There has been a steep increase in the reported prevalence of common childhood allergic diseases (namely asthma, allergic rhinitis, eczema, and food allergy) in the last few decades [1-3]. According to Asher and Pearce [1], the International Study of Asthma and Allergies in Childhood concluded in the early 2000s reported that the prevalence of asthma, allergic rhinitis, and eczema had risen to over 30% in most industrialized countries. In addition, asthma is prevalent among approximately 300 million people worldwide, and by 2025, a further 100 million will likely be affected [4]. It is therefore crucial to evaluate the effectiveness of early life prevention techniques in order to lower the burden of childhood allergic diseases.

Infant feeding guidelines recommend early initiation of breastfeeding, including exclusive breastfeeding for the first 6 months of life and continued breastfeeding up to and after 2 years of age. Additionally, weaning or complementary feeding—defined as the provision of nutrition in the form of liquid or solid other than breast milk or infant milk formula—is introduced to neonates by 6 months of age, depending on the achievement of developmental milestones and the availability of safe complementary foods [5,6]. Besides providing essential nutrients to the growing infants, weaning exposes the developing gut microbiome to different antigens, thus influencing immune system development [7]. Food sensitization frequently occurs early in life and is often the first sign of future allergic disease; this is because the infant’s immune system has yet to develop, if at all, an allergic phenotype [8]. Food items with allergenic properties may resist digestion and enhance allergenicity. Hence, susceptible infants who did not develop tolerance will manifest an allergic phenotype. Additionally, the preservation of “beneficial” gut microbiota in the neonate prevents immunity alteration that subsequently predisposes him/her from developing an allergy [9]. As a result, many researchers propose nutritional allergy interventions during this period, such as prolonged breastfeeding, early introduction of foods, maternal avoidance diets during pregnancy and lactation, use of hypoallergenic formulas, and early allergen avoidance, albeit with varying degrees of success [8,10,11].

The landmark study, Learning Early About Peanut Allergy, was one of the first to suggest early introduction of peanuts to reduce the development of peanut allergies [12]. In 2016, the Enquiring about Tolerance study expanded to multiple allergenic food items (ie, peanuts, cooked eggs, cow’s milk, sesame, whitefish, and wheat) and observed a significant reduction in the prevalence of food allergies in the studied population [13]. These studies, along with others, appear to offer an effective and robust strategy to minimize the burden of allergy in the general population [10,14].

Living with allergic disease affects the quality of life of both patients and their guardians, considering the increasing health care costs. The determinants of health-related quality of life (HRQoL) in children with allergies traverse beyond biophysiological parameters and the symptom status of the child (such as physical limitations and emotional stress) and may include family dynamics and socioeconomic status, the community in which they live (ie, restrictions on participation in activities and social interaction), and organizational and policy-related factors (eg, inadequate food labelling and public information on allergies) [15-17]. Thus, effective allergy management strategy, including allergy prevention is imperative to avert allergic episodes that can be life-threatening.

Current recommendations for infant feeding require more consensus in the area of early life nutrition, specifically for prevention of childhood allergic diseases [18]. Moreover, an increasing number of studies have been examining the effect of early food introduction on reducing allergic sensitization, thus promoting allergy tolerance in these children [19-21]. We acknowledge earlier reports; however, most reviews have focused on the development of food allergies as well as having a diverse methodological approach [22-25]. In addition, there are diverse dietary patterns that may influence the development and progression of allergic diseases and their phenotypic expression in Asian populations. Although the published studies might have promising findings, less is understood about the potential harm that might result from the population-based guidelines and public health programs [26]. Thus, the aim of this systematic review is to identify evidence regarding the effect of early food introduction in preventing childhood allergic diseases.

This study aims to systematically review and carry out a meta-analysis of the effectiveness of early food introduction in preventing childhood allergic diseases.

A systematic and comprehensive literature search will be conducted in various databases including PubMed, CENTRAL, Embase, Scopus, PsycINFO, CINAHL, and Google Scholar from inception to October 2023. A search strategy will be developed for PubMed and adapted for use with other electronic databases (Multimedia Appendix 2). The search will include MeSH terms and keywords relating to the study population (“childhood” OR “children” OR “paediatric” OR “pediatrics” OR “infants”), intervention (“early food introduction” OR “weaning” OR “complementary feeding” OR “supplementary feeding”), and outcomes (“allergies” OR “allergy” OR “allergic diseases” OR “asthma” OR “allergic rhinitis” OR “eczema” OR “dermatitis” OR “food allergy” OR “sensitization”).

Standard Cochrane methods will be used, as described in the Cochrane Handbook for Systematic Reviews of Interventions [34]. Two authors will independently screen all the titles and abstracts to examine all the potential studies. We will code them as “retrieve” (eligible, or potentially eligible or unclear) or “do not retrieve.” We will retrieve full-text reports or publications, and 2 other review authors will independently screen the full text to identify studies for inclusion and will identify and record the reasons for exclusion of the ineligible studies. We will use a standardized data extraction form in accordance with the Cochrane Handbook for Systematic Reviews of Intervention [28]. Data will be independently extracted in accordance with general information (author, source, date of publication, country, and language), study (type of study, study duration, sample size, and control group selection), participants (age, sex, and type of allergy), types of intervention (food avoidance upon diagnosis and food challenge), and, lastly, outcomes (allergic episodes, admissions or emergency visits, duration of illness, and quality of life measured using validated scales) [28].

We will resolve any disagreement through discussion or consult a third review author if necessary. We will identify and exclude duplicates, and if multiple or overlapped reports of the same study are found, we will group them under a single study ID, and assign the report with the most amount of relevant information as the primary publication. We will record the selection process in sufficient detail to complete a PRISMA flow diagram (Figure 1) and construct a table describing the characteristics of the excluded studies [35]. We will resolve any discrepancies through discussion and by involving a third author.

Two reviewers will independently assess the quality of the included studies. The methodological quality of selected studies will be assessed using the Cochrane Risk of Bias Tool [36] for RCTs and cluster-RCTs, which includes the following domains: allocation concealment of random sequence generation, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective outcome reporting, and other bias. We will use ACROBAT-NRSi (A Cochrane Risk Of Bias Assessment Tool for Non-Randomized Studies), which evaluates the risk of bias in the results of non-RCTs studies that compare the health effects of 2 or more interventions [37]. We will use Newcastle-Ottawa scale for observational studies and evaluate the quality parameters (selection, comparability, and outcome) of the selected studies [38]. We will make judgments on each of the abovementioned criteria regarding whether the study has a high, low, or unclear risk of bias. We will summarize the risk-of-bias judgements with justification for each of the domains listed in the Risk of bias table. Any disagreement among the review authors will be resolved by discussion to achieve a consensus.

We will create a summary of findings table by tabulating the following outcomes: (1) total number of allergic diseases (asthma, allergic rhinitis, eczema, and food allergy), (2) rate of sensitization (level of total and specific IgE), (3) total number of adverse events, (4) improvement of HRQoL measured using validated questionnaires, and (5) all-cause mortality [39]. We will use the following 5 GRADE (Grading of Recommendations Assessment, Development and Evaluation) elements to assess the quality of the body of evidence as it relates to the prespecified outcomes: quality of evidence, consistency of effect, imprecision, indirectness, and publication bias. We will assess the quality of evidence for all outcomes using the GRADE methodology [40].

This systematic review is registered with the National Medical Research Register, Ministry of Health Malaysia (ID: NMRR ID-22-01049-HQ4). This protocol registered in PROSPERO (CRD42021256776). We will present the findings of this review in National and international conferences and continuous medical education initiatives, and we will disseminate our findings to policy makers and top managements (stakeholders) of Ministry of Health Malaysia.

This protocol outlines the methods for a systematic review of the literature to assess the effectiveness of early food introduction in the prevention of childhood allergic diseases. Figure 2 illustrates a flow diagram of the study process to be followed as a guide for this review in terms of literature search using keywords identified through discussion among authors, the screening of shortlisted studies following a standardized framework, and the process of full text retrieval. This will be followed by quality assessment with data extraction for evidence synthesis and finally publishing of the study results.

We take note of 2 similar systematic reviews and meta-analyses that are closely related to our study [23,43]. However, their methodology (in terms of population variability and age of weaning) and diverse outcomes are different from those based on our study objective. In our study, we aim specifically to evaluate the effectiveness of early food introduction in infants aged 4-6 months irrespective of risks, and to evaluate outcomes related to 4 common allergic diseases in children. We believe that our findings will provide a reasonable and robust update to the existing literature.

We will base our conclusions only on findings from the quantitative or narrative synthesis of the studies included in this review. The conclusions can be used as guidelines for top managers and stakeholders for evidence-informed policy on infant feeding guidelines for the prevention of childhood allergic diseases. Our implications for research will suggest priorities for future research and outline the remaining uncertainties in the area.