Undoubtedly, except for babies born with some health conditions, the breast milk and its exclusivity remains the optimal dietary option for the infant for a healthy growth and development. Thus, it has been widely recommended that babies be exclusively breastfed for 4–6 months, thereafter new foods can be systematically introduced to complement the breast milk [ 32 ] . For this reason and for the fact that babies cannot be denied breastfeeding, carrying out a randomized controlled trial to assess the effect of age at introduction of new foods on the development of allergies in children seems not ethically feasible [ 22 ] . However, some trials have assessed the role of different dietary advice and restrictions during infancy and others have compared exclusive breastfeeding and formula feeding. Since these studies were not speci fi cally designed to assess the effect of age at introduction of complementary foods on the occurrence of allergies, they are not the focus of this chapter, hence are not discussed here.
The following discussion will be based on the review of the evidence from observational prospective epidemiologic cohort studies, which at present remain the only source to judge the evidence of the effect of introduction of complementary foods on the occurrence of allergies in children.
Search Strategy to Identify Studies
To identify these studies, a systematic search of the published literature was undertaken using the search engines, MEDLINE, EMBASE, and Google Scholar. The search was carried from beginning of March up to the end of June 2011. Using the combination of key search terms (solid foods, comple- mentary foods, new foods, allergies, atopy, asthma, and children), all relevant studies were extracted.
The titles and abstracts of identi fi ed studies were checked, and the full texts of all potentially eligible studies were assessed. The bibliographies of eligible papers were scrutinized to identify additional potential studies. Seventeen studies were identi fi ed [ 26, 27, 33– 47 ] . However, two of these studies were carried out prior to the introduction of the recommendations on complementary foods for the prevention of allergies in children (Actually, the current recommendations were greatly in fl uenced by the fi ndings from these studies.) [ 26, 27 ] . For this reason, these studies were excluded, focusing the review on studies carried out after the introduction of the recommendations. A fourth study was per- formed only on infants born preterm [ 33 ] , thus it is not included in this review since its results cannot be applied to children outside its preterm birth study population. Finally, a fi fth and sixth study per- formed a cross-sectional [ 34 ] and case–control [ 35 ] analysis, respectively, and were also excluded in this review. Table 7.1 presents the features and summary of the results from the 12 remaining studies, organized in descending order of year of publication.
Assessment of Information on Introduction of Complementary Foods and Allergic Outcomes
In practice, information on complementary foods is usually obtained through interviews with parents, and in some cases, diaries or special forms are kept with parents to record the processes and patterns of introduction of complementary foods to the infant’s diet. At least one of these procedures was applied in each of the studies reviewed here, indicating a seemingly standardized and comparative assessment of the dietary exposures across the studies. Assessment of allergies in children is chal- lenging [ 48– 50 ] . A good proportion of allergies at this time are a result of microbial infections, which
Table 7.1 Summary of evidence from prospective epidemiologic studies on the effect of age at introduction of complementary foods on the occurrence of al and asthma in childhood* Study and country
Length of follow-up (years) Subjects ( n ) Complementary foods and de fi nition in the analysis Outcomes and assessment Main fi ndings Joseph et al . [ 36 ] USA 3 594 Eggs, milk, and peanut (<4; ³ 4months) Food allergic sensitization as measured in serum Early introduction of new foods inversely associated with allergic sensitization Chuang et al . [ 37 ] Taiwan 1.5 18,733 Any food (<4, 4–6, >6months) Doctor-diagnosed atopic dermatitis (AD) Age at introduction of new foods was not associated with AD Hesselmar et al . [ 38 ] , Sweden 1.5 184 Cow’s milk products, potatoes, root vegetables, vegetables, meat, fi sh, and egg (median month) Clinical and serum examinations for allergic sensitization and symp- toms of eczema and asthma Early introduction of fi sh inversely associated with eczema Nwaru et al . [ 39 ] , Finland 5 994 Thirds-categorized age at introduction of cow’s milk, potatoes, fruits and barriers, carrots, cabbages, cereals, meat, fi sh, and egg
Speci fi c allergic sensitization (any food, any inhalant, wheat, egg, and milk allergens) from serum
Late introduction of potatoes, oats, wheat, fi sh, and egg was associated with increased risk of allergic sensitization Virtanen et al . [ 40 ] , Finland 5 1302 Thirds-categorized age at introduction of fruits and berries; roots; wheat, barley, rye, and oats; other cereals; cabbages; milk products; fi sh; meat; egg
ISAAC-based asthma, allergic rhinitis, and atopic eczema Early introduction of oats associated with decreased risk of asthma and early introduction of fi sh with decreased risk of allergic rhinitis Zutavern et al . [ 41 ] , Germany 6 2,074 Any food (0–4; 4–6; >6months) and food diversity at 4 months (no foods; 1–2; 3–8 groups) Parental-reported asthma, eczema, and allergic rhinitis. Speci fi c allergic sensitization measured in serum Neither late introduction of foods nor food diversity was associated with the outcomes Snijders et al . [ 42 ] , The Netherlands
2 2,558 Cow’s milk products (0–3; 4–6; 7–9; >9 months); introduction of “other foods” (3; 4–6; >7 months) Speci fi c allergic sensitization from serum; parental reported eczema, AD, and wheeze
Late introduction of cow’s milk products increased the risk for eczema and late introduction of “other foods” increased risk of allergic sensitization Filipiak et al . [ 43 ] , Germany 4 4,753 Vegetables, cereal, fruit, meat, dairy products, egg, fi sh, other food products ( £ 4 5–6, >6months), and food diversity
Parental report of doctor-diagnosed and symptomatic eczema Introduction of new foods was not associated with the outcome
Mihrshahi et al . [ 44 ] , Australia 5 516 “Yes” or “no” answer on whether any new food was given by 3 months Skin-prick test for allergic sensitiza- tion and parental-reported eczema and asthma
Introduction of new foods by 3 months associated with decreased risk of allergic sensitization Zutavern et al . [ 45 ] , Germany 2 2,612 Any food, vegetables, fruit, cereal, meat products, and dairy products (0–4; 5–6; >6 months); egg, fi sh, and “others” (0–6; >6 months); and food diversity
Speci fi c allergic sensitization measured in serum. Parental- reported AD
Introduction of foods >4 months was inversely associated with symptomatic AD Poole et al . [ 46 ] , USA Mean 4.7 1,612 Cereal grains (wheat, barley, rye, oats) and rice cereal categorized as 0–6, ³ 7 months Wheat allergy: wheat-speci fi c IgE in plasma Late introduction of cereal grains associated with increased risk of wheat allergy Zutavern et al. [ 47 ] , UK 5.5 642 Any foods, rice ( £ 3, >3 months); fruit, vegetables, cereal ( £ 4, >4months); meat, fi sh ( £ 5, >5months); milk ( £ 6, >6months); egg ( £ 8, > 8months)
Parental-reported doctor-diagnosed asthma, eczema and wheeze; skin-prick test used for atopy Late introduction of egg and milk associated with eczema *Adapted from: Nwaru BI. The role of diet during pregnancy and infancy in the development of childhood allergies and asthma. National Institute for Health and Welfare, Helsinki, Finland, 2012.
usually disappear with time. Consequently, the criteria for de fi ning allergic endpoints sometimes vary across studies. However, some standard procedures are available and currently being employed in studies. These methods include serum samples particularly used for food allergies and IgE sensiti- zation; doctor’s diagnosis; and the International Study on Allergies in Childhood (ISAAC) question- naire [ 48– 50 ] . Depending on the outcome assessed, at least one of these procedures was applied in the studies reviewed here.
Summary of Studies
The 12 studies summarized here cut across most developed regions, including three studies from Germany [ 41, 43, 45 ] , two studies each from the United States [ 36, 46 ] and Finland [ 39, 40 ] , and one study each from Taiwan [ 37 ] , Sweden [ 38 ] , The Netherlands [ 42 ] , Australia [ 44 ] , and United Kingdom [ 47 ] . The latest among these studies comes from the US, in which the authors assessed the effect of introducing eggs, milk, and peanut (<4 months vs. ³ 4 months) on the risk of sensitization to milk, egg, and peanut allergens in 594 three-year old children [ 36 ] . At the ages of 1, 6, and 12 months, parents were interviewed about the infant’s feeding practices. After taking into account potential confounding variables, introduction of complementary foods before the age of 4 months decreased the risk of sen- sitization to peanut and egg allergens. However, these associations were con fi ned mainly to children who had parents with history of asthma or allergies. The second US study examined the association between the introduction of cereals (wheat, barley, rye, oats, and rice cereal) less than 7 months vs. ³ 7 months and wheat allergic sensitization in 1,612 children with mean age of 4.7 years [ 46 ] . The sub- jects were originally recruited to investigate the natural history of diabetes and celiac disease autoim- munity in children. Although the number of subjects who were affected by wheat allergy in that study was small ( n = 16), thus giving less precise estimates, the authors found that late introduction of cereal grains ( ³ 7months) was associated with increased risk of wheat allergy after adjustment for potential confounders.
The Taiwanese study [ 37 ] constituted a large number of subjects ( n = 18,733) without a history of atopic dermatitis by the age of 6 months. The infants were followed up to the age of 18 months to assess whether introduction of any complementary food at < 4 months, 4–6 months, and >6 months was associated with doctor-diagnosed atopic dermatitis. The parents were interviewed at 6 and 18 months postpartum about the infant’s diet and diagnosis of atopic dermatitis. In adjusted statistical models, there was no association found between the introduction of complementary foods and the risk of atopic dermatitis in the children. The analysis in that study was restricted to children who had no history of atopic dermatitis by the age of 6 months. No speci fi c complementary food was studied, thus possible association between some speci fi c foods and the risk of atopic dermatitis might have been concealed by the use of “any” complementary food [ 37 ] .
In the Swedish study [ 38 ] , 184 infants were followed up to the age of 18 months to assess the effect of age at introduction of new foods (median month of introduction of cow’s milk products, potatoes, root vegetables, vegetables, meat, fi sh, and egg) on allergic sensitization and clinically assessed symp- toms of eczema and asthma. The subjects were recruited at birth and the parents were given diaries to record the feeding patterns of the infants. A telephone interview was used to recall the diary data from the parents when the child was 6 and 12 months of age. The results showed that early introduction of fi sh (<10 months) was bene fi cially associated with eczema, with a dose–response association: for every 2 months of delayed introduction of fi sh, a 16 % increased prevalence of eczema was observed.
The children in this study were young, thus it is unlikely that the asthma symptoms may not be a result of early infant infections, which usually are unrelated to allergy. The diagnosis of asthma is dif fi cult at this age. It is also possible that the small sample size of the study limited the ability to detect apparent potential associations [ 38 ] .
In the Finnish cohort, two studies have been reported on the association between the age at introduction of new foods and allergen-speci fi c sensitization to food and inhalant allergens on one hand [ 39 ] , and asthma, allergic rhinitis, and atopic eczema on the other hand [ 40 ] , in children aged 5 years. The cohort is multidisciplinary and population-based, and the subjects were originally recruited based on their increased risk (human leukocyte antigen (HLA) susceptibility) to type 1 dia- betes. Information on the introduction of complementary foods was gathered using a special form kept with parents up to the age of 2 years to record the pattern of the infant’s feeding. The IgE-based speci fi c allergens were measured in serum while the asthma, rhinitis, and eczema outcomes were assessed using the ISAAC questionnaire. In both analyses, age at introduction of a priori-de fi ned foods (cow’s milk, potatoes, fruits and barriers, carrots, cabbages, cereals, meat, fi sh, and eggs) was categorized using an ad hoc third categorization. In the fi rst study, 994 children were studied, and after adjusting for confounding factors and simultaneous study of all the foods, late introduction of potatoes (> 4 months), oats (> 5 months), wheat (> 7 months), fi sh (> 8.2 months), and egg (> 10.5 months) were associated with increased risk of allergic sensitization [ 39 ] . In the second study ( n = 1,302), with similar modeling strategies, early introduction of oats (< 5 months) was associated with a decreased risk of asthma, while early introduction of fi sh ( £ 6 months) was associated with a decreased risk of allergic rhinitis [ 40 ] .
Of the three German studies, two came from the same cohort [ 41, 45 ] . In the fi rst study of that cohort, the association between the age at introduction of several food products (any food, vegetables, fruit, cereals, meat, dairy products, egg, fi sh, and food diversity) and the risk of speci fi c allergic sen- sitization and symptomatic and doctor-diagnosed atopic dermatitis was investigated in two-year old children ( n = 2,612) [ 41 ] . Because of the young age of the subjects, other allergic outcomes were not included in the two-year old analysis. However, when the children turned 6 years old ( n = 2,074), the authors studied the effect of introduction of the complementary foods (any food, food diversity) on allergic sensitization and parental-reported asthma, eczema, and allergic rhinitis [ 45 ] . Using question- naire assessment, the authors collected detailed information about the outcomes, the child’s feeding practices, and other environmental exposures at reasonable time intervals until the age of 6 years.
At the age of 2 years, in models adjusted for other covariates, introduction of vegetables and meat products after 6 months was moderately positively associated with doctor-diagnosed atopic dermatitis [ 41 ] . At the age of 6 years, no putative effect of age at introduction of any complementary food or the diversity of foods on the allergic outcomes was observed [ 45 ] .
The third German study [ 43 ] was based on a randomized, double-blind trial that was established to investigate the effect of hydrolyzed formulas compared with conventional cow’s milk formula in pre- venting allergies. On the basis of this trial, the authors analyzed the data for 4,753 subjects (2,814 from the intervention group and 1,939 from the control group) who completed the four-year follow-up to investigate whether delaying the introduction of complementary foods past 4 months is protective against the development of eczema. The intervention group constituted children with family history of allergy and received dietary recommendations (parents advised to exclusively breastfeed for at least 4 months, to feed a randomized formula if breast milk was insuf fi cient, to introduce only one new food item per week after 4 months, and to avoid potential allergenic foods during the fi rst year).
The control group had no family history of allergy and received no dietary advice. The analysis was done by the intervention groups. Overall, the authors reported no clear association between age at introduction of new foods (vegetables, cereal, fruit, meat dairy products, egg, fi sh, as well as food diversity) and the risk of eczema [ 43 ] .
In the Dutch study [ 42 ] , the authors focused on assessing whether the timing of introduction of cow’s milk ( £ 3 months, 4–6 months, 7–9 months, > 9 months) and “other food products” ( £ 3 months, 4–6 months, > 7 months) is associated with the risk of speci fi c allergic sensitization and parental-reported eczema, atopic dermatitis, and recurrent wheeze in 2,558 two-year old infants. The detail of the foods included in “other food products” was not given. A repeated questionnaire at 34 weeks gestation and when the child was 3, 7, 12, and 24 months was used to gather the information on the
study. In confounder-adjusted models, late introduction of cow’s milk (> 9 months) increased the risk for eczema while late introduction of “other food products” (>7 months) was associated with eczema, atopic dermatitis, recurrent wheeze, and allergic sensitization [ 42 ] . In children ( n = 642) followed up to the age of 5.5 years in the UK [ 47 ] , the association between the introduction of new foods (rice, fruits, vegetables, cereal, meat, fi sh, milk, and egg) and doctor-diagnosed asthma, eczema, wheeze, and atopy assessed by skin-prick test was investigated. In adjusted models, late introduction of milk (> 6 months) and egg (> 8 months) was associated with increased risk of eczema [ 47 ] .
Finally, the Australian study [ 44 ] was a follow-up from a randomized controlled trial that investi- gated the role of dietary supplementation with omega three fatty acids and avoidance of house dust mite in the incidence of asthma and atopy from birth to 5 years in children with family history of aller- gies. This follow-up analysis included all the subjects in the trial ( n = 516) and examined whether introduction of complementary foods by 3 months (based on a “no” or “yes” answer) was associated with allergic sensitization, parental-reported eczema and asthma at the age of 5 years. After adjusting for potential confounding variables, introduction of new foods by 3 months was not associated with the allergic outcomes [ 44 ] . The restriction of the study to high-risk children may limit the application of the results to the general population.
Synthesis of the Evidence from the Summarized Studies
In synthesizing the fi ndings from these studies, it can be deduced that, for the most part, the evidence points to a potential bene fi cial effect of early introduction of complementary foods as a preventive strategy for allergies in children. Interestingly, these studies cut across most developed regions, thus showing a consistency across different contexts. Against current hypothesis and recommendations, none of these studies has reported a bene fi cial effect of late introduction of complementary foods on the development of allergies. Rather, while few of the studies report no association between introduction of new foods and allergies, majority found a bene fi cial effect of early introduction of new foods. Furthermore, most of the fi ndings suggest that the observed effect of age at introduction of complementary foods on allergies may not be restricted to high-risk children, but may be applica- ble to the general population.
However, it should be reminded that these results have only emanated from observational epide- miologic studies, which may be in fl uenced by some level of bias, including limitation in accounting for all known important confounding variables. Mostly, the studies reviewed here made reasonable efforts to minimize substantial bias affecting their results and adjust for the major known confounders.
Apart from the Swedish study [ 38 ] , the majority of the reviewed studies had reasonably large sample sizes. The collection of the information on infant feeding patterns, as well as the outcomes, was ade- quately done in the studies. Because of ethical issues, using a randomized controlled trial to assess the effect of introduction of complementary foods on the development of allergies may not be feasible [ 22 ] . Consequently, the best and only evidence at present to judge the effect of introduction of com- plementary foods on allergic outcomes remains to come from observational studies.
Two important issues arise from the evidence presented from these studies. First, there is an indica- tion that rather than the effect of introduction of any complementary foods, the fi ndings suggest that speci fi c single foods may be more important than others in relation to the occurrence of allergies in childhood. Particularly, the results suggest that the introduction of the known allergenic foods (egg, cereals, fi sh, and cow’s milk) seem to be the most important consistent determinants of allergies in childhood, and protective for that matter. Second, the results also show that the use of a single cut-off (4–6 months) for the introduction of all complementary foods in some studies and in some of the committees’ recommendations may be inadequate. Usually, complementary foods are introduced consecutively, and not at the same time. Therefore, using the same cut-off for all foods will fail to