Two authors selected studies, extracted data, and assessed risk of bias. Grading of Recommendations Assessment, Development and Evaluation (GRADE) was used to assess certainty of findings. We searched Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica dataBASE (EMBASE), Web of Science, Central Register of Controlled Trials (CENTRAL), and Literatura Latino Americana em Ciências da Saúde (LILACS) between January 1946 and July 2013 for observational studies and until December 2017 for intervention studies that evaluated the relationship between diet during pregnancy, lactation, or the first year of life and future risk of allergic or autoimmune disease. We identified 260 original studies (964,143 participants) of milk feeding, including 1 intervention trial of breastfeeding promotion, and 173 original studies (542,672 participants) of other maternal or infant dietary exposures, including 80 trials of maternal (n = 26), infant (n = 32), or combined (n = 22) interventions. Risk of bias was high in 125 (48%) milk feeding studies and 44 (25%) studies of other dietary exposures. Evidence from 19 intervention trials suggests that oral supplementation with nonpathogenic micro-organisms (probiotics) during late pregnancy and lactation may reduce risk of eczema (Risk Ratio [RR] 0.78; 95% CI 0.68–0.90; I 2 = 61%; Absolute Risk Reduction 44 cases per 1,000; 95% CI 20–64), and 6 trials suggest that fish oil supplementation during pregnancy and lactation may reduce risk of allergic sensitisation to egg (RR 0.69, 95% CI 0.53–0.90; I 2 = 15%; Absolute Risk Reduction 31 cases per 1,000; 95% CI 10–47). GRADE certainty of these findings was moderate. We found weaker support for the hypotheses that breastfeeding promotion reduces risk of eczema during infancy (1 intervention trial), that longer exclusive breastfeeding is associated with reduced type 1 diabetes mellitus (28 observational studies), and that probiotics reduce risk of allergic sensitisation to cow’s milk (9 intervention trials), where GRADE certainty of findings was low. We did not find that other dietary exposures—including prebiotic supplements, maternal allergenic food avoidance, and vitamin, mineral, fruit, and vegetable intake—influence risk of allergic or autoimmune disease. For many dietary exposures, data were inconclusive or inconsistent, such that we were unable to exclude the possibility of important beneficial or harmful effects. In this comprehensive systematic review, we were not able to include more recent observational studies or verify data via direct contact with authors, and we did not evaluate measures of food diversity during infancy.

Competing interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: RJB, VGL, JLB, SC, and DI received support from the UK Food Standards Agency for the submitted work. MT received a consultation fee from the UK Food Standards Agency for methodological work on this systematic review. No other support was received from any organisation for the submitted work. The authors have no financial relationships with any organisations that might have an interest in the submitted work in the previous three years. RJB was a co-investigator and author of two of the trials included in this systematic review. The authors report no other relationships or activities that could appear to have influenced the submitted work.

Immune-mediated health conditions such as allergic and autoimmune diseases appear to have increased in prevalence in many countries and are leading causes of chronic illness in young people [ 1 ]. There is evidence that early dietary exposures may influence the development of these diseases, but a comprehensive analysis of the relationship between all dietary exposures during pregnancy, lactation, or the first year of life and risk of allergic or autoimmune disease has not been undertaken [ 1 ]. Relevant dietary exposures may include intake of individual foods or food groups, nutrients or nutrient groups, dietary supplements, avoidance of specific allergenic foods, timing of introduction of specific foods or food groups to the infant diet, overall dietary pattern, and duration of breastfeeding. A recent World Allergy Organization guideline recommended probiotic and prebiotic supplements for eczema prevention [ 2 , 3 ], but European, North American, and Australasian guidelines do not support this [ 4 – 6 ]. Several guidelines recommend exclusive breastfeeding for at least 4 to 6 months to reduce risk of eczema, food allergy, and wheezing [ 4 , 5 , 7 ], and a recent Australasian guideline recommends oily fish or omega-3 fatty acid supplements during pregnancy to reduce eczema [ 6 ]. Recent focused systematic reviews support a relationship between breastfeeding and reduced asthma risk [ 8 , 9 ] and between probiotics and prebiotics and reduced eczema risk [ 2 , 10 , 11 ]. In order to inform United Kingdom dietary recommendations for infants and their pregnant or lactating mothers, we undertook an updated and comprehensive systematic review of diet during pregnancy and infancy and risk of allergic sensitisation, allergic disease, or autoimmune disease.

Methods

This review is reported in accordance with PRISMA guidance. The review is part of a series of systematic reviews commissioned by the UK Food Standards Agency in order to inform UK dietary recommendations for infants and their pregnant or lactating mothers, under the title ‘Review of scientific published literature on infant feeding and development of atopic and autoimmune disease'. The protocols for the systematic reviews were registered with the International Prospective Register of Systematic Reviews (PROSPERO CRD42013003802 ‘Review A:milk feeding’; CRD42013004239 ‘Review B:timing of allergenic food introduction’; CRD42013004252 ‘Review C:maternal and infant diet’) on 5 August 2013, prior to title screening or selecting any studies from the search results. This manuscript reports findings from the majority of the project, comprising Reviews A and C, ‘milk feeding’ and ‘maternal and infant diet’. Review B, regarding timing of introduction of allergenic foods, and one part of Review C, regarding use of hydrolysed infant formula, have been published separately [12,13]. Thus, this manuscript describes outcomes for maternal or infant intake of individual foods or food groups, nutrients or nutrient groups, dietary supplements, maternal allergenic food avoidance, timing of introduction of solid foods or nonallergenic foods to the infant diet, overall dietary pattern and duration of breastfeeding. This manuscript does not include timing of introduction of allergenic foods (milk, soya, egg, peanuts, tree nuts, fish, seafood, wheat) to the infant diet or use of hydrolysed formula in infants. Measures of dietary diversity and objective measures of nutritional status (with the exception of blood vitamin D level) were not included in these systematic reviews. These measures were considered to be too indirect as indicators of dietary intake to be used to inform public health guidance in the UK. As part of this project, we also searched for other systematic reviews covering the same topic published since 1 January 2011.

Study interventions and comparators Studies of total breastfeeding duration, exclusive breastfeeding duration [14], and timing of solid food introduction were included in Review A ‘milk feeding’. Studies of any other nutritional exposure, ranging from dietary pattern to specific micronutrient supplementation and from single to multifaceted interventions, were included in Review C ‘maternal and infant diet’. For observational studies, data on dietary exposures were acquired from interviews, health records, diaries, and questionnaires. With the exception of blood vitamin D level, we did not include assessments of nutrient status as an exposure, and we did not include measures of dietary diversity as an exposure.

Study designs and populations We included all intervention trials, and observational studies described as cohort, case control or cross-sectional analytic studies. Intervention trials were classified as randomised controlled trials (RCTs), where the method of treatment allocation was random, and as controlled clinical trials (CCTs), where treatment allocation was nonrandom and likely to lead to significant imbalance between treatment groups. CCTs were analysed separately from RCTs. Prospective and retrospective observational studies were analysed separately. We included studies of diet during pregnancy or lactation and of infant feeding between birth and 12 months of age. We excluded studies in which participants or their mothers were defined by the presence of a preexisting disease state, including very low birth weight or very premature infants.

Study outcomes Allergic and autoimmune outcomes were selected on the basis of their population prevalence in children and young adults [15]. We included diseases with a prevalence of at least 1 in 1,000 in children/adolescents or young adults (aged <40 years) but did not include rarer diseases. We did not include pernicious anaemia or adult-onset rheumatoid arthritis despite a high prevalence in middle-aged and elderly people because their prevalence in young people is lower than 1 in 1,000, and prospective studies of infant feeding in relation to diseases of older adults were thought unlikely to have been reported. Allergic outcomes that met our inclusion criteria were asthma or wheeze, eczema, allergic rhinitis and/or conjunctivitis, food allergy (defined by food challenge, medical diagnosis, or self/parent report), allergic sensitisation, i.e., skin prick or specific immunoglobulin E (sIgE) assessment, and total immunoglobin E (IgE) level. We categorised asthma as wheeze, recurrent wheeze, or atopic wheeze depending on the definition used in the original publication, and we included measures of lung function, specifically bronchial hyper-reactivity, forced vital capacity, peak expiratory flow rate, and forced expiratory volume in 1 second. Physician-diagnosed asthma was included within the category ‘recurrent wheeze’, unless defined as a single episode of wheeze. Autoimmune diseases that met our inclusion criteria were type 1 diabetes mellitus (TIDM) (doctor diagnosed or serological diagnosis), coeliac disease defined serologically or clinically (positive Immunoglobulin A tissue Transglutaminase antibodies on one or more visits or a positive small bowel biopsy), inflammatory bowel disease, autoimmune thyroid disease, juvenile rheumatoid arthritis, vitiligo, and psoriasis, all as doctor diagnosis. For clinical allergic outcomes, we grouped age at assessment as 0–4 years, 5–14 years, and ≥15 years. Allergic sensitisation and autoimmune diseases were not stratified by age at outcome assessment.

Data sources We searched The Cochrane Library (2013, Issue 7), Excerpta Medica dataBASE (EMBASE) (1947 to July 2013), Literatura Latino Americana em Ciências da Saúde (LILACS) (1982 to July 2013), Medical Literature Analysis and Retrieval System Online (MEDLINE) (1946 to July 2013), and Web of Science (1970 to July 2013) on 25 July 2013. We reran the searches for intervention trials and systematic reviews on 26 February 2017 and for intervention trials again on 15 December 2017. We included all studies published up to that date and studies in progress or completed but unpublished studies identified through http://apps.who.int/trialsearch/. Both peer-reviewed publications and abstract publications were included. We reviewed the bibliography of eligible studies for possible additional publications and included all eligible publications, regardless of the language. Study authors were not contacted for original data. The search strategies were extensively piloted and refined to optimise sensitivity, comparing search results with those of other systematic reviews. The search strategies are shown in S1 Text.

Study selection Title and abstract screening was undertaken by a team of 9 trained researchers (RJB, VGL, DI, NG, KJ, JC, ZR, AR, PD). Two researchers undertook title screening independently and met to agree upon included and excluded titles. Their screening was checked by a third person, and uncertainties were resolved at a weekly team meeting between February and April 2014, 2015, and 2017 (RB, SC, VGL). The full texts of all potentially eligible studies were reviewed.

Risk of bias assessment Risk of bias assessment was undertaken in duplicate, using modified versions of the Cochrane Collaboration Risk of Bias tool for intervention trials and the National Institute for Clinical Excellence methodological checklist for cohort and case–control studies [16]. Risk of bias domains for intervention trials were Selection bias (sequence generation and allocation concealment), Assessment bias (blinding of outcome assessors and validity of the outcome assessment tool), and Attrition bias (considered high when <70% of randomised participants had outcome data). Risk of bias domains for observational studies were Selection bias (low if cases and controls came from similar populations and participation rate ≥80%), Assessment bias (the validity of exposure and outcome assessment tools), and Confounding bias (whether study design and analysis accounted for most potential confounders). We separately included an assessment of Conflict of Interest for each study, judged as low where there was no evidence of industry involvement in study design, analysis, interpretation, or publication and no evidence that study authors received remuneration from relevant industry partners for other activities.

Data extraction Data extraction was undertaken in duplicate. Disagreements and uncertainties about data coding and risk of bias were discussed within the team. For foreign language studies, data were extracted by VGL together with a native speaker of the relevant language (see Acknowledgemnts section). We extracted all relevant data from included studies, including data not able to be meta-analysed. Data were extracted using either raw frequencies or crude or adjusted effect estimates. Random effects meta-analysis was undertaken, and where this was not possible, study results were summarised in a narrative table.

Data selection for analysis For intervention trials, we extracted outcome data that adhered to the intention-to-treat principle in preference to data based on per protocol analyses. Where studies included multiple intervention groups, we performed pairwise comparisons where we split the number of events and no events in the unexposed/control group to prevent double counting. Where studies reported data at multiple timepoints, we extracted the most complete dataset available beyond the intervention period (i.e., from 1 year of age onwards); this is the dataset with the largest denominator or, where the denominator is identical for multiple time points, the largest numerator (number of events). Where studies reported multiple assessments of the same outcome at the same timepoint, clinical assessments were selected in preference to serological assessments, and skin prick in preference to sIgE assessment of allergic sensitisation. For observational studies of breastfeeding or timing of solid or other food introduction to the infant diet, data were only included in meta-analysis where the reference group was complete, i.e., ‘less than’ a certain duration or, in some cases, ‘never’. Where more than one exposure group was compared with the reference group, we analysed data for the latest exposure group. For all observational studies, adjusted effect estimates were used in preference to unadjusted estimates for meta-analysis if both were reported.