgE-mediated allergic disease. The recommended method of prick testing includes the appropriate use of specific allergen extracts, positive and negative controls, interpretation of the tests after 15 – 20 minutes of application, with a positive result defined as a wheal ≥3 mm diameter.12 An oral food challenge (OFC) provides a more definitive diagnosis and is usually done when skin and blood tests are inconclusive. An OFC is a procedure in which food is eaten slowly, in gradually increasing amounts under supervision, and shows whether the food ingested produces symptoms or triggers a reaction.13
The most common IgE associated food allergens in children in the U.S. are cow’s milk, hen’s egg, soy, wheat, peanut, tree nuts and seafood.2 Food allergens are defined as the specific components of food or ingredients within food (typically proteins, but sometimes also chemical haptens) that are recognized by allergen-specific immune cells and elicit specific immunologic reactions.1 This results in characteristic symptoms such as hives, flushing, facial angioedema, and mouth or throat itching are common. In severe cases, angioedema of the tongue, uvula, pharynx, or upper airway can occur. Gastrointestinal symptoms include abdominal discomfort or pain, nausea, vomiting, and diarrhea. For all IgE-mediated reactions to foods, these symptoms occurs within minutes and up to two hours after ingestion.1
Food allergy is a known provoking cause of AD and vice versa. The filaggrin mutations are considered a major risk factor for the development of AD, particularly in children who have onset of AD at or before age two years. One study found that early sensitization to food and the presence of a filaggrin mutation in infants with early onset eczema increased the risk for persistent eczema and subsequent asthma. Many of the key structural proteins in the epidermis have genes that encode for filaggrin.4 In patients with AD, the skin barrier function is impaired and predisposes patients to early infection and allergic sensitization. One study found that filaggrin mutations increased the risk of eczema and food sensitization but not clinical food allergy among one year old infants, suggesting that decreased skin barrier function increases the risk of food sensitization.14 Another study showed a significant association of two filaggrin gene mutations with asthma and allergic rhinitis seen in subjects with the co-existence of AD and was not apparent in subjects without concomitant AD.4 This strongly supports the role of filaggrin mutation in the pathogenesis of AD as well as the role of genetics in early onset AD and the subsequent progression along the atopic march.
Infant Feeding Practices
The American Academy of Pediatrics (AAP) has been an advocate of breastfeeding as the ideal way to nourish an infant. Researchers believed that breastmilk may prevent atopy by decreasing allergic sensitizations through avoidance of allergens and by modulating the infant’s immune system. In 2005, the AAP changed their recommendations from gradually introducing solids between four and six months to exclusively breastfeeding for the first six months of life. Exclusive breastfeeding means that the infant receives only breast milk and that other liquids or solids except vitamin D are not to be given. After the first six months and until the infant is a year old, it is recommended that the mother continue breastfeeding while gradually introducing complementary foods into the infant’s diet. After one year, breastfeeding can be continued if desired by the mother and her infant.15 Complementary feeding is indicated when breast milk alone is no longer sufficient to meet the nutritional requirements of infants. Similar indications were recommended by UNICEF and the World Health Organization.
The AAP and World Health Organization together formulated recommendations on solid food introduction. These recommendations were updated because there was no convincing evidence that delaying solid foods beyond this time increased the rate of atopic disease. There was also support found in the differences in health outcomes of infants breastfed exclusively for four vs six months, for gastrointestinal disease, otitis media, respiratory illnesses, and atopic disease, as well as differences in maternal outcomes of lactation-induced infertility and postpartum weight loss.15 The American Academy of Allergy, Asthma and Immunology recommended the same guidelines and that highly allergenic foods in particular can be introduced between four and six months of age after other solid foods have been fed and tolerated.16
The AAP then took into consideration that feeding practices should be individualized based on the infants risk factors. High risk infants are any infant with a first degree relative (at least one parent or sibling) with an allergic condition such as AD, a food allergy, asthma or allergic rhinitis. From 1997 to 2008 alone, the prevalence of peanut allergy among U.S. children more than tripled, from 0.4% to 1.4%. Traditionally the recommendations for introduction of complementary foods to infants at increased risk for atopy were to delay the introduction of various highly allergenic foods from one to three years of age; specifically restrict introduction of cow’s milk until one year of age, eggs until two years of age and peanuts, tree nuts and fish until three years of age. These recommendations were made on the basis of two studies. One study with a sample size of 135 Finnish infants of atopic parents, the author found that exclusive breastfeeding showed a significant decrease in the development of pollen allergies at five years of age than infants introduced to solid foods at three months. The other examined a birth cohort of 1265 children studied to the age of ten years. The major findings were children who had risks of eczema and exposed to a diverse solid food diet during their first four months, had a 2.5 time higher risk of eczema than those who were not introduced to solids.34 However, neither of these studies were randomized trials.
After these guidelines were issued, more studies showed no benefit in delaying the introduction of allergenic foods. In 2008, the AAP withdrew their earlier recommendations due to lack of evidence but also refrained from advising early or late introduction of allergenic foods.4 In 2015, in the wake of the LEAP study15, strong consideration was given to peanut introduction as early as age four-six months in children meeting the high-risk criteria for peanut allergy. This raised the need to further interpret the LEAP findings by developing clinical recommendations focusing on peanut allergy prevention. To achieve this goal, as of January 2017, the National Institute of Allergy and Infectious Diseases facilitated development of addendum guidelines to specifically address the prevention of peanut allergy. The addendum provides three separate guidelines for infants at various risk levels. In cases of severe eczema, egg allergy or both, strong consideration should be given for in-office evaluation for peanut sensitization, followed by oral food challenge (OFC) for children with a by specific IgE (sIgE) measurement >0.35 and/or skin prick test (SPT) result of 3-7 mm at the earliest four-six months. Based on the test results, children with an SPT of 0-2 mm and children with an SPT> 8 mm have a high likelihood of peanut allergy. For infants with mild-moderate eczema, peanut should be introduced around age six months, but in-office evaluation is not required. Finally, for infants without eczema or any food allergy peanut-containing foods should be freely introduced in the diet together with other solid foods in accordance with family preferences and cultural practices. The guidelines do caution that peanuts and peanut butter are choking hazards and advise forms that are safe for infants such as pureed into fruits and vegetables. At present, there are no guidelines for early introduction of other allergenic foods such as egg, tree nuts or fish.
Choice of Formula
All current recommendations favor breastfeeding over formula feeding. There is limited evidence to suggest that allergies can be prevented in high risk infants through the use of certain hydrolyzed formulas compared with cow’s milk formula. In one recent study it was found that hydrolyzed casein formula is more likely to be effective in preventing AD compared to partially hydrolyzed whey formula.17 However, there have been no long term studies to date therefore this is not an official recommendation. There is also no conclusive evidence whether formula feeding has any role in preventing allergic conditions other than AD, so more research is needed.
Numerous observational studies within the last decade have suggested that the introduction of allergenic solid foods before six months of age may provide a protective effect on the development of food allergy. In 2008, Du Toit et al designed a questionnaire-based study and found a 10-fold higher prevalence of peanut allergy among Jewish schoolchildren in the United Kingdom compared with Jewish schoolchildren in Israel (1.85% vs 0.17%; P < .001).18 This difference was attributed to earlier peanut exposure in the first year of life in Israel compared with the United Kingdom. In 2010, an Australian population-based cross-sectional study of 2589 infants found a decreased egg allergy with egg introduction at 4-6 months compared with later introduction (aOR, 1.6 for introduction at 10-12 months and 3.4 for introduction after 12 months).19 In the same year, a prospective study conducted by Katz et al reviewed the feeding history of more than 13,000 Israeli infants and found that regular exposure to cow’s milk formula starting within the first 14 days of life was associated with a lower risk of cow’s milk allergy compared with later exposure (OR, 19.3 for introduction after 14 days).20 In addition, a retrospective case-control study completed in 2016 noted that delaying cow’s milk introduction for more than one month after birth, or infrequent cow’s milk exposure, was associated with a higher rate of cow’s milk allergy (aOR, 23.7 compared with control and 10.2 compared with the egg allergy group).21
Several recently published observational studies also have suggested that increased food diversity early in life can decrease the risk of allergic diseases, including food allergy. In 2011, a longitudinal birth cohort of 594 infant–mother pairs in the US noted a decreased peanut sensitization with complementary food introduction before four months of age (aOR, 0.2; P = .007), and decreased egg sensitization as well (if egg-specific IgE ≥ 0.70 kU/L was used as a cutoff; OR, 0.5; P = .022) at age two years in children with parental atopy.22 Data from a prospective Finnish birth cohort of 994 children found that delayed introduction of multiple foods, including oats (> five months) and wheat (> six months), was significantly associated with food allergen sensitization.23
In attempt to investigate the associations between the duration of breast-feeding and timing of complementary foods and the development of asthma and allergies this same author trialed another study. The sample size was large and the data were analyzed for 3781 consecutively born children. The median duration of exclusive and total breast-feeding was 1.4 months and 7 months, respectively. Total breast-feeding of 9.5 months or less was associated with an increased risk of non-atopic asthma. Introduction of wheat, rye, oats, or barley at 5 to 5.5 months was inversely associated with asthma and allergic rhinitis, whereas introduction of other cereals at less than 4.5 months increased the risk of atopic eczema. Introduction of egg at 11 months or less was inversely associated with asthma, allergic rhinitis, and atopic sensitization, whereas introduction of fish at 9 months or less was inversely associated with allergic rhinitis and atopic sensitization. Therefore, it was concluded that from this Finnish cohort early introduction of cereals, fish, and egg in infancy (respective to the timing of introduction of each food) might confer protection against the development of asthma, allergic rhinitis, and atopic sensitization by the age of five years. Furthermore, this study reported that total duration of breastfeeding was associated with a decrease of asthma in childhood compared to exclusive breastfeeding.24
The above summary of observational studies have been further supported by key randomized controlled trials. Gideon Lack and colleagues published the first randomized control trial to investigate whether early consumption of peanuts can prevent the development of peanut allergy in infants at high risk for the allergy. This study was based on a prior observation25 that the prevalence of peanut allergy was 10-fold higher among Jewish children in the United Kingdom compared with Israeli children. The LEAP study15 randomized 640 children between 4 and 11 months of age with severe eczema, egg allergy, or both to consume or avoid peanut-containing foods until five years of age, at which time a peanut oral food challenge (OFC) was conducted to determine the prevalence of peanut allergy. The participants were separated into two cohorts on the basis of pre-existing sensitization to peanut, as determined by means of skin prick testing: one cohort consisted of infants with a negative skin test response, i.e. no measureable skin test wheal to peanut and the other consisted of those with a wheal response of 1-4 mm in diameter. Infants with a 5 mm wheal diameter or greater were not randomized because the majority of infants at this level of sensitization were presumed to be allergic to peanut. Among the 530 participants with a negative baseline skin test response to peanut, the prevalence of peanut allergy at 5 years of age was 13.7% in the peanut avoidance group and 1.9% in the peanut consumption group (P < .001; an 86.1% relative reduction in the prevalence of peanut allergy). Among the 98 participants with a measurable peanut skin test response at entry, the prevalence of peanut allergy was 35.3% in the avoidance group and 10.6% in the consumption group (P = .004; a 70% relative reduction in the prevalence of peanut allergy). The study also demonstrated a significant reduction in the development of peanut allergy with early peanut introduction; peanut allergy developed in 3.2% of the early introduction group, compared with 17.2% of the avoidance group (P < .001; absolute risk reduction, 14; number needed to treat [NNT], 7.1).
The outcome of the LEAP results were widely accepted and affected the advice given to many parents regarding peanut allergy, but were not enough to change the guidelines at the time. The question remained whether continued consumption of peanuts throughout life is required to safely eat peanuts without a future reaction. A follow-up study (LEAP-ON) investigated persistent tolerance to peanut by assessing the effect of 12 months of cessation of peanut consumption after five years of consumption versus continued avoidance of peanut from the LEAP study. There were 556 eligible participants from the primary trial. The rate of adherence to avoidance in the follow-up study was high (90.4% in the peanut-avoidance group and 69.3% in the peanut-consumption group). Peanut allergy at 72 months was significantly more prevalent among participants in the peanut-avoidance group than among those in the peanut-consumption group (18.6% and 4.8%, respectively, P<0.001). After 12 months of avoidance there was no significant increase in the prevalence of allergy among participants in the consumption group (3.6% at 60 months and 4.8% at 72 months, P=0.25). Fewer participants in the peanut-consumption group than in the peanut-avoidance group had high levels of Ara h2 (a component of peanut protein)–specific IgE and peanut-specific IgE; in addition, participants in the peanut-consumption group continued to have a higher level of peanut-specific IgG4 and a higher peanut-specific IgG4:IgE ratio.25In both groups for 12 months after the end of the LEAP study from age five-six years there was no significant increase in peanut allergy in either group. This subsequent study supports the idea that early peanut tolerance will not transiently result in a later development of peanut allergy.
A similar trial, the Enquiring About Tolerance (EAT) study, examined 1,303 exclusively breastfed infants in the general population without preexisting risk of allergic disease randomized to early introduction of multiple, sequential allergenic foods.26 The infants were randomized to an early group (three months) or standard group (six months) introduction of six allergenic foods. Cow’s milk was given first for all children, then randomly ordered introduction of egg, wheat, sesame, peanut, and fish. The prevalence of food allergy was then examined at age one to three years. This study found no significant difference in the rates of food allergy development between groups. However, there were significant decreased rates of peanut allergy (0% vs 2.5%; P = .003; NNT, 40) and egg allergy (1.4% vs 5.5%; P = .009; NNT, 26) in the early introduction group. This study additionally found that early introduction alone was insufficient to draw conclusions, but regular exposure was just as important. It was noted that this study presented limitations due to protocol adherence; only 42.8% of the patients in the early introduction group adhered to the diet, to some foods better than others, raising the issues of possible reverse causality.
Similarly, in the WHEALS birth cohort study, researchers explored the relationship between the introduction of complementary food before four months and IgE to egg, milk, and peanut allergen at two years. The only finding that reached statistical significance was the reduction of peanut sensitization with early feeding only in children with a parental history of asthma or allergy. The relationship also became significant for egg when a cut-off for IgE of > 0.70 IU/ml was used.27
There have also been several studies showing the effects of early egg introduction. The most successful results are from a randomized controlled trial of Japanese infants with eczema.28 Results from this study of 121 infants with eczema show that randomization to heated egg powder at age six months showed decreased egg allergy compared with avoidance until age 12 months (8% vs 38%; P = .0001). Other early egg introduction trials have had less success in demonstrating any significant effect in reducing risk of egg allergy development. Tan et al found that in 319 infants with a family history of atopy, introduction of pasteurized whole egg powder at age four months vs placebo up to age 8 months was associated with a significantly lower risk of developing egg sensitization (OR, 0.46; P = .03). However, there was a nonsignificant trend toward reduced egg allergy with introduction at age four months vs eight months.29 Although approximately 10% of participants reacted to an initial egg exposure despite negative egg skin tests at age four months, no cases of anaphylaxis occurred, and overall there were no differences in the rates of adverse events between groups. In the Starting Time of Egg Protein study, in 820 infants without eczema with a family history of atopy, early introduction of pasteurized raw egg powder at age 4-6.5 months vs 10 months was associated with a nonsignificant trend toward a reduced risk of egg allergy (7.0% vs 10.3%; absolute risk reduction, 0.75; P = .20), although significantly decreased egg sensitization was noted in the early introduction group.30 Data from the Hen’s Egg Allergy Prevention study are the most potentially concerning. In that trial of 406 infants from the general population, early introduction of pasteurized raw egg powder at age four to six months was not associated with any difference in the rate of development of egg allergy or egg sensitization at age one year compared with placebo.31 However, among 23 children with baseline egg sensitization who were excluded from randomization but then challenged with egg separately, 11 of 17 experienced anaphylaxis on this initial introduction, calling into question the safety of early introduction of pasteurized raw egg.
A recent meta-analysis of studies investigating the timing of introduction of allergenic foods and the risk of developing allergic disease found evidence of moderate certainty indicating that egg introduction at age four to six months reduced the rate of egg allergy (relative risk, 0.56; P = .009).32 After analyzing more trials the authors noted that many additional participants were needed to reach a 30% effect size for the intervention with certainty. Similarly, this meta-analysis found moderately certain evidence based on two trials (1550 patients) that introduction of peanut between age 4 and 11 months reduced the risk of peanut allergy (relative risk, 0.29; P = .009), although sequential analysis could not be performed owing to insufficient numbers of participants in these trials.
There is little data available on the effect of early solid food introduction and the duration of total breastfeeding. Nonetheless, from the data gathered it does not suggest that early solid food introduction has an impact on breastfeeding duration. In the EAT study, early introduction of solid foods did not affect breastfeeding rates. At age six months, 97% of infants in the early solid food introduction group were still breastfeeding in the United Kingdom and was not significantly different from the breastfeeding rate of 98% in the standard introduction group when the study began.26 In this study, it was intended that the infants in the standard introduction group continue to exclusively breastfeed until the introduction of solid food at age six months, and that breast milk continue to remain an important source of nutrition until age six months in the early introduction group, who started eating solid foods at age three months, thus it did not have impact on total months breast fed. In the LEAP study, there was no significant difference in breastfeeding duration after randomization between the peanut consumption group and the peanut avoidance group.15 However, only approximately 10% of the overall study population was exclusively breastfed at study entry, and only 39.6% the peanut consumption group and 44.2% of the peanut avoidance group continued to breastfeed after enrollment.
Infant Gut Microbiota and Risk of Atopic Disease
Prenatal and infant feeding is a key environmental exposure that plays a fundamental role in the immune system. Feeding shapes the composition of the gut microbiota beginning with human milk and other dietary exposures. Nwaru and colleagues33 in a prospective cohort study evaluated the bacterial diversity of the intestinal flora and the diversity of foods introduced during the first year of life and the associated development of allergies in childhood. This study relied heavily on parental recall questionaries used to obtain history of food exposure during the first year of life and the subsequent presence of allergic disease. The allergic end points measured were incidence of asthma, wheeze, AD and allergic rhinitis. The results showed by three and four months of age, food diversity was not associated with any of the allergic end points. By six months of age, less food diversity was associated with an increased risk of allergic rhinitis, but not the other endpoints. And by 12 months of age, less food diversity was associated with an increased risk of asthma, wheeze and allergic rhinitis; thus concluding that less food diversity during the first year of life might increase the risk of allergic disease.
These outcomes support that early complementary feeding might protect against the risk of atopic diseases but also suggest that exposure to food proteins in the time period between 6 and 12 months of age might be an important time window for protection against the subsequent development of allergic diseases.
It has been determined in this paper that avoidance of allergenic foods is not preventive of food allergy, and early introduction of peanut is in fact preventive. Because of the findings in many studies, most importantly the outcomes of the LEAP study, the American Academy of Allergy Asthma and Immunology, AAP and other organizations suggests strong evidence that infants at high risk, as defined previously, should be introduced to peanut early in life (between 4 and 11 months).11 The consensus is that these infants would benefit from being evaluated by an allergist before peanut introduction at home. Additionally, the addendum guidelines discuss the amount of peanut containing foods to introduce weekly. Based on the LEAP study, 6-7 grams of peanut protein given over three or more feedings per week until age 5 was safe and had no effect on duration or frequency of breastfeeding and also did not influence infant growth or nutrition. Current research on immunological responses suggests that regular ingestion of newly introduced foods is important to maintain tolerance.25
The degree to which 6 months of exclusive breastfeeding is superior to 4 months was not conclusive. Within the studies examined in this paper, early introduction of complementary food before age 6 months did not affect total breastfeeding duration. However, it was found that total duration of breastfeeding for at least 6 months may be more protective than exclusively breastfeeding for 6 months.
An issue in analyzing this research was the low prevalence of exclusive breastfeeding at 6 months in the study populations. This presented as a limitation and made these results difficult to interpret because the timing of introducing solid foods in partially breastfed infants may not be applicable to exclusively breastfed infants. A concern that presented during the research analysis was the potential bias caused by reverse causality. This was apparent in the studies that evaluated children diagnosed with AD before the first year of life or among children with allergic parents or both. This presents a concern because introduction of certain complementary food tends to be delayed in these populations because of the expected outcome. Nonetheless, this material was important to see how this group of children are affected.
Multiple observational studies, randomized controlled trials, and a recent meta-analysis support the early introduction of egg, as a means of food allergy prevention. However, changes in policy are lacking reflecting changes in early introduction of egg. With the data at hand, it can not be concluded that early exposure reduces the incidence of other allergies. The studies on other allergenic foods have either been observational or too small to provide reliability. Therefore further evaluation is needed to examine the difference between cooked and raw egg as well as introducing cow’s milk. It should be noted that observational studies provide a limitation compared to clinical studies because they simply can show association but not causation.
Feeding practices may represent a modifiable risk factor in the prevention of allergic disease. Delaying the introduction of certain allergenic foods for periods previously recommended has been shown to have no protective effect on allergic sensitization and allergic disease development. There is sufficient evidence not to delay introduction of allergenic foods after six months for the prevention of AD and asthma. Among children with parental history of asthma or allergy and exposure to complementary food before age four months there is a reduced risk of peanut allergen sensitization. This is supported by the addendum guidelines developed for early introduction of peanut containing foods into diets of infants at various risk levels for peanut allergy.
The timing of introduction of solids to infants is an important issue clinicians frequently confront while caring for infants. When giving guidance to parents it is important to individualize this advice based on patient history. Any child who has a sibling with peanut allergy, known history of an immediate reaction to a food, parent with atopy or moderate to severe AD should undergo assessment by an allergist. It should also be recommended that once these allergenic foods are introduced, regular exposure is important, so children should be fed the food on a regular basis. It is important to note that despite current recommendations, counseling parents will still be complicated because there may be parents that disagree with the guidelines.
At this time, we cannot advise maternal dietary elimination as methods of allergy prevention. Future research may explore the role of maternal diet avoidance during pregnancy and lactation and the subsequent effect on prevention of allergic disease. There is need for more research for early introduction of staple foods, such as egg and milk.
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