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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Appendix C

Risk Determinants Literature Search Strategy

Electronic literature searches of published systematic reviews (from 2010 to September 2015) and primary studies (from 2012 to September 2015) indexed in Medline, Cochrane Database of Systematic Reviews, EMBASE, and ISI Web of Science were conducted. For systematic reviews, a broad search was conducted to identify all systematic reviews with or without meta-analysis from 2010 onward related to food allergies or food sensitizations without restrictions to any interventions or exposures. For primary studies, search strategies in European Academy of Allergy & Clinical Immunology (EAACI) (de Silva et al., 2014) and Marrs et al. systematic reviews (Marrs et al., 2013) were adopted. The EAACI search strategies were developed to identify all randomized controlled trials, quasi-randomized controlled trials, controlled clinical trials, controlled before-and-after studies, interrupted time series studies, and prospective cohort studies that were primarily concerned with preventing sensitization to food(s) and/or the development of food allergy. The Marrs et al. search strategy was intended to capture any study designs describing food allergy or sensitization overall and to individual foods (milk, egg, peanut, tree nuts, fish, wheat, sesame, shellfish, and seafood) combined with search terms of factors that directly or indirectly influence microbial exposure (Marrs et al., 2013). All searches were restricted to human studies that were published in the English language from 2012 onward. Duplicate citations across databases were removed before screening. Medline searches conducted for this report for systematic reviews and individual studies are in Table C-1. Medline searches were used to develop the search strategies for the EMBASE and Web of Science databases.

Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Abstrackr software (abstrackr.cebm.brown.edu), Endnote, and Microsoft Excel were used to manage the search outputs, screening, and data abstraction. After a training session to ensure understanding of the inclusion and exclusion criteria, title/abstract screening was conducted independently by two reviewers using a screening form that listed the inclusion and exclusion criteria and allowed selection of reasons for exclusion. A third reviewer reconciled the discrepant title/abstract selections. Full-text articles of all accepted title/abstracts were then retrieved and screened by one reviewer based on the study eligibility criteria. Second-level screening of full text articles was conducted by two reviewers and differences reconciled by a third reviewer. Boxes C-1 and C-2 list the study inclusion and exclusion criteria, respectively. Figure C-1 illustrates the study selection flow. Summary tables for the systematic reviews and studies selected for the evidence-based review are included in Tables C2-C6.

Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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TABLE C-1 Medline Search Strategy to Identify Relevant Literature

Search Number Search Terms
a. Systematic Reviews Search Strategy
1 exp food hypersensitivity/or exp egg hypersensitivity/or exp milk hypersensitivity/or exp nut hypersensitivity/or exp peanut hypersensitivity/or exp wheat hypersensitivity/
2 (food$ adj2 (allergy$ or hypersensitivity)).mp.
3 ((milk or egg$ or shellfish or fish or nut$ or peanut$ or wheat or soybean$ or seasame or seafood$) adj1 (allerg$ or hypersensitivity or sensitization)).mp.
4 (sensitization or hypersensitivity).mp.
5 (food$ or diet$).mp.
6 4 and 5 (13121)
7 1 or 2 or 3 or 6 (15068)
8 (rat or rats or cow or cows or chicken? or horse or horses or mice or mouse or bovine or animal?).ti.
9 exp animals/not humans.sh.
10 8 or 9
11 7 not 10
12 MEDLINE.tw.
13 systematic review.tw.
14 meta analysis.pt.
15 or/12-14
16 11 and 15
17 limit 16 to (English language and yr=“2010 -Current”)
b. Primary Studies: EAACI Search Strategy
1 exp food hypersensitivity/or exp egg hypersensitivity/or exp milk hypersensitivity/or exp nut hypersensitivity/or exp peanut hypersensitivity/or exp wheat hypersensitivity/
2 (food$ adj2 (allergy$ or hypersensitivity)).mp.
3 ((milk or egg$ or shellfish or fish or nut$ or peanut$ or wheat or soybean$ or seasame or seafood$) adj1 (allerg$ or hypersensitivity or sensitization)).mp.
4 (sensitization or hypersensitivity).mp.
5 (food$ or diet$).mp.
6 4 and 5 (13121)
7 1 or 2 or 3 or 6 (15068)
8 (rat or rats or cow or cows or chicken? or horse or horses or mice or mouse or bovine or animal?).ti.
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Search Number Search Terms
9 exp animals/not humans.sh.
10 8 or 9
11 7 not 10
12 randomized controlled trial.pt.
13 controlled clinical trial.pt.
14 randomized.ab.
15 placebo.ab.
16 clinical trials as topic.sh.
17 randomly.ab.
18 trial.ti.
19 or/16-22
20 intervention?.ti. or (intervention? adj6 (clinician? or collaborat$ or community or complex or DESIGN$ or doctor? or educational or family doctor? or family physician? or family practitioner? or financial or GP or general practice? or hospital? or impact? or improv$ or individuali?e? or individuali?ing or interdisciplin$ or multicomponent or multi-component or multidisciplin$ or multidisciplin$ or multifacet$ or multi-facet$ or multimodal$ or multimodal$ or personali?e? or personali?ing or pharmacies or pharmacist? or pharmacy or physician? or practitioner? or prescrib$ or prescription? or primary care or professional$ or provider? or regulatory or regulatory or tailor$ or target$ or team$ or usual care)).ab.
21 (pre-intervention? or preintervention? or “pre intervention?” or postintervention? or postintervention? or “post intervention?”).ti,ab.
22 (hospital$ or patient?).hw. and (study or studies or care or health$ or practitioner? or provider? or physician? or nurse? or nursing or doctor?).ti,hw.
23 demonstration project?.ti,ab.
24 (pre-post or “pre test$” or pretest$ or posttest$ or “post test$” or (pre adj5 post)).ti,ab.
25 (pre-workshop or post-workshop or (before adj3 workshop) or (after adj3 workshop)).ti,ab.
26 trial.ti. or ((study adj3 aim?) or “our study”).ab.
27 (before adj10 (after or during)).ti,ab.
28 (“quasi-experiment$” or quasiexperiment$ or “quasi random$” or quasirandom$ or “quasi control$” or quasicontrol$ or ((quasi$ or experimental) adj3 (method$ or study or trial or design$))).ti,ab,hw.
29 (“time series” adj2 interrupt$).ti,ab,hw.
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Search Number Search Terms
30 (time points adj3 (over or multiple or three or four or five or six or seven or eight or nine or ten or eleven or twelve or month$ or hour? or day? or “more than”)).ab.
31 pilot.ti.
32 Pilot projects/
33 (clinical trial or controlled clinical trial or multicenter study).pt.
34 (multicentre or multicenter or multi-centre or multi-center).ti.
35 random$.ti,ab. or controlled.ti.
36 (control adj3 (area or cohort? or compare? or condition or design or group? or intervention? or participant? or study)).ab. not (controlled clinical trial or randomized controlled trial).pt.
37 comment on.cm. or review.ti,pt. or randomized controlled trial.pt.
38 or/24-41
39 exp cohort studies/
40 cohort$.tw.
41 controlled clinical trial.pt.
42 epidemiologic methods/
43 exp case-control studies/
44 (case$ and control$).tw.
45 or/43-48
46 11 and 19
47 11 and 38
48 11 and 45
49 or/46-48
50 limit 49 to yr=“2012 -Current”
51 limit 50 to “review articles”
52 50 not 51
c. Primary Studies: Marrs et al. Search Strategy
1 Measles/or measles.mp,
2 exp Mumps/or mumps.mp,
3 Whooping Cough/or whooping cough.mp,
4 exp Pneumonia/or pneumonia.mp,
5 exp Chickenpox/or chickenpox.mp,
6 hepatitis/or hepatitis a/or exp hepatitis b/
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Search Number Search Terms
7 Hepatitis A/or exp Hepatitis B/
8 hepatitis.mp,
9 exp Herpes Simplex/or herpes simplex.mp,
10 exp Rubella/or rubella.mp,
11 exp Helicobacter pylori/or helicobacter pylori.mp,
12 exp Tuberculosis/or tuberculosis.mp,
13 exp Mycobacterium bovis/
14 exp Helminthiasis/
15 helminthiasis.mp,
16 exp Helminths/
17 helminths.mp,
18 exp Necator americanus/
19 Necator americanus.mp,
20 exp Trichuris/or trichuris.mp,
21 exp Ascaris lumbricoides/or Ascaris lumbricoides.mp,
22 exp Schistosomiasis/or Schistosomiasis.mp,
23 exp Enterobius/
24 enterobius vermicularis.mp,
25 exp Bacterial Infections/
26 bacterial infection*.mp,
27 or/1-26
28 hygiene/or skin care/
29 hygiene.mp,
30 hygiene hypothesis.mp,
31 exp Anthroposophy/
32 anthroposoph*.mp,
33 Child Day Care Centers/
34 day care.mp,
35 Siblings/
36 sibling*.mp,
37 Birth Order/
38 birth order.mp,
39 nurser*.mp,
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Search Number Search Terms
40 agriculture/or animal husbandry/
41 agriculture.mp,
42 farming.mp,
43 farms.mp,
44 farm.mp,
45 Animals, Domestic/
46 pets.mp,
47 pet.mp,
48 Cats/
49 cats.mp,
50 cat.mp,
51 Dogs/
52 dog.mp,
53 dogs.mp,
54 exp Endotoxins/
55 endotoxin*.mp,
56 exp Probiotics/
57 probiotic*.mp,
58 lactobacillus.mp,
59 exp Lactobacillus/
60 intestinal microflora.mp,
61 mycobacterium vaccae.mp,
62 Prebiotics/
63 pre-biotic*.mp,
64 prebiotic*.mp,
65 pro-biotic*.mp,
66 exp Anti-Bacterial Agents/
67 antibiotic*.mp,
68 Disinfectants/or disinfectant.mp,
69 vaccination.mp,
70 vaccinat*.mp,
71 unpasteuri* milk.mp,
72 unpasteuri* cow* milk.mp,
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Search Number Search Terms
73 pasteuri* milk.mp,
74 pasteuri* cow* milk.mp,
75 raw milk.mp,
76 raw cow* milk.mp,
77 unhomogeni* milk.mp,
78 unhomogeni* cow* milk.mp,
79 un-pasteuri* milk.mp,
80 un-homogeni* milk.mp,
81 or/28-80
82 27 or 81
83 exp food hypersensitivity/or exp egg hypersensitivity/or exp milk hypersensitivity/or exp nut hypersensitivity/or exp peanut hypersensitivity/or exp wheat hypersensitivity/
84 (food$ adj2 (allergy$ or hypersensitivity)).mp.
85 ((milk or egg$ or shellfish or fish or nut$ or peanut$ or wheat or soybean$ or seasame or seafood$) adj1 (allerg$ or hypersensitivity or sensitization)).mp,
86 (sensitization or hypersensitivity).mp,
87 (food$ or diet$).mp,
88 86 and 87
89 83 or 84 or 85 or 88
90 88 and 89
91 Cesarean Section/
92 caesarian section.mp,
93 cesarian section.mp,
94 mode of delivery.mp,
95 microbiota.mp,
95 82 or 91 or 92 or 93 or 94 or 95
96 90 and 95
97 limit 96 to “review articles”
98 96 not 97
99 limit 98 to yr=“2012 -Current”
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Image
FIGURE C-1 Literature search and study selection process.
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×

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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×

TABLE C-2a Microbial Exposure Hypothesis (Randomized Controlled Trials)

Author, Year Study Design, Country Population N Age When Outcome Was Ascertained
Prebiotics/Probiotics
Ivakhnenko and Nyankovskyy, 2013 Randomized controlled trial (formula feeding) + 1 BF group (nonrandomized), Ukraine Healthy, term newborns 80 BF infants; 160 formula fed infants (80 formula enriched with the specific mixture of oligosaccharides; 80 standard formula) 18 months

NOTE: BF = breastfed; CI = confidence interval; GI = gastrointestinal; OFC = oral food challenge.

a Bold indicates statistical significance at P<0.05. Results were reported as odds ratio (95% confidence interval) unless otherwise noted. Adjusted results were extracted in the summary table unless otherwise noted.

Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Food Allergy or Sensitization Outcome Definition Exposure Odds Ratioa (95% CI) of Food Allergy Comments
Allergic reactions to food (not defined) Allergic reactions to cow milk protein (not defined) GI symptoms of food allergy (not defined) BF (group 1) versus formula enriched with oligosaccharides (scGOS/lcFOS; 9:1; 8 g/L) (group 2) versus standard formula (group 3) Allergic reactions to food: 2/51 (3.92%) versus 3/62 (4.84%) versus 9/53 (16.98%); P<0.05

Allergic reactions to cow milk: 1/51 (1.96%) versus 2/62 (3.23%) versus 8/53 (15.09%); P<0.05
 
GI symptoms of food allergy: 1/51 (1.96%) versus 2/62 (3.23%) versus 7/53 (13.21%); P<0.05
51 (63.7%), 62 (77.5%), and 53 (66.3%) infants in groups 1, 2, and 3, respectively, completed the study. Analysis was done in completers only. Duration and exclusivity of BF were not measured.

Food allergy not confirmed by OFC.
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×

TABLE C-2b Microbial Exposure Hypothesis (Observational Studies)

Author Year Study Design, Country Population N Age When Outcome Was Ascertained
Prebiotics/Probiotics
Loo et al., 2014 Long-term follow-up of a RCT, Singapore Asian infants at risk for allergic disease 226 3-5 years
West et al., 2013 Long-term follow-up of an RCT, Sweden Healthy, term infants with no prior allergic manifestations 121 8-9 years
Route of Delivery
McGowan et al., 2015 Prospective cohort, Baltimore, Boston, New York City, St. Louis Children from the Urban Environment and Childhood Asthma (URECA) study 516 1-5 years
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Food Allergy or Sensitization Outcome Definition Exposure Odds Ratioa (95% CI) of Food Allergy Comments
Ever had food allergy (history of convincing symptoms of food allergy and the presence of IgE allergen) since year 3 Intervention: Cow milk formula supplemented with probiotics (BL999 and LPR) from birth to age 6 months (N=117)

Control: Cow milk formula supplemented without probiotics (N=109)
RR=1.1 (0.1-17.0) 245 infants were randomized; 220 (87%) completed 5-year follow-up. The analysis was done in 226 children (number of dropouts by groups was not reported).
IgE-associated food allergy Intervention: Infant cereals with addition of probiotics (LF19 1 × 108 CFU per serving) from 4 to age 13 months (N=59)

Control: Infant cereals without addition of probiotics (N=62)
1.05 (0.14-7.73) 171/179 randomized infants completed the trial; 121 children in the long-term follow-up. More children in the placebo group received antibiotics during intervention than probiotic group (32.3% versus 16.9%, P=0.05).

Unadjusted analysis.
Food allergy (N=51) or sensitization (N=286): sIgE to milk, egg, peanut; clinical history (1) Caesarean section (food allergy versus not allergic)
(2) Caesarean section (food sensitized versus not sensitized)
(1) 23.5% versus 31.6%; P=0.31

(2) 31.5% versus 30.9%; P=0.96
Unadjusted analysis.
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Author Year Study Design, Country Population N Age When Outcome Was Ascertained
Peters et al., 2015 Prospective cohort, Australia Infants from the HealthNuts study 5,276 1 year
Grimshaw et al., 2014 Prospective nested case-control study, UK Cases: all infants with food allergy by age of 2 years from the Prevalence of Infant Food Allergy (PIFA) study Controls: age-matched controls from the PIFA study 123 (41 with food allergy; 82 controls) 1-2 years
Luccioli et al., 2014 Prospective cohort, US Children who participated in the Infant Feeding Practices Study (IFPS) II 1,363 6 years
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Food Allergy or Sensitization Outcome Definition Exposure Odds Ratioa (95% CI) of Food Allergy Comments
IgE-mediated food allergy = positive OFC in the presence of positive test of sensitization (SPT ≥2 mm or sIgE ≥0.35 kua/L). Separate analysis for single egg allergy (9% of the cohort), multiple food allergies predominantly peanut (3% of the cohort), and multiple food allergies predominantly egg (2% of the cohort), comparing to no allergic disease at baseline. Caesarean section versus vaginal birth Single egg allergy: 1.02 (0.81-1.29)

Multiple food allergies - peanut: 1.24 (0.86-1.78)

Multiple food allergies - egg: 0.93 (0.56-1.60)
5,142 infants underwent SPT to egg, peanut, or sesame and 1,089 infants were eligible for hospital assessment, of whom 908 participated in OFC.
Food allergy determined by SPT, physical exam, clinical history, sIgE, DBPCOFC Birth by caesarean section (cases versus controls) 31.7% versus 24.4%; P=0.255 Unadjusted analysis except for pet ownership.
Physician-diagnosed food allergy as reported by parent Caesarean section versus vaginal birth 1.37 (0.84-2.21)
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Author Year Study Design, Country Population N Age When Outcome Was Ascertained
Depner et al., 2013 Prospective cohort, Austria, Finland, France, Germany, Switzerland Children from the Protection against Allergy-Study in Rural Environments (PASTURE) birth cohort 686 Birth to 1 year
Pele et al., 2013 Prospective cohort, France Respondents to the 2-year follow-up FFQ of the PELAGIE mother–child cohort study 1,487 2 years
Pyrhonen et al., 2013 Retrospective cohort study, Finland Children identified from the South Karelian Allergy Research Project (SKARP), a population-based study comprising all children of a given age range and living in the same province. 3,181 1-4 years
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Food Allergy or Sensitization Outcome Definition Exposure Odds Ratioa (95% CI) of Food Allergy Comments
sIgE to food allergens (hen egg, cow milk, peanut, hazlenut, carrot, wheat flour) Caesarean section 1.18 (0.69-2.03) 793 (378 farm and 415 nonfarm) children were included in the analyses, of whom 686 were included in IgE to food allergens model.
Mother-reported food allergy in children (N=136): 37 had a medical diagnosis of cow milk allergy, 41 had a medical diagnosis of food allergy, and 22 of both, while 36 children had no doctor’s diagnosis Cesarean section (yes versus no) 8.7% versus 9.1%; P=0.10 Nonrespondents (N=1,496) were younger at the birth of the child, less educated, and more likely to smoke. These factors were considered as covariates in the paper. Unadjusted analysis results only.
Physician-diagnosed allergic manifestations: positive specific IgE test, SPT, open food challenge (did not specify which foods) Caesarean section 1.15 (0.80-1.63) Large nonresponse rate.
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Author Year Study Design, Country Population N Age When Outcome Was Ascertained
Dowhower Karpa et al., 2012 Retrospective case-control study, US Cases: children visiting an allergy specialty clinic for a food allergy–related concern who were also born at the institution’s medical center. Age- and sex-matched controls: children visiting primary care practice who were also born at the institution’s medical center. 99 case; 192 controls No data
Antibiotics Use
Grimshaw et al., 2014 Prospective nested case-control study, UK Cases: all infants with food allergy by age of 2 years from the PIFA study Controls: age-matched controls from the PIFA study 123 (41 with food allergy; 82 controls) 1-2 years
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Food Allergy or Sensitization Outcome Definition Exposure Odds Ratioa (95% CI) of Food Allergy Comments
ICD-9-CM coding consistent with food-related allergic reactions and a confirmed presence of food allergies documented by either a positive serum specific IgE test or positive SPT Caesarean (cases versus controls) 32.2% versus 33.9%; P=0.79 Retrospective chart review. Possible selection bias. Unadjusted analysis results only.
Food allergy determined by SPT, physical exam, clinical history, sIgE, double-blind placebo controlled food challenge Maternal antibiotic use (cases versus controls) No significant associations during or after pregnancy or while breastfeeding Unadjusted analysis except for pet ownership.
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Author Year Study Design, Country Population N Age When Outcome Was Ascertained
Metsala et al., 2013 Prospective nested case-control study, Finland Cases: infants who had received a special reimbursement for the cost of special infant formulas based on diagnosed cow milk allergy. Controls: randomly selected and matched for date of birth, sex, and the hospital district of birth. 16,237 case-control pairs 0-2 years
Dowhower Karpa et al., 2012 Retrospective case-control study, US Cases: children visiting an allergy specialty clinic for a food allergy-related concern who were also born at the institution’s medical center. Age-and-sex matched controls: children visiting primary care practice who were also born at the institution’s medical center. 99 case; 192 controls No data
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Food Allergy or Sensitization Outcome Definition Exposure Odds Ratioa (95% CI) of Food Allergy Comments
Pediatric certification of cow milk allergy based on clinical exam, symptoms, elimination diet, SPT, and elevated serum-specific IgE or open challenge test (1) Maternal use of antibiotics before pregnancy
(2) Maternal use of antibiotics during pregnancy
(3) Child’s use of antibiotics from birth to 1 month
(1) 1.26 (1.20-1.33)

(2) 1.21 (1.14-1.28)

(3) 1.71 (1.59-1.84)
ICD-9-CM coding consistent with food-related allergic reactions and a confirmed presence of food allergy documented by either a positive serum specific IgE test or positive SPT (1) Neonatal antibiotics (cases versus controls)
(2) Peripartum antibiotics (cases versus controls)
(1) 16.2% versus 12.5%; P=0.39

(2) 28.3% versus 28.1%; P=1.0
Retrospective chart review.

Possible selection bias.

Unadjusted analysis results only.
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Author Year Study Design, Country Population N Age When Outcome Was Ascertained
Exposure to Animals
Martin et al., 2015 Prospective cohort, Australia Infants from the HealthNuts study 4,453 (2,795 without eczema; 1,903 with eczema) 1 year
Peters et al., 2015 Prospective cohort, Australia Infants from the HealthNuts study 5,276 1 year
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Food Allergy or Sensitization Outcome Definition Exposure Odds Ratioa (95% CI) of Food Allergy Comments
SPT or sIgE, OFC (egg white, peanut, sesame) or parent report of recent immediate-type reaction (1) Pet dog among infants without eczema; among infants with eczema
(2) Pet cat among infants without eczema; among infants with eczema
(1) 0.9 (0.6-1.5); 0.7 (0.5-0.9)

(2) 0.9 (0.5-1.6); 0.6 (0.4-0.8)
Same cohort as Peters et al., 2015, but different analyses and outcome definitions. [Note: cesarean section results were not extracted for this study because for this factor the analysis was unadjusted.]
IgE-mediated food allergy = positive OFC in the presence of positive test of sensitization (SPT ≥2 mm or sIgE ≥0.35 kua/L). Separate analysis for single egg allergy (9% of the cohort), multiple food allergies, predominantly peanut (3% of the cohort), and multiple food allergies predominantly egg (2% of the cohort), compared to no allergic disease at baseline. (1) Dogs allowed inside the home versus no dogs

(2) Dogs outside only versus no dogs

(3) Pet cats versus no dogs
(1) Single egg allergy: 0.76 (0.56-1.05) Multiple food allergies - peanut: 0.40 (0.21-0.73) Multiple food allergies - egg: 0.59 (0.26-1.34)

(2) Single egg allergy: 1.56 (1.10-2.21) Multiple food allergies - peanut: 0.82 (0.44-1.54) Multiple food allergies - egg: 0.39 (0.13-1.18)

(3) Single egg allergy: 0.80 (0.57-1.12) Multiple food allergies - peanut: 0.83 (0.47-1.47) Multiple food allergies - egg: 0.86 (0.38-1.91)
5,142 infants underwent SPT to egg, peanut or sesame and 1,089 infants were eligible for hospital assessment, of whom 908 participated in OFC.
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Author Year Study Design, Country Population N Age When Outcome Was Ascertained
Grimshaw et al., 2014 Prospective nested case-control study, UK Cases: all infants with food allergy by age of 2 years from the PIFA study Controls: age-matched controls from the PIFA study 123 (41 with food allergy; 82 controls) 1-2 years
Stelmach et al., 2014 Prospective cohort, Poland Children from the Polish Mother and Child Cohort Study (REPRO_ PL cohort) 501 1-2 years
Depner et al., 2013 Prospective cohort, Austria, Finland, France, Germany, Switzerland Children from the Protection against PASTURE birth cohort 686 Birth to 1 year
Goldberg et al., 2013 Prospective case-cohort study, Israel Cases: IgEcow milk allergy children identified from a cohort study (Katz, 2010) Controls: healthy children randomly chosen from the cohort 66 cases 156 controls 2-3 years
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Food Allergy or Sensitization Outcome Definition Exposure Odds Ratioa (95% CI) of Food Allergy Comments
Food allergy determined by SPT, physical exam, clinical history, sIgE, DBPCOFC Pet ownership (yes versus no) 1.275 (0.49-3.33)
Food allergy ever diagnosed by doctor according to international guidelines Pets at home during pregnancy (yes versus no) 1.48 (1.02-2.16) Frequency of cleaning was not associated with food allergy and was dropped out from multivariate model.
sIgE to food allergens (hen egg, cow milk, peanut, hazlenut, carrot, wheat flour) (1) Early contact with sheep, goats, hares

(2) Farming
(1) 0.92 (0.75-1.13)

(2) 2.11 (1.33-3.34)
793 (378 farm and 415 nonfarm) children were included in the analyses, of whom 686 were included in IgE to food allergens model.
IgE-mediated cow milk allergy defined by a suggestive history of an immediate response, a positive SPT response, and, in most cases, a positive challenge result to cow milk protein Pets in home (cases versus controls) 26.2% versus 30.1%; P=0.72 Unadjusted analysis.
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Author Year Study Design, Country Population N Age When Outcome Was Ascertained
Pele et al., 2013 Prospective cohort, France Respondents to the 2-year follow-up FFQ of the PELAGIE mother–child cohort study 1,487 2 years
Koplin et al., 2012 Prospective cohort, Australia Infants from the HealthNuts study 4,963 1 year

NOTE: CI = confidence interval; DBPCOFC = double-blind, placebo-controlled oral food challenge; FFQ = food frequency questionnaire; IgE = immunoglobulin E; OFC = oral food challenge; RAST = radioallergosorbent test; RR = relative risk; sIgE = food-specific serum IgE; SPT = skin prick test; UK = United Kingdom; US = United States.

a Bold indicates statistical significance at P<0.05. Results were reported as odds ratio (95% confidence interval) unless otherwise noted. Adjusted results were extracted in the summary table unless otherwise noted.

Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Food Allergy or Sensitization Outcome Definition Exposure Odds Ratioa (95% CI) of Food Allergy Comments
Mother-reported food allergy in children (N=136): 37 had a medical diagnosis of cow milk allergy, 41 a medical diagnosis of food allergy, and 22 of both, while 36 children had no doctor’s diagnosis Farm animal contact (yes versus no) 8.9% versus 9.1%; P=0.88 Nonrespondents (N=1,496) were younger at the birth of the child, less educated, and more likely to smoke. These factors were considered as covariates in the paper.

Unadjusted analysis results only.
IgE-mediated egg allergy: Allergic on formal egg challenge or previous history of clear reaction to egg occurring within 1 month of a positive SPT or RAST (1) Dog outside only versus no dog
(2) Dog allowed inside versus no dog
(3) Cat outside only versus no cat
(4) Cat allowed inside versus no cat
(1) 1.09 (0.75-1.57)

(2) 0.72 (0.52-0.99)

(3) 0.93 (0.49-1.77)

(4) 0.75 (0.52-1.09)
Same cohort as Peters et al., 2015 but different analyses and outcome definitions.
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×

TABLE C-3a Allergen Avoidance Hypothesis (Randomized Controlled Trials)

Author Year Study Design, Country Population N Age When Outcome Was Ascertained
Breastfeeding
Ivakhnenko and Nyankovskyy, 2013 Randomized controlled trial (formula feeding) + 1 BF group (nonrandomized), Ukraine Healthy, term newborns 80 BF infants; 160 formula fed infants (80 formula enriched with the specific mixture of oligosaccharides; 80 standard formula) 18 months
Infant Formula
Lowe et al., 2011 RCT, Australia Infants with a family history of allergic disease 620 6, 12, and 24 months

NOTE: BF = breastfed; CI = confidence interval; GI = gastrointestinal; pHWF = partially hydrolyzed whey formula.

a Bold indicates statistical significance at P<0.05. Results were reported as odds ratio (95% confidence interval) unless otherwise noted. Adjusted results were extracted in the summary table unless otherwise noted.

Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Food Allergy or Sensitization Outcom Definitione Exposure Odds Ratioa (95% CI) of Food Allergy Comments
Allergic reactions to food (not defined) Allergic reactions to cow milk protein (no defined) GI symptoms of food allergy (not defined) BF (group 1) versus formula enriched with oligosaccharides t (scGOS/lcFOS; 9:1; 8 g/L) (group 2) versus standard formula (group 3) Allergic reactions to food: 2/51 (3.92%) versus 3/62 (4.84%) versus 9/53 (16.98%); P<0.05

Allergic reactions to cow milk: 1/51 (1.96%) versus 2/62 (3.23%) versus 8/53 (15.09%); P<0.05

GI symptoms of food allergy: 1/51 (1.96%) versus 2/62 (3.23%) versus 7/53 (13.21%); P<0.05
51 (63.7%), 62 (77.5%), and 53 (66.3%) infants in groups 1, 2, and 3, respectively, completed the study. Analysis was done in completers only. Duration and exclusivity of BF were not measured.

Food allergy not confirmed by OFC.
Food reaction, SPT (milk, egg, peanut) Soy-based formula, pHWF, or cow milk formula at cessation of breastfeeding Positive SPT to cow milk within first 2 years:

pHWF versus CMF: 0.79 (0.35-1.77)

Soy formula versus CMF: 0.78 (0.32-1.92)

Any food reaction: pHWF versus CMF: 0.95 (0.51-1.75)

Soy formula versus CMF: 1.21 (0.67-2.19)
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×

TABLE C-3b Allergen Avoidance (Observational Studies)

Author, Year Study Design, Country Population N Age When Outcome Was Ascertained
Maternal Intake During Pregnancy and Lactation
Bunyavanich et al., 2014 Prospective cohort, US Mother-child pairs in the Project Viva prebirth cohort recruited from a large multidisciplinary practice 1,277 mother–child pairs 7.9 years (mean)
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Food Allergy or Sensitization Outcome Definition Exposure Odds Ratioa (95% CI) of Food Allergy Comments
Food allergy to peanut, milk, wheat, egg, and/or soy based on sIgE to the particular food and EpiPen prescribed. Food allergy to peanut was more specifically defined by parent report of convincing symptoms of a peanut allergic reaction (history of peanut allergy AND a cutaneous, respiratory, cardiovascular, gastrointestinal and/or anaphylactic symptom following peanut ingestion). Maternal intake (total servings per day as measured by FFQ) during first and second trimester of:

(1) peanut
(2) milk
(3) wheat
(4) egg
(5) soy

Intake reported as z-scores
First trimester
(1) 0.53 (0.30-0.94)
(2) 0.90 (0.50-1.62)
(3) 1.26 (0.75-2.12)
(4) 0.76 (0.28-2.08)
(5) 0.61 (0.16-2.31)

Second trimester
(1) 0.88 (0.61-1.27)
(2) 1.47 (0.91-2.37)
(3) 1.07 (0.62-1.85)
(4) 0.77 (0.28-2.15)
(5) 1.18 (0.95-1.48)
All ORs are adjusted for child age, sex, breastfeeding history, parental atopy, and maternal education.
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Author, Year Study Design, Country Population N Age When Outcome Was Ascertained
Frazier et al., 2014 Prospective cohort, US Boys and girls (born between 1990 and 1994) participating in the Growing Up Today Study 2 (GUTS2) and their mothers.

(These are children of women in the Nurse’s Health Study II.)
8,205 mother–child pairs Unclear
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Food Allergy or Sensitization Outcome Definition Exposure Odds Ratioa (95% CI) of Food Allergy Comments
Peanut or tree nut (walnut, almond, pistachio, cashew, pecan, hazelnut, macadamia, and Brazil nut) allergy in offspring based on maternal confirmation of food allergy diagnosis, review of physical copies of laboratory results of testing (SPT, sIgE, OFC) by two board-certified pediatricians, and confirmation of food allergy in writing from the child’s treating physician Peripregnancy maternal consumption of peanuts or tree nuts:

(1) <1 serving/month

(2) 1-3 servings/month

(3) 1-4 servings/week

(4) ≥5 servings/week
Multivariable OR
(1) reference group
(2) 0.90 (0.55-1.48)
(3) 0.65 (0.43-0.97)
(4) 0.58 (0.34-0.99) Ptrend=0.04
The dietary questionnaires were not specific for the actual dates of the pregnancy but were chosen as the one completed closest to the child’s date of birth. Only 45% of the dietary questionnaires were completed during the pregnancy; 76% were within 1 year of the pregnancy.

Multivariable models control for continuous maternal age, maternal history of non-nut food allergy, maternal allergic rhinitis, eczema, or asthma, and season at child’s birth (spring or summer versus fall or winter).
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Author, Year Study Design, Country Population N Age When Outcome Was Ascertained
Pele et al., 2013 Prospective cohort, France Respondents to the 2-year follow-up FFQ of the PELAGIE mother–child cohort study 1,500 mother–child pairs 2 years
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Food Allergy or Sensitization Outcome Definition Exposure Odds Ratioa (95% CI) of Food Allergy Comments
Mother-reported food allergy in children (N=136): 37 had a medical diagnosis of cow milk allergy, 41 a medical diagnosis of food allergy, and 22 of both, while 36 children had no doctor’s diagnosis (1) Maternal pre-pregnancy consumption of fish (<1 time/month versus 1-4 times/month)

(2) Maternal pre-pregnancy consumption of fish (<1 time/month versus ≥2 times/week)

(3) Maternal pre-pregnancy consumption of shellfish (<1 time/month versus ≥1 time/month)

All exposures measured by FFQ
(1) 1.27 (0.72-2.24)

(2) 1.48 (0.80-2.76)

(3) 1.62 (1.11-2.37)
Nonrespondent mothers (N=1,496) were younger at the birth of the child, less educated, and more likely to smoke than the participants (N=1,500). These factors were considered as covariates in the paper.

ORs adjusted for: mother’s age, maternal education, folic acid supplementation, familial history of asthma/allergy, child’s sex, small-for-gestational age, infant’s method of feeding, day care attendance, postnatal exposure to tobacco, and child’s age at follow-up.
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Author, Year Study Design, Country Population N Age When Outcome Was Ascertained
Breastfeeding
McGowan et al., 2015 Prospective cohort, Baltimore, Boston, New York City, St. Louis Children from the Urban Environment and Childhood Asthma (URECA) study 516 1-5 years
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Food Allergy or Sensitization Outcome Definition Exposure Odds Ratioa (95% CI) of Food Allergy Comments
Food allergy (N=51) or sensitization (N=286): sIgE to milk, egg, peanut; clinical history (1) Ever BF (1) Food allergy versus no food allergy: 35/51 (68.8%) versus 193/377 (52.9%); P=0.05 Food sensitization versus no food sensitization: 161/286 (58.3%) versus 121/230 (53.8%); P=0.35 Of the 609 children initially enrolled, 516 (85%) were included. Unadjusted analysis.
(2) BF at 3 months (2) Food allergy versus no food allergy: 16/51 (32.7%) versus 76/377 (22.8%); P=0.18 Food sensitization versus no food sensitization: 64/286 (25.1%) versus 48/230 (23.4%); P=0.76
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Author, Year Study Design, Country Population N Age When Outcome Was Ascertained
Peters et al., 2015 Prospective cohort, Australia Infants from the HealthNuts study 5,276 1 year
Grimshaw et al., 2013 Prospective nested case-control study, UK Cases: all infants with food allergy by age of 2 years from the Prevalence of Infant Food Allergy (PIFA) study Controls: age-matched controls from the PIFA study 123 (41 with food allergy; 82 controls) 1-2 years
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Food Allergy or Sensitization Outcome Definition Exposure Odds Ratioa (95% CI) of Food Allergy Comments
IgE-mediated food allergy = positive OFC in the presence of positive test of sensitization (SPT ≥2 mm or sIgE ≥0.35 kua/L). Separate analysis for single egg allergy (9% of the cohort), multiple food allergies predominantly peanut (3% of the cohort), and multiple food allergies predominantly egg (2% of the cohort), comparing to no allergic disease at baseline Duration of BF (up to 12 months) Single egg allergy: 1.02 (0.99-1.04) Multiple food allergy (predominantly peanut): 1.00 (0.96-1.05) Multiple food allergy (predominantly egg): 1.17 (1.09-1.24) 5,142 infants underwent SPT to egg, peanut, or sesame and 1,089 infants were eligible for hospital assessment, of whom 908 participated in OFC. Multinomial logistic regression was used to determine risk factors for each class, also weighted for posterior probabilities of class membership. Three separate multivariable models were fitted for the three categories of risk factors (parental, infant, and environmental).
Food allergy determined by SPT, physical exam, clinical history, sIgE, DBPCOFC (1) BF duration, median weeks

(2) Exclusive BF, median weeks

(3) % BF initiation
(1) Cases versus controls: 21.0 (3.0-30.5) versus 24.0 (7.0-31.0); P=0.295

(2) Cases versus controls: 5.0 (2.8-16.3) versus 8.5 (4.0-15.0); P=0.933

(3) Cases versus controls: 92.7% versus 96.3%; P=0.21
Only age adjusted (matching factor).
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Author, Year Study Design, Country Population N Age When Outcome Was Ascertained
Liao et al., 2014 Prospective cohort, Taiwan Infants ≥37 weeks from the The Prediction of Allergy in Taiwanese Children (PATCH) cohort 258 (238, 226, 217, 210, and 198 completed 6, 12, 18, 24, and 36 months of follow-ups) 6, 12, 18, 24, and 36 months
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Food Allergy or Sensitization Outcome Definition Exposure Odds Ratioa (95% CI) of Food Allergy Comments
sIgE antibody included a mix of six common allergens: Dermatophagoides pteronyssinus (Dp) Dermatophagoides farinae (Df), egg white, cow milk, Cladosporium herbarum (Hormodendrum), and wheat. Participants were characterized as atopic or been sensitized if any of the sIgE level was greater than 0.35 IU/ml. (1) Exclusive BF ≥4 versus <4 months,

(2) Partial BF
(1) Cow milk sensitization at 6, 12, 18, 24, 36 months: 1.0 (0.3, 3.3); 0.2 (0.07-0.5; 0.2 (0.07-0.5); 0.3 (0.1-0.7); 0.6 (0.2-1.7)

Egg sensitization at 6, 12, 18, 24, 36 months: 1.3 (0.5-3.5); 1.4 (0.5-3.7); 1.6 (0.7-3.8); 1.6 (0.7-3.7); 0.7 (0.2-2.0)

(2) Cow milk sensitization: There was a trend of reduced risk for cow milk protein sensitization as duration of partial breastfeeding was increased; the result was not statistically significant
Of the original 258 neonates, blood samples and questionnaires were available from 238 infants at the age of 6 months. 226, 217, 210, and 198 children completed 12, 18, 24 and 36 months of follow-ups, respectively.

Unadjusted analysis only.
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Author, Year Study Design, Country Population N Age When Outcome Was Ascertained
Luccioli et al., 2014 Prospective cohort, US Children who participated in the Infant Feeding Practices Study (IFPS) II 1,363 (823 high-risk group) 6 years
Mailhol et al. 2014 Cross-sectional study, France Children (0 to 18 years of age) with atopic dermatitis seen consecutively at multidisciplinary clinics from May 2002 to December 2008 386 0 to 18 years
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Food Allergy or Sensitization Outcome Definition Exposure Odds Ratioa (95% CI) of Food Allergy Comments
Total pFA (all children with a current physician diagnosis of food allergy at age 6 years). (N=89, 7%)

New pFA (subset of children with physician diagnosis of food allergy at age 6 years but with no diagnosis before 1 year of age) (N=71, 5.2%)

High-risk pFA (subset of children with pFA at age 6 years and report of any of the following atopic risk factors: family history of food allergy, family history of other atopy, or eczema before age 1 year)
Exclusive BF duration 1-3 months, ≥4 months versus 0 months (reference group) Total pFA: Exclusive BF 1-3 month = 0.72 (0.42-1.23) Exclusive BF ≥4 months = 0.69 (0.36-1.29)

New pFA: Exclusive BF 1-3 month = 0.78 (0.43-1.38) Exclusive BF ≥4 months = 0.51 (0.24-1.03)

High risk pFA: Exclusive BF 1-3 month = 0.81 (0.42-1.51) Exclusive BF ≥4 months = 0.58 (0.26-1.25)
Adjusted for mother’s education, race, income, child’s gender, parity, type of delivery, family history of food allergy, family history of other atopy, reported eczema before age 1 year, maternal tobacco smoke, other tobacco smoke exposure in home, complementary food introduction by infant age.
SPT. Positive (histamine 10 mg/mL [Stallergenes, Antony, France]) and negative controls and fresh foods or commercial extracts in the case of food items with histamine-releasing properties were used Exclusive BF yes versus no 1.8 (0.9-3.5) Among the 386 evaluated children, food allergy was diagnosed in 69 children, of whom 26 children had a reaction to more than one food item. Duration of exclusive BF was not measured.

Note: exclusive BF was dropped out in the final model.
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Author, Year Study Design, Country Population N Age When Outcome Was Ascertained
Stelmach et al., 2014 Prospective cohort, Poland Children from the Polish Mother and Child Cohort Study (REPRO_ PL cohort) 501 1-2 years

NOTE: BF = breastfed; CI = confidence interval; FFQ = food frequency questionnaire; IgE = immunoglobulin E; OFC = oral food challenge; OR = odds ratio; pFA = probable food allergy; RCT = randomized controlled trial; sIgE = food-specific serum IgE; SPT = skin prick test; UK = United Kingdom; US = United States.

a Bold indicates statistical significance at P<0.05. Results were reported as odds ratio (95% confidence interval) unless otherwise noted. Adjusted results were extracted in the summary table unless otherwise noted.

Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Food Allergy or Sensitization Outcome Definition Exposure Odds Ratioa (95% CI) of Food Allergy Comments
Food allergy ever diagnosed by doctor according to international guidelines Duration of BF (up to 12 months) 0.88 (0.82-0.95) A stepwise forward procedure was then used to select variables.
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×

TABLE C-4a Dual Antigen Hypothesis (Randomized Controlled Trials)

Author, Year Study Design, Country Population N Age When Outcome Was Ascertained
Timing of Introduction of Solid Foods and Infant Feeding
DuToit et al., 2016 RCT, UK (follow-up to primary trial [DuToit et al., 2015]) Children, median age 61.3 months, who had completed the primary trial. Half were in the peanut-avoidance group; the other half were in the peanut-consumption group. 628 72 months
Perkin et al., 2016 RCT, UK Exclusively breastfed infants age 3 months in the general population 1,303 3 years
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Food Allergy or Sensitization Outcome Definition Exposure Odds Ratioa (95% CI) of Food Allergy Comments
DBPCOFC to peanut 12 months of peanut avoidance (peanut-avoidance versus peanut-consumption group based on primary trial) Prevalence of peanut allergy at 72 months:

Peanut-avoidance group: 18.6% Peanut-consumption group: 4.8%

P<0.001
DBPCOFC (peanut, cooked egg, cow milk, sesame, whitefish and wheat) Early Introduction Group (EIG): early introduction of 6, allergenic foods

Or

Standard Introduction Group (SIG): exclusive BF to ~6 months of age. After 6 months, the consumption of allergenic foods was allowed according to parental discretion.
Intention to Treat Analysis
  • Food allergy to ≥1 allergen (EIG versus SIG); RR=0.80 (0.51-1.25)
  • Food allergy to individual allergens: all nonsignificant


Per Protocol analysis
  • Food allergy to ≥1 allergen (EIG versus SIG): RR=0.33 (0.13-0.83)
  • Food allergy to peanut (EIG versus SIG): RR=0
  • Food allergy to egg (EIG versus SIG): RR=0.25 (0.08-0.82)
No significant effects with respect to milk, sesame, fish, or wheat
Low adherence to the protocol in the EIG (42.8%).
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Author, Year Study Design, Country Population N Age When Outcome Was Ascertained
DuToit et al., 2015 RCT, UK Infants, age least 4 months and less than 11 months at enrollment with severe eczema, egg allergy, or both 640 60 months
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Food Allergy or Sensitization Outcome Definition Exposure Odds Ratioa (95% CI) of Food Allergy Comments
Clinical history, SPT, OFC, DBPCOFC, sIgE (peanut)

530 had negative SPT at baseline

98 had positive SPT at baseline
Peanut intake (avoidance versus consumption) Prevalence of peanut allergy at 60 months:

SPT Negative Group
13.7% avoidance group
1.9% consumption group
(P<0.001)

(86.1% relative reduction in the prevalence of peanut allergy)

SPT Positive Group
35.3% avoidance group
10.6% consumption group
(P=0.004)

(70.0% relative reduction in the prevalence of peanut allergy)

No significant between-group difference in the incidence of serious adverse events
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Author, Year Study Design, Country Population N Age When Outcome Was Ascertained
Palmer et al., 2013 RCT, Australia Singleton term infants with symptoms of moderate-to-severe eczema. Infants who had begun solids before 4 months of age or who had any previous known direct ingestion of egg were excluded 86

49 egg group 37 rice group (control)
12 months

NOTE: CI = confidence interval; EIG = Early Introduction Group; IgE = immunoglobulin E; OFC = oral food challenge; SIG = Standard Introduction Group; sIgE = food-specific serum IgE; SPT = skin prick test; UK = United Kingdom; US = United States.

a Bold indicates statistical significance at P<0.05. Results were reported as odds ratio (95% confidence interval) unless otherwise noted. Adjusted results were extracted in the summary table unless otherwise noted.

Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Food Allergy or Sensitization Outcome Definition Exposure Odds Ratioa (95% CI) of Food Allergy Comments
IgE-mediated egg allergy, as defined based on the results of an observed pasteurized raw egg challenge and SPT 1 teaspoon of pasteurized raw whole egg powder versus rice powder (control) daily from 4 to 8 months of age

Cooked egg was introduced to both groups after an observed feed at 8 months
RR: 0.65 (0.38-1.11) At 4 months of age, before any known egg ingestion, 36% (24/67) of infants already had egg-specific IgE levels of greater than 0.35 kilounits of antibody (kUA)/L.

Egg-specific IgG4 levels were significantly (P<0.001) greater in the egg group at both 8 and 12 months.
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×

TABLE C-4b Antigen Exposure Hypothesis (Observational Studies)

Author, Year Study Design, Country Population N Age When Outcome Was Ascertained
Diet Diversity
Grimshaw et al., 2014 Nested case control, UK Infants from the PIFA Study who had been diagnosed as having a food allergy and their 2 age-matched controls 41 cases
82 controls
2 years
Roduit et al., 2014 Prospective cohort, Europe Children from rural areas in five European countries 856 Up to age 6 years

NOTE: CI = confidence interval; DBPCOFC = double-blind, placebo-controlled oral food challenge; sIgE = food-specific serum IgE; SPT = skin prick testing; UK = United Kingdom.

a Bold indicates statistical significance at P<0.05. Results were reported as odds ratio (95% confidence interval) unless otherwise noted. Adjusted results were extracted in the summary table unless otherwise noted.

Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Food Allergy or Sensitization Outcome Definition Exposure Odds Ratioa (95% CI) of Food Allergy Comments
Parent report, physical exam, SPT, sIgE, exclusion diet, DBPCOFC Dietary patterns during first year of life Scores were significantly different between the food allergic and control infants (P=0.002) for component 1 (diet high in fruits and vegetables) Early infant feeding patterns did not have an association with the later development of food allergy. Children who did not have a food allergy by the age of 2 years had a dietary pattern in later infancy characterized by higher intake of fruits, vegetables, and home-prepared foods as compared to children who had a food allergy.

Unadjusted analysis only.
Parent report of doctor diagnosis; sIgE (hen egg, cow milk, peanut, hazelnut, carrot, and wheat flour) Food diversity during first year of life
(1) 0-3 items
(2) 4-5 items
(3) 6 items (ref)
(4) diversity score continuous
(1) 4.43 1.62-12.10
(2) 1.85 1.02-3.35
(3) 1
(4) 0.70
(0.57-0.86)
,
Adjusted for center, farmer, parents with allergy, sex, breastfeeding, siblings, and maternal education.
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×

TABLE C-5 Nutritional Immunomodulation Hypothesis (Observational Studies)

Author, Year Study Design, Country Population N Age When Outcome Was Ascertained
Lipids/Omega-3 Fatty Acids (see systematic reviews below)
Vitamin D
Koplin et al., 2016 Prospective cohort, Australia Infants participating in the HealthNuts study 5,276 1 year
Baek et al., 2014 Cross-sectional, Korea Children with atopic dermatitis or suspected food allergy, who had not been on vitamin supplementation for at least 1 month before the study 226 3-24 months
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Food Allergy or Sensitization Outcome Definition Exposure Odds Ratioa (95% CI) of Food Allergy Comments
SPT, sIgE, OFC Serum 25(OH)D3

≤50 nmol/L = vitamin D insufficiency

51-74 nmol/L = intermediate vitamin D

≥75 nmol/L = high vitamin D
Infants with GG genotype (insufficient versus intermediate): 6.0 (0.9-38.9)

Infants with GT/TT phenotypes (insufficient versus intermediate): 0.7 (0.2-2.0)

Infants with GG genotype (high versus intermediate): 4.0 (1.3-12.9)
Adjusted for infants’ consumption of egg and formula use and parents’ country of birth and used a seasonally adjusted measure of serum 25(OH)D3.
History of acute reaction + sIgE ≥0.35 kU/L or >95% predictive decision points Serum 25(OH)D3

Deficiency: <20ng mL

Insufficiency: 20-29ng/mL

Sufficiency: ≥30ng/mL
Deficient versus sufficient

Food allergens: 5.0 (1.8-14.1)

Milk: 10.4 (3.3-32.7)

Wheat: 4.2 (1.1-15.8)
Vitamin D deficiency increased the risk of sensitization to food allergens, especially to milk and wheat.

The Scoring Atopic Dermatitis index was independently related to 25(OH)D levels after adjusting for the level of sensitization.
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Author, Year Study Design, Country Population N Age When Outcome Was Ascertained
Norizoe et al., 2014 Longitudinal Study, Japan Infants with facial eczema and their mothers 164 3-24 months
Wawro et al., 2014 Cross-sectional, Germany Samples from two German birth cohort studies 2,815 10 years
Allen et al., 2013 Cross-sectional, Australia Infants from HealthNuts population-based cohort 5,276 1 year
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Food Allergy or Sensitization Outcome Definition Exposure Odds Ratioa (95% CI) of Food Allergy Comments
Doctor-diagnosed allergic incidents, including atopic dermatitis, food allergy with or without being positive for IgE food allergens, or wheeze or asthma with or without being positive for IgE inhaled allergens Maternal vitamin D (800 IU/day) supplement RR=3.42 (1.02-11.77) Vitamin D supplementation may not decrease the severity of infantile eczema at 3 months of age, but may rather increase the risk of later food allergy up to 2 years of age.

Unadjusted analysis only.
sIgE >0.35 kU/l Serum 25(OH)D
Q1: <57.9 (nmol/L)
Q2: 57.9- <71.5
Q3: 71.5- <87.8
Q4: ≥87.8
Continuous variable
1
0.91 (0.67-1.25)
1.25 (0.93-1.69)
1.30 (0.97-1.75)
1.07 (1.02-1.11)
Lifetime prevalence also was significantly related to vitamin D status.
OFCs + SPT/sIgE ≥0.35 kU/L Vitamin D ≥50 nmol/L (insufficiency)

(1) All infants
(2) Infants with one or both parents born overseas
(3) Infants with both parents born in Australia
Any food allergy versus none:
(1) 1.29 (0.51-3.25)
(2) 0.39 (0.08-1.76)
(3) 3.08 (1.10-8.59)

Peanut allergy versus none (infants with both parents born in Australia): 11.51 (2.01-65.79)

Egg allergy versus none (infants with both parents born in Australia): 3.79 (1.19-12.08)
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Author, Year Study Design, Country Population N Age When Outcome Was Ascertained
Liu et al., 2013 Prospective longitudinal cohort study, US Children in the Boston Birth cohort 460 0-3 years
Weisse et al., 2013 Prospective longitudinal cohort study, Germany Mother–child pairs from the Lifestyle and environmental factors and their Influence on Newborns Allergy risk (LINA) cohort study 378 First 2 years
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Food Allergy or Sensitization Outcome Definition Exposure Odds Ratioa (95% CI) of Food Allergy Comments
sIgE >0.35 kU/l Vitamin D (ng/ml) cord blood/postnatal
≥11/≥30 (reference)
≥11/<30
<11/≥30
<11/<30
All children:

1

0.73 (0.42-1.29)
0.90 (0.54-1.51)
2.03 (1.02-4.04)

Children with C allele of rs2243250:
1
0.52 (0.23–1.18)
1.26 (0.65–2.43)
3.23 (1.37-7.60)
There was no association between low vitamin D status and food sensitization at any single time point alone.

Adjusted for a child’s sex and ancestry proportion, breastfeeding, postnatal maternal smoking, household income, and maternal age.
Parental report of a doctor diagnosis. tIgE levels >0.7 kU/l in cord blood and >3.8 kU/l at age of 1 or 2 yrs, or sIgE >0.35 kU/l Maternal vitamin D Median = 22.2 ng/ml (55.41 nmol/ml)

Cord blood vitamin D Median = 10.95 ng/ml (27.33 nmol/ml)
1st year of life: 1.27 (0.67–2.40)

2nd year of life: 3.66 (1.36–9.87)

2-year lifetime period: 1.91 (1.09–3.37)

1st year of life: 0.92 (0.45–1.85)

2nd year of life: 4.65 (1.50–14.48)

2-year lifetime period: 1.70 (0.92-3.14)
Adjusted for sex, number of siblings, increased cord blood tIgE levels, family atopy history, cotinine levels during pregnancy, breastfeeding, UV intensity at birth and vitamin D supplementation within the first year of life.
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Author, Year Study Design, Country Population N Age When Outcome Was Ascertained
Jones et al., 2012 Prospective longitudinal cohort study, Australia High-risk infants 231 12 months
Liu et al., 2011 Prospective longitudinal birth cohort, US Mother-infant pairs in the Boston Birth Cohort 649 children Around 2 years
Lipids/Omega-3 Fatty Acids (see systematic reviews below)
Folate
Okupa et al., 2013 Cohort study, US Children at high risk of developing asthma and allergic disease 138 2, 4, 6, and 8 years
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Food Allergy or Sensitization Outcome Definition Exposure Odds Ratioa (95% CI) of Food Allergy Comments
SPT History of immediate symptoms + SPT Cord blood vitamin D

<50 nmol/L versus ≥75 nmol/L (reference)
Risk of allergen sensitization: 1.0 (0.9-1.01)

Risk of developing IgE-mediated food allergy: 1.00 (0.99-1.02)
Adjusted for season of birth, pets in the home, infant sex, maternal age, maternal education, and ethnicity.
sIgE (milk, egg white, peanut, soy, shrimp, walnut, cod fish, and wheat) Cord blood plasma total 25(OH)D concentrations (<11 ng/ml = deficiency) Vitamin D deficient versus not deficient (reference)

Any food sensitization: 1.16 (0.83-1.63)

Egg sensitization: 0.84 (0.56-1.27)

Milk sensitization: 1.15 (0.76-1.73)

Peanut sensitization: 1.06 (0.64-1.75)
Allergic sensitization (sIgE to milk/egg/peanut for years 1 to 3 and egg/peanut for years 5+) Plasma folate levels High versus low folate levels at or before age 6 years): 8% versus 26% (P=0.02) Unadjusted analysis only.
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Author, Year Study Design, Country Population N Age When Outcome Was Ascertained
Dunstan et al., 2012 Prospective cohort, Australia Pregnant women (healthy nonsmokers with uncomplicated term pregnancies) 628 women

484 infants
12 months
Magdelijns et al., 2011 Prospective birth cohort, the Netherlands Children in the KOALA birth cohort 2,834 2 years
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Food Allergy or Sensitization Outcome Definition Exposure Odds Ratioa (95% CI) of Food Allergy Comments
IgE-mediated food allergy was defined as a history of immediate symptoms following contact and/or ingestion and a positive SPT to the implicated food

Allergic sensitization (milk, peanut, whole egg) was assessed by SPT at 1 year of age
Tertiles of maternal folate intake from supplements (FFQ during 3rd trimester)

(1) <200 mg/day
(2) 200-499 mg/day
(3) >500 mg/day

Tertiles of cord blood folate at delivery

(1) <50.3 nmol/l
(2) 50.3-75.1 nmol/l
(3) >75.1 nmol/l
Folate intake:

IgE-mediated food allergy
(1) reference group
(2) 1.4 (0.7-3.0)
(3) 1.1 (0.5-2.4)

Sensitized to food allergens
(1) reference group
(2) 1.3 (0.7-2.3)
(3) 1.1 (0.6-2.0)

Cord blood folate:

IgE-mediated food allergy
(1) 1.7 (0.5-5.6)
(2) reference group
(3) 2.6 (0.9-8.1)

Sensitized to food allergens
(1) 2.2 (0.9-5.6)
(2) reference group
(3) 1.1 (0.5-2.4)

All ORs adjusted for maternal allergy and infant postnatal diet
Also looked at maternal intake of folate from food, but found no differences in the maternal dietary folate intakes of infants with any allergic outcomes.

Because of the focus on allergy in the primary study, sensitized allergic mothers were over represented (70.6%).

All ORs adjusted for maternal allergy and infant postnatal diet.
sIgE (hen egg, cow milk, peanut, and aeroallergens) Folic acid supplement use during pregnancy (measured as quintiles of intracellular folate status during 3rd trimester) Folic acid supplement use versus no use (reference)

Increased sIgE: 1.06 (0.67-1.68)
Allergic sensitization was to both food allergens and aeroallergens.
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Author, Year Study Design, Country Population N Age When Outcome Was Ascertained
Other Nutrient Intakes
West et al., 2012 Prospective cohort, Australia Pregnancy cohort with a family history of allergic rhinitis, asthma, eczema, food or other allergy 300 mother–infant pairs 12 months

NOTE: CI = confidence interval; FFQ = food frequency questionnaire; IgE = immunoglobulin E; OFC = oral food challenge; OR = odds ratio; RCT = randomized controlled trial; RR = relative risk; sIgE = food-specific serum IgE; SPT = skin prick test; tIgE = total IgE; UK = United Kingdom; US = United States; UV = ultraviolet.

a Bold indicates statistical significance at P<0.05. Results were reported as odds ratio (95% confidence interval) unless otherwise noted. Adjusted results were extracted in the summary table unless otherwise noted.

Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Food Allergy or Sensitization Outcome Definition Exposure Odds Ratioa (95% CI) of Food Allergy Comments
IgE-mediated food allergy was defined as a history of immediate symptoms after contact with and/or ingestion and a positive SPT at 12 months (milk, egg, peanut) Quartiles of daily maternal dietary and total intakes during pregnancy
(1) b-carotene
(2) vitamin C
(3) vitamin E
(4) copper
(5) zinc

Quartiles
Q1 lowest (reference)
Q2
Q3
Q4 highest

Measured by semiquantitative FFQ administered after 28 weels gestation
(1) b-carotene
0.40 (0.12-1.32)
1.16 (0.43-3.11)
0.38 (0.11-1.27)
Ptrend=0.2

(2) Vitamin C
 0.22 (0.06-0.78)
0.75 (0.27-2.06)
0.46 (0.16-1.36)
Ptrend=0.1

(3) Vitamin E
0.96 (0.32-2.84)
0.86 (0.29-2.54)
0.57 (0.19-1.72)
Ptrend=0.8

(4) copper
0.60 (0.22-1.60)
0.40 (0.13-1.22)
0.38 (0.11-0.95)
Ptrend=0.2

(5) zinc
0.67 (0.22-2.03)
1.28 (0.46-3.53)
0.52 (0.16-1.73)
Ptrend=0.4
Adjusted for maternal education, paternal history of allergic disease, birth weight, and exposure to furred pets at home; all were included in the multiple logistic regression model.
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×

TABLE C-6 Systematic Review Summaries

Author, year Best et al., 2016
Aims/Key questions To develop a clearer understanding of the effect to the developing fetus, before commencement of the progression of atopy (“atopic march”) and establishment of allergic disease symptoms.
Study eligibility criteria Inclusion criteria:
  • Study design: prospective studies, including longitudinal observational studies and RCTs and quasi-randomized trial.
  • Exposure: maternal fish or n-3 LCPUFA intake during pregnancy.
  • Intervention and comparator: intervention modifying maternal n-3 LCPUFA intake during pregnancy with a parallel control group or placebo.
  • Outcome measures: Incidence of atopic disease (i.e., IgE-mediated allergic disease) or sensitization in the offspring during infancy, childhood, or adolescence. The presence of IgE-mediated allergic disease is defined as a clinician diagnosis, parent report of symptoms of allergic disease, or parent report of a physician’s diagnosis. Sensitization is defined as a positive SPT or IgE serology indicating sensitization.
Exclusion criteria:
  • Animal studies, cross-sectional studies, and retrospective and case-control studies.
  • Studies of maternal n-3 LCPUFA consumption or supplementation in the postnatal period only (breastfeeding or direct supplementation of the infant).
  • Studies that reported immune biomarkers by laboratory assessment in the absence of evaluation of symptoms or clinical diagnosis of allergic disease in the offspring.
Literature search dates or year range Inception to July 30, 2015
Number of food allergy studies included 3 RCTs (based on SPT)
Synthesis methods Summary tables and meta-analysis
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Key findings Three RCTs with sensitization outcomes at age 12 months were combined in meta-analysis. Definitions of sensitization were inconsistent. Overall risk of bias of the three RCTs was low to moderate. One RCT was rated high risk of bias for incomplete outcome data reporting and one was rated high risk of bias for selective reporting.
  • Fixed effect meta-analysis showed a significant reduction in “sensitization to egg” at 0-12 months (pooled RR: 0.55; 95% CI: 0.39-0.76; P=0.0004)
  • Fixed effect meta-analysis showed a significant reduction in “sensitization to any food” at 12 months (pooled RR: 0.59; 95% CI: 0.46-0.76; P<0.0001)
Limitations
  • This systematic review did not focus on food allergy.
  • Fixed effect meta-analysis ignores clinical heterogeneity (e.g., different doses of n-3 fatty acids) and produced more significant results.
Note: Discordant results with Klemens et al. (2011) meta-analysis. Overlaps in two RCTs. Best et al. (2016) did not include one study that was included in Klemens et al. (2011). Klemens et al. (2011) performed random-effects meta-analysis while Best et al. (2016) performed fixed-effects meta-analysis.
AMSTAR rating
An a priori design? Y
Duplicate study selection and data extraction? N
Comprehensive literature search? Y
Status of the publication as an inclusion criterion? Y
List of studies (included and excluded) provided? Y
Characteristics of included provided? Y
Scientific quality of the included studies assessed and reported? Y
Scientific quality used in formulating conclusions? Y
Methods used to combine the findings appropriate? N
Likelihood of publication bias assessed? Y (the authors noted that the risk of publication bias cannot be excluded because only published studies were included in meta-analysis)
Conflict of interest (COI) stated? Y/N (COI of the systematic review authors was provided but not provided for included studies)
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Author, year Boyle et al., 2016
Aims/Key questions To determine whether feeding infants with hydrolyzed formula reduces their risk of allergic or autoimmune disease.
Study eligibility criteria Interventions and comparators:
  • Inclusions: Any hydrolyzed formula of cow milk origin compared with any nonhydrolyzed cow milk formula, human milk, or another type of hydrolyzed cow milk formula. Also included were studies in which hydrolyzed formula was given as part of a multifaceted intervention, which the authors defined as an intervention with at least two other components in addition to the hydrolyzed formula—for example, exclusion of allergenic food from the mother’s diet, promotion of breastfeeding, delayed introduction of solid food, or measures to avoid exposure to house dust mite. Studies in which other interventions were applied to both intervention and control groups, such as exclusion of cows’ milk from the mother’s diet during lactation also were included.
  • Exclusions: Studies of hydrolyzed formula of milk other than cow milk, such as hydrolyzed rice, goat milk, or soy formula.
Study designs of interest: All intervention trials. Populations of interest:
  • Inclusions: Studies of infant feeding between birth and age 12 months.
  • Exclusions: Studies in which infants or their mothers were defined by the presence of a pre-existing disease state, including very low birth weight or premature infants.
Outcomes of interest:
  • Atopic outcomes included were asthma (categorized as wheeze, recurrent wheeze, atopic wheeze, bronchial hyper-reactivity, forced vital capacity, peak expiratory flow rate, forced expiratory volume in 1 second), eczema, allergic rhinitis and/or conjunctivitis, food allergy, allergic sensitization (that is, SPT or sIgE assessment, or tIgE level).
  • Autoimmune outcomes included were type 1 diabetes mellitus (defined serologically and/or clinically), celiac disease (defined serologically and/or clinically), inflammatory bowel disease, autoimmune thyroid disease, juvenile rheumatoid arthritis, vitiligo, or psoriasis.
Literature search dates or year range The Cochrane Library (2013, issue 7), EMBASE (1947 to July 2013), LILACS (1982 to July 2013), Medline (1946 to July 2013), and Web of Science (1970 to July 2013). Searches run on July 25, 2013, and rerun on April 17, 2015.
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Number of food allergy studies included 13
Synthesis methods Narrative text and meta-analysis
Key findings There was no significant difference in risk of “any food allergy” with partially (pooled RR: 1.73; 95% CI: 0.79-; I2=42%) or extensively (pooled RR 0.86; 95% CI: 0.26-2.82; I2=42%) hydrolyzed formula compared with standard formula at age 0-4 years, nor for extensively hydrolyzed formula at age 5-14 years. [Note that number of studies included in each meta-analysis was not reported in text.] No difference was found in food allergy to cow milk, egg, or (partially hydrolyzed formula only) peanut. Direct comparison of the two formulas (egg allergy) and casein versus whey dominant extensively hydrolyzed formula showed no significant difference in risk of food allergy. [Note: no other details reported in text.] There was no significant difference in risk of allergic sensitization to cow milk with partially (pooled RR: 1.30; 95% CI: 0.65-2.60; I2=0%; seven studies) or extensively (pooled RR: 0.77; 95% CI: 0.09-6.73; I2=77%; three studies) hydrolyzed formula, and no significant difference between groups for risk of allergic sensitization to “any allergen” or raised total IgE level. The strength of evidence was graded as moderate for partially hydrolyzed formula, and as very low for exclusively hydrolyzed formula.
Limitations Many studies of allergic outcomes included in this review had unclear or high risk of bias and evidence of conflict of interest, often because of inadequate methods of randomization and treatment allocation (selection bias) and support of the study or investigators from manufacturers of hydrolyzed formula. In many cases study participants were infants with early full formula feeding, so findings might not be applicable to populations with more typical feeding patterns.
AMSTAR rating
An a priori design? Y
Duplicate study selection and data extraction? Y
Comprehensive literature search? Y – Appendix 1
Status of the publication as an inclusion criterion? Y
List of studies (included and excluded) provided? Partially – List of excluded studies was not reported
Characteristics of included provided? Y – Characteristics of included studies are summarized in tables A and B in appendix 3.
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Scientific quality of the included studies assessed and reported? Y
Scientific quality used in formulating conclusions? Y – GRADE approach
Methods used to combine the findings appropriate? Y
Likelihood of publication bias assessed? Y
Conflict of interest stated? Y
Author, year Cuello-Carcia et al., 2016
Aims/Key questions To provide evidence-based recommendations about the use of prebiotic supplements for the primary prevention of allergies.
Study eligibility criteria According to the evidence profiles table, the study eligibility criteria can be assumed to be:
  • Population: healthy infants
  • Intervention: prebiotic supplementation
  • Comparison: no prebiotic supplementation
  • Main outcomes: development of allergy, nutritional status, adverse effects
  • Setting: outpatient
Literature search dates or year range Up to January 2015, with an update on July 29, 2015
Number of food allergy studies included 1
Synthesis methods GRADE approach
Key findings Outcome Without prebiotics (per 1,000) With prebiotics (per 1,000) Difference (95% CI) (per 1,000) Relative effect (95% CI) Certainty of the evidence (GRADE)
Food allergy 170 48 (14 to 170) 122 fewer (0 to 156 fewer) RR 0.28 (0.08 to 1.00) VERY LOW
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Conclusions and research needs The guideline panel determined that there is a low certainty of a net benefit from using prebiotics in infants. Based on the body of available evidence, it is likely that prebiotic supplementation in infants reduces the risk of developing recurrent wheezing and possibly also the development of food allergy. There is very low certainty prebiotics have an effect on other outcomes. However, because of low certainty of evidence or no published information about other outcomes, the fact that the authors did not find evidence of an effect on these outcomes does not imply that such an effect does not exist.
Limitations This publication is a guideline paper. Although the guideline appears to be based on a systematic review, the methods of systematic review were not fully reported in this publication. No other source or citation to the systematic review was found.
AMSTAR rating
An a priori design? Yes
Duplicate study selection and data extraction? Not reported
Comprehensive literature search? Yes
Status of the publication as an inclusion criterion? Not reported
List of studies (included and excluded) provided? Partially – Excluded studies were not reported
Characteristics of included provided? Yes
Scientific quality of the included studies assessed and reported? Yes
Scientific quality used in formulating conclusions? Yes
Methods used to combine the findings appropriate? Yes
Likelihood of publication bias assessed? No
Conflict of interest stated? Yes
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Author, year Newberry et al., 2016
Aims/Key questions To update a prior systematic review on the effects of omega-3 fatty acids (n-3 fatty acids) on maternal and child health and to assess the evidence for their effects on, and associations with, additional outcomes.
Key Question 2: Fetal/childhood exposures – What is the influence of maternal intakes of n-3 fatty acids or the n-3 fatty acid content of maternal breast milk (with or without knowledge of maternal intake of n-3 fatty acids) or n-3 fatty acid-supplemented infant formula or intakes of n-3 fatty acids from sources other than maternal breast milk or supplemented infant formula on the following outcomes in term or preterm human infants?
  • Growth patterns
  • Neurological development
  • Visual function
  • Cognitive development
  • Autism
  • Learning disorders
  • ADHD
  • Atopic dermatitis
  • Allergies (Note: including food allergies)
  • Respiratory illness
Study eligibility criteria Populations of interest:
  • Healthy preterm or term infants of healthy women/mothers whose n-3 fatty acid exposures were monitored during pregnancy.
  • Breastfed infants of healthy mothers whose n-3 fatty acid exposure was monitored and/or who participated in an n-3 fatty acid intervention during breastfeeding beginning at birth.
  • Healthy preterm or term infants with and without family history of respiratory conditions (for outcomes related to atopic dermatitis, allergy, respiratory conditions) of mothers whose n-3 exposures were monitored during pregnancy and/or breastfeeding.
  • Healthy children or children with a family history of a respiratory disorder, a cognitive or visual development disorder, autism spectrum disorder, ADHD, or learning disabilities, age 0 to 18 years who participated in an n-3 fatty acid-supplemented infant formula intervention or an n-3 supplementation trial during infancy.
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Interventions of interest:
  • N-3 fatty acid supplements (e.g., EPA, DHA, ALA, singly or in combination);
  • N-3 fatty acid supplemented foods (e.g., eggs) with quantified n-3 fatty acid content
  • High-dose pharmaceutical grade n-3 fatty acids, e.g., Omacor®, Ropufa®, MaxEPA®, Efamed, Res-Q®, Epagis, Almarin, Coromega, Lovaza®, Vascepa® (icosapent ethyl)
    • Exclude doses of more than 6g/d, except for trials that report adverse events
  • N-3 fatty acid fortified infant formulae
    • E.g., Enfamil® Lipil®; Gerber® Good Start DHA & ARA®; Similac® Advance®
    • N-3 fatty acid fortified follow-up formula
    • Exclude parenterally administered sources
  • Marine oils, including fish oil, cod liver oil, menhaden oil, and algal with quantified n-3 fatty acid content
  • Algal or other marine sources (e.g., phytoplankton) of omega-3 fatty acids with quantified n-3 content
Exposures of interest:
  • Dietary n-3 fatty acids from foods if concentrations are quantified in food frequency questionnaires
  • Breast milk n-3 fatty acids (KQ2)
  • Biomarkers (EPA, DHA, ALA, DPA, SDA), including but not limited to the following:
    • Plasma fatty acids
    • Erythrocyte fatty acids
    • Adipocyte fatty acids
Comparators of interest:
  • Inactive comparators:
    • Placebo
    • Nonfortified infant formula
  • Active comparators:
    • Different n-3 sources
    • Different n-3 concentrations
    • Alternative n-3 fortified infant formula
    • Soy-based infant formula
    • Diet with different level of Vitamin E exposure
Outcomes of interest:
  • Risk for allergies. Validated allergy assessment procedures, preferably challenge (SPT or validated blood tests accepted)
Timing of interest:
  • Interventions implemented within 1 month of birth or exposures measured within 1 month of birth
  • Follow-up duration is 0 to 18 years
Literature search dates or year range Update searches were from the year 2000. For the newly added topics (e.g., allergies), the authors “reference mined” articles that they identified to determine whether any studies conducted and published before 2000 should be obtained and included.
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Number of food allergy studies included 3 RCTs
Synthesis methods Narrative text and meta-analysis
Key findings All three RCTs recruited pregnant women whose infants were at high risk of atopy (e.g., parent diagnosis of allergy, or sibling has diagnosed or suspected allergy).
  • Among the three prenatal n-3 interventions and two follow-up studies, three found associations between maternal n-3 fatty acid supplementation (DHA + EPA, varying doses ranging from 0.8 to 3.09 g/d) and lower risk of allergies (denoted by sensitization to egg allergen and positive skin prick test). However, in all but one study, these relationships were no longer observed or became marginal after adjusting for potential confounders or after long-term follow-up.
  • Meta-analysis of three RCTs (N=949) with 12-month food allergy outcomes yielded an insignificant summary effect size for DHA+EPA supplementation and risk of food allergy (OR: 0.54; 95% CI 0.05-6.2; I2=42.3%).
  • Note that the strength of evidence was graded as low for the conclusion of no significant effect of DHA or DHA+EPA supplementation during pregnancy on food allergies.
Limitations
  • The risk for allergies is an additional outcome of interest that was not included in the original review.
  • The search strategy was not designed specifically for food allergies outcomes.
AMSTAR rating
An a priori design? Y
Duplicate study selection and data extraction? Y
Comprehensive literature search? Y/N (The search strategy was not designed to specifically for food allergies outcomes because “food allergies” were not one of the pre-specified outcomes of interest)
Status of the publication as an inclusion criterion? Y
List of studies (included and excluded) provided? Y
Characteristics of included provided? Y
Scientific quality of the included studies assessed and reported? Y
Scientific quality used in formulating conclusions? Y
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Methods used to combine the findings appropriate? Y
Likelihood of publication bias assessed? N (only published studies were included)
Conflict of interest stated? Y
Author, year Cuello-Carcia et al., 2015
Aims/Key questions To synthesize the evidence supporting use of probiotics to prevent allergies and inform World Allergy Organization guidelines on probiotic use. Three key questions of this systematic review are:
  1. Should supplementation of probiotics versus no such supplementation be used in pregnant women to prevent development of allergy in their children?
  2. Should supplementation of probiotics versus no such supplementation be used in breastfeeding mothers to prevent development of allergy in their children?
  3. Should supplementation of probiotics versus no such supplementation be used in infants to prevent development of allergy?
Study eligibility criteria
  • Types of studies: RCTs with a minimum follow-up of 4 weeks that compared any type of probiotic with placebo, irrespective of their language or publication status.
  • Types of participants: Pregnant women, breastfeeding mothers, and infants and children (up to age 9 years).
  • Types of interventions: Any probiotic supplementation, irrespective of formulation (capsules, oil droplets, suspension, and supplements in infant formulas or cereals), microorganism, supplement composition (single versus multiple strains), or dose.
  • Types of outcome measures: The World Allergy Organization guideline panel members in a formal process determined the outcomes of interest. The following outcomes were deemed critical to the decision whether to use probiotics to prevent allergies: eczema, asthma and/or wheezing, food allergy, allergic rhinitis, any adverse effects, and severe adverse effects.
Literature search dates or year range From inception to December 2014
Number of food allergy studies included 6 RCTs [Note: some RCTs contributed data for more than one meta-analysis.]
Synthesis methods Narrative text, meta-analysis, and GRADE
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Key findings
  • No RCTs for the comparison of probiotics versus no probiotics in pregnant women for prevention of allergy in their children (direct evidence).
  • No RCTs for the comparison of probiotics versus no probiotics in breastfeeding women for prevention of allergy in their children (direct evidence)
Outcomes No. of participants (studies) Strengtd of evidence (GRADE) Relative effect, RR (95% CI) Anticipated absolute effects
Risk witd no probiotics Risk difference with probiotics
Probiotics versus no probiotics in pregnant women for prevention of allergy in their children (indirect evidence)
Food allergy, follow-up: range, 12-24 months 355 (3 RCTs) •ooo Very low 1.08 (0.73-1.59) Study popuation
Note: 1.49 (0.58, 3.81) in the forest plot 39 per 1,000 3 more per 1,000 (11 fewer to 23 more)
Probiotics compared with no probiotics in breastfeeding women to prevent allergies in their children (indirect)
Food allergy, follow-up: range, 12-24 months 167 (2 RCTs) •ooo Very low 1.7 (0.58-4.96) Study population
59 per 1,000 41 more per 1,000 (25 fewer to 233 more)
Probiotics compared with no probiotics in infants to prevent allergies (direct)
Food allergy, follow-up: range, 6-24 months 349 (3 RCTs) •ooo Very low 0.88 (0.55-1.43) Study population
167 per 1,000 20 fewer per 1,000 (75 fewer to 72 more)
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Outcomes No. of participants (studies) Strengtd of evidence (GRADE) Relative effect, RR (95% CI) Anticipated absolute effects
Risk witd no probiotics Risk difference with probiotics
Probiotics compared with no probiotics in infants to prevent allergies (indirect)
Food allergy, follow-up: range, 6-24 months 295 (2 RCTs) •ooo Very low 1 (0.25-3.91) Study population
27 per 1,000 0 fewer per 1,000 (20 fewer to 79 more)
Limitations
  • There were moderate-to-serious concerns about the risk of bias in most studies.
  • Some inconsistency in reporting of the meta-analysis results.
  • Confidence that one would observe effects in real life is low to very low (low to very low certainty in the evidence). This is a result of the relative paucity of direct evidence in any of the three groups in whom probiotics could be used, the high likelihood of bias in primary studies, and the serious imprecision of the estimated pooled effects.
AMSTAR rating
An a priori design? Y
Duplicate study selection and data extraction? Y
Comprehensive literature search? Y
Status of the publication as an inclusion criterion? Y
List of studies (included and excluded) provided? Y
Characteristics of included provided? Y – Table E3 and online repository
Scientific quality of the included studies assessed and reported? Y
Scientific quality used in formulating conclusions? Y
Methods used to combine the findings appropriate? Y
Likelihood of publication bias assessed? N
Conflict of interest stated? Y
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Author, year Gunaratne et al., 2015
Aims/Key questions To assess the effect of n-3 LCPUFA supplementation in pregnant and/or breastfeeding women on allergy outcomes (food allergy, atopic dermatitis [eczema], allergic rhinitis [hay fever] and asthma/wheeze) in their children.
Study eligibility criteria Inclusion criteria:
  • Types of studies: RCTs focusing on n-3 LCPUFA supplementation of pregnant and/or breasfeeding women (compared with placebo or no treatment) and assessed allergy outcomes of the infants or children. Quasi-RCTs and RCTs using a cluster-randomized design were eligible for inclusion but none were identified.
  • Types of participants: Women and their children, with either a normal or high risk of developing allergic disease, were included. A fetus or a child with a first degree relative with medically diagnosed allergies, or a positive SPT, or a positive RAST was defined as being at high risk of allergies. Infants were also considered at high risk of allergies if their cord blood IgE level was above 0.70 IU/mL.
  • Types of interventions: All randomized comparisons of n-3 LCPUFA supplementation given to pregnant or lactating women (either with or without arachidonic acid), with placebo or no supplementation as a control, regardless of dose regimens and duration of intervention. Trials in which fish was the intervention were included if appropriately controlled, for example, if the diet was appropriately adjusted to match the protein contribution of fish.
  • Primary outcomes:
    • Medically diagnosed any allergy with sensitization, i.e., IgE-mediated allergies where both the signs and symptoms of the allergic disease and a positive SPT and/or RAST test are present.
    • Medical diagnosis or parental report (using validated questionnaire) of any allergy, +/– IgE sensitization.
  • Secondary outcomes: Children with specific forms of allergy, including food allergy, atopic dermatitis (eczema), asthma/wheeze, allergic rhinitis (hay fever) with IgE sensitization and +/– IgE sensitization, SPT results, and parent-reported allergies using non-validated questionnaires.
Exclusion criteria:
  • Types of studies: Trials published in abstract form only, trials using a crossover design, and trials examining biochemical outcomes only.
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Literature search dates or year range Inception to August 2014
Number of food allergy studies included Five
Synthesis methods Narrative text and meta-analysis
Key findings Three of the five trials had high risk of bias for incomplete outcome data (attrition bias) and/or selective reporting bias.
  • N-3 LCPUFA supplementation reduced the incidence of IgE-mediated food allergies in children up to 12 months of age (117 infants, RR: 0.13; 95% CI: 0.02-0.95), but there were no clear differences found between the intervention and control groups at any other age (12 to 36 months, 825 children, average RR: 0.58; 95% CI: 0.18-1.88; >36 months, 706 children, RR: 1.43; 95% CI: 0.63-3.26).
  • When food allergies +/– IgE sensitivity were considered, results showed few differences from those for IgE-mediated allergies with no differences in the direction of findings from those for IgE-mediated allergies:
    • Up to 12 months of age, 117 infants, RR: 0.13; 95% CI: 0.02-0.95.
    • Between 12 and 36 months, random-effects meta-analysis of four trials (973 children) showed pooled RR: 0.72; 95% CI: 0.40-1.30.
    • >36 months of age, 706 children, RR: 1.43; 95% CI: 0.63-3.26.
Limitations
  • Review authors MM and CTC were investigators on two trials included in the review.
  • Studies included in this review used differing doses, DHA to EPA ratios, and duration of n-3 LCPUFA supplementation, and did not take into account the baseline n-3 LCPUFA status of the women.
AMSTAR rating
An a priori design? Y
Duplicate study selection and data extraction? Y
Comprehensive literature search? Y
Status of the publication as an inclusion criterion? Y
List of studies (included and excluded) provided? Y
Characteristics of included provided? Y
Scientific quality of the included studies assessed and reported? Y
Scientific quality used in formulating conclusions? Y
Methods used to combine the findings appropriate? Y
Likelihood of publication bias assessed? Y
Conflict of interest stated? Y
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Author, year de Silva et al., 2014
Aims/Key questions This systematic review is one of the series of systematic reviews for developing EAACI Guidelines for Food Allergy and Anaphylaxis. This systematic review examined ways to prevent the development of food allergy in children and adults.
Study eligibility criteria
  • This review focused solely on studies that were primarily concerned with preventing sensitization to food(s) and/or the development of food allergy. Studies seeking to prevent potential manifestations of food allergy, such as atopic dermatitis (eczema) or asthma, but not including an explicit diagnosis of sensitization to food or food allergy, were not included.
  • Systematic reviews and meta-analyses, RCTs, quasi-RCTs, controlled clinical trials, controlled before-and-after studies, interrupted time series studies, and prospective cohort studies were eligible.
  • No language restrictions were applied and, where possible, relevant studies in languages other than English were translated.
Literature search dates or year range The following databases were searched: Cochrane Library, MEDLINE, Embase, CINAHL, ISI Web of Science, TRIP Database, and Clinicaltrials.gov from inception to September 30, 2012
Number of food allergy studies included 74
Synthesis methods Narrative synthesis and summary tables
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Key findings Table 1 summarized key evidence about prevention strategies:
  • Overall, the evidence is not strong enough to recommend changing the diet or supplements of pregnant or breastfeeding women at normal or high risk. Although breastfeeding may have many other benefits, the evidence in relation to the prevention of food allergy is not strong. This, to a large extent, reflects the ethical challenges of randomizing infants to a nonbreastfeeding arm.
  • There is more evidence about the benefits of alternatives to cow milk formula for babies at high risk. Extensively hydrolyzed whey or casein formula and partially hydrolyzed formula may have a protective effect, but it appears that soy formula does not protect against food allergies.
  • Probiotics do not seem to be protective in infants at high or normal risk, and neither does delaying the introduction of solid foods until later than the recommended minimum weaning age. Combining dietary with environmental modifications during infancy may be the best way forward for infants at high risk.
Limitations
  • The studies included were heterogeneous, and as a result, it was not appropriate to quantitatively synthesize this evidence.
  • There are also limitations with the studies themselves. To date, the focus of research has largely been on preventing IgE-mediated food allergy rather than on non-IgE-mediated food allergy. Many studies are small, short term, and focus on the surrogate measure of food sensitization rather than food allergy. Sensitization may be a normal, harmless, and transitory phenomenon, which does not necessarily correlate with allergic disease.
AMSTAR rating
An a priori design? Y
Duplicate study selection and data extraction? Y
Comprehensive literature search? Y (protocol published elsewhere)
Status of the publication as an inclusion criterion? Y (protocol published elsewhere)
List of studies (included and excluded) provided? Y
Characteristics of included provided? Y
Scientific quality of the included studies assessed and reported? Y
Scientific quality used in formulating conclusions? Y
Methods used to combine the findings appropriate? Y
Likelihood of publication bias assessed? N
Conflict of interest stated? Y
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Author, year Kong et al., 2014
Aims/Key questions To investigate the preventive effect of probiotics on pediatric food allergy.
Study eligibility criteria
  • Study design of interest: RCTs with any sample size.
  • Population of interest: Infants and their mothers whose first-degree relatives have a history of allergic disease (asthma, allergic nose inflammation, allergic conjunctivitis, allergic eczema, food allergies, etc.).
  • Interventions of interest: Probiotics may be of single or multiple mixed bacteria type with any treatment course and dose.
  • Outcome of interest: Incidence of food allergy diseases.
Literature search dates or year range Last search conducted September 30, 2013
Number of food allergy studies included 10
Synthesis methods Meta-analysis
Key findings
  • Total 1,349 subjects in the probiotics groups and 1,352 subjects in the control groups. Individual study sample size ranged from 60 to 888.
  • Fixed-effects meta-analysis of 10 RCTs showed no significant difference in the incidence of food allergies (pooled RR: 0.88; 95% CI: 0.76-1.03) with moderate heterogeneity (I2=33%) comparing prenatal and postnatal probiotics supplementation with placebo or control.
Limitations
  • Major sources of heterogeneity include: follow-up durations (ranging from 1 to 7 years); flora types of probiotic bacteria; dose and concentration of probiotics.
  • Individual study characteristics were not reported, overall risk of bias (or quality) for the included 10 RCTs was moderate, and some methodological concerns regarding the systematic review (see AMSTAR rating below).
  • Food allergy outcome definitions were not reported.
AMSTAR rating
An a priori design? Y
Duplicate study selection and data extraction? Y
Comprehensive literature search? N – Only one database used
Status of the publication as an inclusion criterion? N
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
List of studies (included and excluded) provided? N – Excluded studies not provided
Characteristics of included provided? N
Scientific quality of the included studies assessed and reported? Y
Scientific quality used in formulating conclusions? Y
Methods used to combine the findings appropriate? Y
Likelihood of publication bias assessed? Y
Conflict of interest stated? N – COI not provided for either the review of the included studies
Author, year Marrs et al., 2013
Aims/Key Questions To systematically review the evidence on the associations between microbial exposure and food allergies.
Study eligibility criteria Inclusion criteria:
  • Food allergy outcomes included food challenge data, physician-diagnosed food allergy, reported doctor diagnosis of food allergy or food sensitization diagnosed by either SPT or elevated sIgE levels.
  • Using a study design appropriate to assess impact of microbial exposure. [Note: not explicitly defined.]
Exclusion criteria:
  • Management guidance documents, reviews and studies investigating celiac disease, food intolerance and animal models were excluded.
Literature search dates or year range Medline from inception to July 2012
Number of food allergy studies included 46
Synthesis methods
  • Summary tables.
  • Qualitative synthesis using a pragmatic score (quality grading/rating scores) developed for this study. Publications were awarded greater weight of evidence if they used food challenge data rather than reported doctor diagnosis or only sensitization data (challenge-proven food allergy +2; [reported] physician-diagnosis +1, SPT or IgE measurement sensitization +0).
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Key findings
  • Mode of delivery: All 13 studies reported that being born by caesarean was associated with an increased risk of developing food allergy or food sensitization, except the study of lowest quality. Six of these associations were significant. However, only two pertained to clinical food allergy diagnoses. The overall quality of these 13 studies was moderate (2 studies received a quality score of 4, 4 received a score of 3, 5 received a score of 2, and 2 received a score of 1).
  • Farming lifestyle and animal exposure: Of four studies investigating farm and animal exposure on food allergy, the Healthnuts Study found significantly less challenge-proven egg, sesame and peanut allergy among infants living with a dog during the first year of life (aOR: 0.6 [0.5-0.8]). However the quality of this study was poor (score of 2).
  • Endotoxin exposure: Two studies were included but the quality was very poor (score of 0 and 1).
  • Childhood infections: No studies investigated the association between viral and bacterial infections and challenge-proven food allergy.
  • Childhood vaccinations: No association was found for any of the recommended childhood vaccinations.
  • Antibiotic use: Some evidence suggests that antibiotic exposure increases the risk of eczema, but no such relationship has been found for food allergy.
  • Gut microbiota: Five studies investigated gut microbiota characteristics, two of which compared data with respect to food challenge outcomes and the other three used food sensitization parameters. The two studies ranking highest in quality originated from the same Spanish infants who were diagnosed with IgE-mediated cow milk allergy by milk challenge at a tertiary referral center. [Note that studies were not summarized in the summary tables. Summary of individual study findings was provided in text.]
  • Pro- and prebiotics: Eleven probiotic RCTs (quality score ranged from 0 to 3) have assessed whether microbial supplementation may be used in the prevention or treatment of food allergy or sensitization, but results have been disappointing overall.
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Limitations
  • Some methodological concerns regarding the search and study selection process. The authors seem to “up-play” some positive results, not taking into account the quality scores in their synthesis. Most of the studies were rated poor quality.
  • With exception of probiotics, all studies for other microbial exposures were observational studies.
  • The studies selected were highly heterogeneous in design and quality.
  • Most studies were primarily designed to investigate respiratory allergies or eczema, and hence lacked objective characterization of clinical food allergy and statistical power to detect significant risk estimates.
AMSTAR rating
An a priori design? Y
Duplicate study selection and data extraction? Not reported
Comprehensive literature search? N (Medline only)
Status of the publication as an inclusion criterion? Y
List of studies (included and excluded) provided? No but available on request
Characteristics of included provided? Y
Scientific quality of the included studies assessed and reported? Y
Scientific quality used in formulating conclusions? Y
Methods used to combine the findings appropriate? Y
Likelihood of publication bias assessed? N
Conflict of interest stated? Y/N – COI of the systematic review authors were reported but COI not provided for the included studies
Author, year Kramer and Kakuma, 2012
Aims/Key questions To assess the effects of prescribing an antigen avoidance diet during pregnancy or lactation, or both, on maternal and infant nutrition and on the prevention or treatment of atopic disease in the child; positive SPTs to dietary antigens; and cord blood levels of IgE (a predictor of subsequent atopic disease).
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Study eligibility criteria Inclusion criteria:
  • Study design: All acceptably controlled (randomized or quasi-randomized) comparisons of maternal dietary antigen avoidance prescribed to pregnant (at any time during pregnancy) or lactating women at high risk, regardless of degree (number of foods eliminated from the diet) or duration.
  • Population: Pregnant or lactating women at high risk of giving birth to an atopic child, based on a history of atopic disease (eczema, asthma, or hay fever) in the mother, father, or a previous child. Lactating mothers of infants with established atopic eczema.
  • Intervention: Prescription of diet with exclusion (or reduced quantity) of potentially antigenic foods such as cow milk, egg, peanut, fish, and chocolate.
  • Outcome measures:
    • Primary outcomes: Occurrence and severity of atopic disease in the child.
    • Secondary outcomes: Nutritional status of mother (gestational weight gain) and fetus (birth weight); other pregnancy outcomes (e.g., preterm birth); positive SPT to ingested antigen (especially egg and milk); and cord blood IgE levels.
Exclusion criteria:
  • Trials of multimodal interventions that include, in addition to maternal dietary antigen avoidance, manipulation of the infant’s diet other than breast milk or of other non-dietary aspects of the infant’s environment (i.e., exposure to inhaled allergens).
Literature search dates or year range Unspecified; search conducted on July 6, 2012
Number of food allergy studies included Three (based on SPT results)
Synthesis methods Summary tables and meta-analysis
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Key findings
  • Antigen avoidance during pregnancy: Results from two trials involving 334 pregnant women at high risk of atopic offspring suggest a lower incidence of positive SPT to egg antigen at 6 months of age, but the effect was no longer evident at 18 months, nor was any benefit apparent at either age for SPT to milk antigen (random-effects meta-analysis pooled RR: 0.95; 95% CI: 0.52-1.74). The risk of bias of the two trials is mixed (one was low risk and one was high risk of bias).
  • Antigen avoidance during lactation: A larger included trial (N=497) did not report on atopic eczema or other allergic disease outcomes, but found no evidence of sensitization to milk, egg, or peanut antigen on SPT at 1, 2, or 7 years of age. The risk of bias of this trial was unclear because the information available is based solely on a published abstract.
Limitations
  • This Cochrane systematic review did not focus on food allergies or sensitization. Out of 12 trials, only 3 reported SPT results.
  • Food sensitization outcomes were based on SPT results only.
  • Included trials had small sample sizes.
AMSTAR rating
An a priori design? Y
Duplicate study selection and data extraction? Y
Comprehensive literature search? Y
Status of the publication as an inclusion criterion? Y
List of studies (included and excluded) provided? Y
Characteristics of included provided? Y
Scientific quality of the included studies assessed and reported? Y
Scientific quality used in formulating conclusions? Y
Methods used to combine the findings appropriate? Y
Likelihood of publication bias assessed? Y
Conflict of interest stated? Y/N (funding sources of included studies were not reported but the systematic review authors reported no conflict of interest)
Author, year Fisher et al., 2011
Aims/Key questions To determine whether specific oral tolerance induction is more effective than avoidance in inducing tolerance in children ages 0 to 18 years who have IgE-mediated food allergy.
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Study eligibility criteria Inclusion criteria:
  • Population: Children ages 0 to 18 years with IgE-mediated food allergy proven by DBPCOFC at the start of the study.
  • Outcome measures: The success of specific oral tolerance induction was objectively assessed using oral food challenge or DBPCOFC for tolerance but DBPCOFC for allergy.
  • Quality of trial: Scored ≥1+ using the National Institute for Health and Clinical Excellence (NIHCE) criteria for quality assessment.
  • Other: English language publications.
Literature search dates or year range 1950 to July 2009
Number of food allergy studies included Three
Synthesis methods Summary tables and meta-analysis
Key findings
  • All three RCTs examined the effect of oral tolerance induction to cow milk protein, with one study enrolling children who were exquisitely sensitive, reacting at <1 ml of whole cow milk at the start of the study. Age ranges of children included in each RCT were wide (0.6-12.9; 5-17; 6-17 years).
  • One RCT also performed oral tolerance induction to hen egg, although each child was desensitized to only one food (cow milk or hen egg) during the study. In two RCTs, children who were not randomized to receive specific oral tolerance induction practiced avoidance of the relevant allergen. Children in the third RCT consumed a placebo, although no details of the substance used for the placebo were provided.
  • Meta-analysis: Total of 127 children were included in the meta-analysis. Although a reduction in allergy after treatment is highlighted, this fails to meet statistical significance (pooled RR: 0.61; 95% CI: 0.32-1.12; P=0.1302). Cochran Q (8.87; P=0.0118) and I2 (77.5%; 95% CI: 0%-91%) found high heterogeneity between studies, which further reduces the significance of findings.
Limitations
  • One author reviewed the studies using the NIHCE quality framework, but no details about quality assessment were reported. It is unclear how many studies were excluded based on quality score.
  • Included studies performed specific oral tolerance induction only to cow milk or hen egg, and although these are the most common childhood food allergens trials had small sample size.
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
AMSTAR rating
An a priori design? Y
Duplicate study selection and data extraction? N (only one author conducted the search and one author reviewed the studies)
Comprehensive literature search? Y
Status of the publication as an inclusion criterion? N
List of studies (included and excluded) provided? Y
Characteristics of included provided? Y
Scientific quality of the included studies assessed and reported? Y
Scientific quality used in formulating conclusions? Y
Methods used to combine the findings appropriate? Y
Likelihood of publication bias assessed? N
Conflict of interest stated? Y/N (COI of the systematic review authors was provided but not provided for included studies)
Author, year Klemens et al., 2011
Aims/Key questions To determine if n-3 PUFA supplementation during pregnancy and lactation reduces risk for childhood allergic disease.
Study eligibility criteria Inclusion criteria:
  • RCTs comparing supplementation in pregnancy and lactation with n-3 PUFA or placebo for primary prevention of allergic disease in neonates, infants, and children.
  • Study participants were pregnant or lactating women and their offspring.
  • Studies had to report on one of the following clinical or immunological outcomes in neonates, infants, or children: asthma, atopy, and food allergy as a clinical diagnosis or as response to the egg SPT at any time during the first 12 months of life. Diagnoses must be verified by medical or nursing clinicians.
Literature search dates or year range 1950 to October 2010
Number of food allergy studies included Three
Synthesis methods Summary tables, meta-analysis and narrative synthesis
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Key findings
  • Three RCTs (N=264) reported on clinical diagnoses of food allergy in children. All RCTs were rated high quality.
  • Random-effects meta-analysis showed no significant difference in food allergy between children of mothers who received n-3 PUFA supplementation and children of mothers receiving placebo (6/128 versus 16/136, pooled OR: 0.46; 95% CI: 0.156-1.38). There was no significant between-study heterogeneity (P=0.226, I2=32.777) nor was there evidence of publication bias (Egger’s regression intercept P=0.998).
    • When only RCTs in which supplementation was started during pregnancy were considered, fewer children with food allergies were born to n-3 PUFA-supplemented mothers than to placebo-supplemented mothers, but this difference was not significant (4/92 versus 15/108, pooled OR: 0.34; 95% CI: 0.10-1.15).
  • Two of the included studies (N=187) reported on the period prevalence of positive response to the egg SPT in children up to age 12 months after maternal n-3 PUFA supplementation during pregnancy. Supplementation significantly reduced a positive SPT response to egg (12/87 versus 32/100, pooled OR: 0.33; 95% CI: 0.16-0.70). There was no significant between-study heterogeneity (P=0.957, I2=0.000).
Limitations
  • The different doses of supplementation in the combined studies also may represent a weakness of this meta-analysis, given that n-3 PUFA supplementation may have an inverted U-shaped dose–response curve, with moderate doses conferring more benefit than high doses in some models.
  • Although a positive SPT indicates the presence of food-specific IgE antibodies, a positive response may be seen in tolerant individuals and does not necessarily represent food allergy.
AMSTAR rating
An a priori design? Y
Duplicate study selection and data extraction? Y
Comprehensive literature search? Y
Status of the publication as an inclusion criterion? N
List of studies (included and excluded) provided? Y
Characteristics of included provided? Y
Scientific quality of the included studies assessed and reported? Y
Scientific quality used in formulating conclusions? Y
Methods used to combine the findings appropriate? Y
Likelihood of publication bias assessed? Y
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Conflict of interest stated? Y/N (COI of the systematic review authors was provided but not provided for included studies)
Author, year Osborn and Sinn, 2006
Aims/Key questions
  • To determine the effect of feeding hydrolyzed formulas on allergy and food intolerance in infants and children compared to adapted cow milk or human breast milk. If hydrolyzed formulas are effective, to determine what type of hydrolyzed formula is most effective, including extensively and partially hydrolyzed formulas.
  • To determine which infants benefit, including infants at low or high risk of allergy and infants receiving early, short-term, or prolonged formula feeding.
Study eligibility criteria Inclusion criteria:
  • Types of studies: RCTs and quasi-RCTs that compare the use of a hydrolyzed infant formula to human milk or an adapted cow milk formula. Random and quasi-random (e.g., using alternation) trials with ≥80% follow-up of participants were eligible for inclusion.
  • Types of participants: Infants in the first 6 months of life without clinical evidence of allergy.
  • Types of interventions: Hydrolyzed cow milk and soy formulas, and extensively and partially hydrolyzed formulas. Hydrolyzed formulas may be used for either
    • early, short-term supplementary or sole formula feeding in infants unable to be exclusively breastfed in the first days of life;
    • prolonged supplementation of breastfed infants or sole formula feeding in infants in the first months of life; or
    • weaning from the breast using infant formula.
  • Type of controls: The control group may include infants who receive exclusive human milk (either breast fed or expressed) or an adapted cow milk formula.
  • Primary outcomes:
    • All allergy including asthma, atopic dermatitis, allergic rhinitis or food allergy.
    • Food intolerance.
Literature search dates or year range Inception to March 2006
Number of food allergy studies included Five
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Synthesis methods Meta-analysis, summary table, narrative text
Key findings For Comparison 01 Early short-term feeding: Hydrolyzed formula versus human milk feeding among low-risk infants:
  • (90 infants) no significant difference in any allergy (RR: 1.43; 95% CI: 0.38-5.37), food allergy (RR: 1.43; 95% CI: 0.38-5.37), and cow milk allergy (RR: 7.11; 95% CI: 0.35-143.84) at age 3 years.
  • (3,559 infants) no significant difference in cow milk allergy up to mean age of 27 months (RR: 0.87; 95% CI: 0.52-1.46).
For Comparison 03 Early short-term feeding: Hydrolyzed formula versus cow milk formula:
  • (77 infants) no significant difference in childhood allergy incidence (RR: 1.37; 95% CI: 0.33-5.71), childhood food allergy (RR: 1.37; 95% CI: 0.33-5.71), and childhood cow milk allergy (RR: 5.13; 95% CI: 0.25-103.43).
  • (3,478 infants) a reduction in infant cow milk allergy of borderline significance (RR: 0.62; 95% CI: 0.38-1.00).
For Comparison 04 Prolonged feeding: Hydrolyzed formula versus cow milk formula:
  • (141 infants) no significant difference in infant food allergy (RR: 1.82; 95% CI: 0.64-5.16).
  • (67 infants) a significant reduction in infant cow milk allergy (RR: 0.36; 95% CI: 0.15-0.89).
For Comparison 07 Prolonged feeding: Extensively hydrolyzed formula versus cow milk formula:
  • (96 infants) no significant difference in food allergy (RR: 1.15; 95% CI: 0.33-4.02).
For Comparison 08 Prolonged feeding: Partially hydrolyzed formula versus cow milk formula:
  • (91 infants) no significant difference in infant food allergy (RR: 2.56; 95% CI: 0.86-7.56).
  • a significant reduction in cow milk allergy in infancy (RR: 0.36; 95% CI: 0.15-0.89).
For Comparison 09 Prolonged feeding: Extensively hydrolyzed formula versus partially hydrolyzed formula:
  • Meta-analysis of two studies (N=341) found a significant reduction in infant food allergy (typical RR: 0.43; 95% CI: 0.19-0.99).
  • (246 infants) no significant difference in infant cow milk allergy (RR: 0.13; 95% CI: 0.01-1.16).
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Key findings (continued) For Comparison 11 Prolonged feeding: Hydrolyzed formula versus cow milk formula: Allergy/intolerance confirmed by test:
  • (141 infants) no significant difference in infant food allergy confirmed by specific IgE (RR: 1.82; 95% CI: 0.64-5.16).
  • significant reduction in infant cow milk allergy confirmed by specific IgE (RR: 0.36; 95% CI: 0.15-0.89).
  • no significant difference in infant food intolerance confirmed by DBPCOFC (RR: 0.48; 95% CI: 0.07-3.33).
For Comparison 14 Prolonged feeding: Partially hydrolyzed whey formula versus cow milk formula:
  • significant reduction in infant cow milk allergy (RR: 0.36; 95% CI: 0.15-0.89).
For Comparison 15 Prolonged feeding: Partially hydrolyzed casein containing formula versus cow milk formula:
  • (91 infants) no significant difference in infant food allergy (RR: 2.56; 95% CI: 0.86-7.56).
For Comparison 17 Prolonged feeding: Extensively hydrolyzed casein containing formula versus cow milk formula:
  • (96 infants) no significant difference in infant food allergy (RR: 1.15; 95% CI: 0.33-4.02).
Limitations
  • Many “meta-analyses” of small number of studies.
  • Infant and childhood allergy had different definitions, timing of measurement and methods for measurement from study to study. Most studies were small or had methodological limitations, with benefits not persisting when analysis was restricted to trials with blinding of measurement to study formula or to studies of adequate methodology.
AMSTAR rating
An a priori design? Y
Duplicate study selection and data extraction? Y
Comprehensive literature search? Y
Status of the publication as an inclusion criterion? N
List of studies (included and excluded) provided? Y
Characteristics of included provided? Y
Scientific quality of the included studies assessed and reported? Y
Scientific quality used in formulating conclusions? Y
Methods used to combie the findings appropriate? N (many “meta-analysis” had one study)
Likelihood of publication bias assessed? N
Conflict of interest stated? Y
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Author, year Kramer and Kakuma, 2004
Aims/Key questions To assess the effects on child health, growth, and development, and on maternal health, of exclusive breastfeeding for 6 months versus exclusive breastfeeding for 3 to 4 months with mixed breastfeeding (introduction of complementary liquid or solid foods with continued breastfeeding) thereafter through 6 months.
Study eligibility criteria Inclusion criteria:
  • Study design: Controlled clinical trials and observational studies, published in all languages, examining whether or not exclusive breastfeeding until age 6 months has an impact on growth, development, morbidity, and survival of healthy, term infants and their mothers.
  • Comparison: The comparisons must have been based on one group of infants who received exclusive breastfeeding for at least 3 but less than 7 months and mixed breastfeeding until 6 months or later (i.e., infants were introduced to liquid or solid foods between 3 and 6 months of age), and another group of infants who were exclusively breastfed for at least 6 months. Studies comparing infants receiving prolonged exclusive breastfeeding (more than 6 months) to those exclusively breastfed for 6 months and continued mixed breastfeeding after 6 months also were included. Among infants exclusive breastfeeding for at least 3 months, the interventions/exposures compared were continued exclusive breastfeeding versus mixed breastfeeding. The “complementary” foods used in mixed breastfeeding included juices, formula, other milks, other liquids, or solid foods. Although the WHO defines exclusive breastfeeding as breastfeeding with no supplemental liquids or solid foods other than medications or vitamins, few studies strictly adhered to the WHO’s definition.
  • Population: Lactating mothers and their healthy, term, singleton infants.
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Study eligibility criteria (continued)
  • Outcome measures: Any infant or maternal health outcomes. The infant outcomes specifically sought (but not necessarily found) included growth (weight, length, and head circumference and z-scores (based on the WHO/CDC reference) for weight-for-age, length-for-age, and weight-for-length), infections, morbidity, mortality, micronutrient status, neuromotor and cognitive development, asthma, atopic eczema, other allergic diseases, type 1 diabetes, blood pressure, and subsequent adult chronic diseases such as coronary heart disease, hypertension, type 2 diabetes, and inflammatory and autoimmune diseases. Maternal outcomes sought included postpartum weight loss, duration of lactational amenorrhea, and such chronic diseases as breast and ovarian cancer and osteoporosis.
Exclusion criteria:
  • Studies of (or including) low birthweight (less than 2,500 g) infants were not excluded, provided that such infants were born at term (at least 37 completed weeks). Only those studies with an internal comparison group were included in the review, i.e., the authors excluded studies based on external comparisons (with reference data).
  • Studies comparing exclusive breastfeeding and mixed breastfeeding from birth were excluded, as were those that investigated the effects of age at introduction of nonbreast milk liquid or solid foods but did not ensure exclusive breastfeeding at least 3 months before their introduction.
Literature search dates or year range Inception to June 15, 2011
Number of food allergy studies included One cohort study
Synthesis methods Narrative synthesis; meta-analysis (N/A for food allergy outcome because only one study was included)
Key findings
  • 1 cohort study enrolled 135 healthy Finnish infants of atopic parents reported food allergy outcome. This study was rated unclear overall risk of bias.
  • For the comparison of exclusive breastfeeding for 6-7 months versus 3-4 months, this study also reported a reduced risk of a history of food allergy at 1 year but double food challenges showed no significant risk reduction (RR: 0.77; 95% CI: 0.25-2.41).
Limitations
  • This systematic review did not focus on food allergy. Only 1 cohort study reported food allergy outcomes.
Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
AMSTAR rating
An a priori design? Y
Duplicate study selection and data extraction? Y
Comprehensive literature search? Y
Status of the publication as an inclusion criterion? Y
List of studies (included and excluded) provided? Y
Characteristics of included provided? Y
Scientific quality of the included studies assessed and reported? Y
Scientific quality used in formulating conclusions? N
Methods used to combine the findings appropriate? N (many “meta-analysis” only has 1 study)
Likelihood of publication bias assessed? N
Conflict of interest stated? N

NOTE: ALA = alpha-linolenic acid; CDC = Centers for Disease Control and Prevention; CI = confidence interval; DBPCOFC = double-blind, placebo-controlled oral food challenge; DHA = docosahexaenoic acid; DPA = docosapentaenoic acid; EAACI = European Academy of Allergy & Clinical Immunology; EPA = eicosapentaenoic acid; IgE = immunoglobulin E; IU = international units; LCPUFA, long-chain polyunsaturated fatty acid; N/A = not available; OR = odds ratio; PUFA = polyunsaturated fatty acid; RAST = radioallergosorbent; RCT = randomized controlled trial; RR = relative risk; SDA = stearidonic acid; SPT = skin prick test; tIgE = total IgE; WHO = World Health Organization.

Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×

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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×

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Kramer, M. S., and R. Kakuma. 2004. The optimal duration of exclusive breastfeeding: A systematic review. Adv Exp Med Biol 554:63-77.

Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Kramer, M. S., and R. Kakuma. 2012. Maternal dietary antigen avoidance during pregnancy or lactation, or both, for preventing or treating atopic disease in the child. Cochrane Database Syst Rev 9:CD000133.

Liao, S. L., S. H. Lai, K. W. Yeh, Y. L. Huang, T. C. Yao, M. H. Tsai, M. C. Hua, and J. L. Huang. 2014. Exclusive breastfeeding is associated with reduced cow’s milk sensitization in early childhood. Pediatr Allergy Immunol 25(5):456-461.

Liu, X., G. Wang, X. Hong, D. Wang, H. J. Tsai, S. Zhang, L. Arguelles, R. Kumar, H. Wang, R. Liu, Y. Zhou, C. Pearson, K. Ortiz, R. Schleimer, P. G. Holt, J. Pongracic, H. E. Price, C. Langman, and X. Wang. 2011. Gene-vitamin D interactions on food sensitization: A prospective birth cohort study. Allergy 66(11):1442-1448.

Liu, X., L. Arguelles, Y. Zhou, G. Wang, Q. Chen, H. J. Tsai, X. Hong, R. Liu, H. E. Price, C. Pearson, S. Apollon, N. Cruz, R. Schleimer, C. B. Langman, J. A. Pongracic, and X. Wang. 2013. Longitudinal trajectory of vitamin D status from birth to early childhood in the development of food sensitization. Pediatr Res 74(3):321-326.

Loo, E. X., G. V. Llanora, Q. Lu, M. M. Aw, B. W. Lee, and L. P. Shek. 2014. Supplementation with probiotics in the first 6 months of life did not protect against eczema and allergy in at-risk Asian infants: A 5-year follow-up. Int Arch Allergy Immunol 163(1):25-28.

Lowe, A. J., C. S. Hosking, C. M. Bennett, K. J. Allen, C. Axelrad, J. B. Carlin, M. J. Abramson, S. C. Dharmage, and D. J. Hill. 2011. Effect of a partially hydrolyzed whey infant formula at weaning on risk of allergic disease in high-risk children: A randomized controlled trial. J Allergy Clin Immunol 128(2):360-365.

Luccioli, S., Y. Zhang, L. Verrill, M. Ramos-Valle, and E. Kwegyir-Afful. 2014. Infant feeding practices and reported food allergies at 6 years of age. Pediatrics 134(Suppl 1):S21-S28.

Magdelijns, F. J., M. Mommers, J. Penders, L. Smits, and C. Thijs. 2011. Folic acid use in pregnancy and the development of atopy, asthma, and lung function in childhood. Pediatrics 128(1):e135-e144.

Mailhol, C., F. Giordano-Labadie, V. Lauwers-Cances, A. Ammoury, C. Paul, and F. Rance. 2014. Point prevalence and risk factors for food allergy in a cohort of 386 children with atopic dermatitis attending a multidisciplinary dermatology/paediatric allergy clinic. Eur J Dermatol 24(1):63-69.

Marrs, T., K. D. Bruce, K. Logan, D. W. Rivett, M. R. Perkin, G. Lack, and C. Flohr. 2013. Is there an association between microbial exposure and food allergy? A systematic review. Pediatr Allergy Immunol 24(4):311-320.

Martin, P. E., J. K. Eckert, J. J. Koplin, A. J. Lowe, L. C. Gurrin, S. C. Dharmage, P. Vuillermin, M. L. Tang, A. L. Ponsonby, M. Matheson, D. J. Hill, and K. J. Allen. 2015. Which infants with eczema are at risk of food allergy? Results from a population-based cohort. Clin Exp Allergy 45(1):255-264.

McGowan, E. C., G. R. Bloomberg, P. J. Gergen, C. M. Visness, K. F. Jaffee, M. Sandel, G. O’Connor, M. Kattan, J. Gern, and R. A. Wood. 2015. Influence of early-life exposures on food sensitization and food allergy in an inner-city birth cohort. J Allergy Clin Immunol 135(1):171-178.

Metsala, J., A. Lundqvist, L. J. Virta, M. Kaila, M. Gissler, and S. M. Virtanen. 2013. Mother’s and offspring’s use of antibiotics and infant allergy to cow’s milk. Epidemiology 24(2):303-309.

Newberry, S. J., M. Chung, M. Booth, M. A. Maglione, A. M. Tang, C. E. O’Hanlon, D. D. Wang, A. Okunogbe, C. Huang, A. Motala, M. Timmer, W. Dudley, R. Shanman, T. R. Coker, and P. G. Shekelle. 2016. Omega-3 fatty acids and maternal and child health: An updated systematic review. Evidence Report/Technology Assessment No. 224. AHRQ Publication No. 16-E003-EF. Rockville, MD: Agency for Healthcare Research and Quality.

Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Norizoe, C., N. Akiyama, T. Segawa, H. Tachimoto, H. Mezawa, H. Ida, and M. Urashima. 2014. Increased food allergy and vitamin D: Randomized, double-blind, placebo-controlled trial. Pediatr Int 56(1):6-12.

Okupa, A. Y., R. F. Lemanske, Jr., D. J. Jackson, M. D. Evans, R. A. Wood, and E. C. Matsui. 2013. Early-life folate levels are associated with incident allergic sensitization. J Allergy Clin Immunol 131(1):226-228.

Osborn, D. A., and J. Sinn. 2006. Formulas containing hydrolysed protein for prevention of allergy and food intolerance in infants. Cochrane Database Syst Rev(4):CD003664.

Palmer, D. J., J. Metcalfe, M. Makrides, M. S. Gold, P. Quinn, C. E. West, R. Loh, and S. L. Prescott. 2013. Early regular egg exposure in infants with eczema: A randomized controlled trial. J Allergy Clin Immunol 132(2):387-392.

Pele, F., E. Bajeux, H. Gendron, C. Monfort, F. Rouget, L. Multigner, J. F. Viel, and S. Cordier. 2013. Maternal fish and shellfish consumption and wheeze, eczema and food allergy at age two: A prospective cohort study in Brittany, France. Environ Health 12:102.

Perkin, M. R., K. Logan, A. Tseng, B. Raji, S. Ayis, J. Peacock, H. Brough, T. Marrs, S. Radulovic, J. Craven, C. Flohr, G. Lack, and EAT Study Team. 2016. Randomized trial of introduction of allergenic foods in breast-fed infants. N Engl J Med 374(18):1733-1743.

Peters, R., K. Allen, S. Dharmage, C. Lodge, J. Koplin, A. Ponsonby, M. Wake, A. Lowe, M. Tang, M. Matheson, and L. Gurrin. 2015. Differential factors associated with challenge-proven food allergy phenotypes in a population cohort of infants: A latent class analysis. Clin Exp Allergy 45(5):953-963.

Pyrhonen, K., S. Nayha, L. Hiltunen, and E. Laara. 2013. Caesarean section and allergic manifestations: Insufficient evidence of association found in population-based study of children aged 1 to 4 years. Acta Paediatr 102(10):982-989.

Roduit, C., R. Frei, M. Depner, B. Schaub, G. Loss, J. Genuneit, P. Pfefferle, A. Hyvarinen, A. M. Karvonen, J. Riedler, J. C. Dalphin, J. Pekkanen, E. von Mutius, C. Braun-Fahrlander, and R. Lauener. 2014. Increased food diversity in the first year of life is inversely associated with allergic diseases. J Allergy Clin Immunol 133(4):1056-1064.

Stelmach, I., M. Bobrowska-Korzeniowska, K. Smejda, P. Majak, J. Jerzynska, W. Stelmach, K. Polanska, W. Sobala, J. Krysicka, and W. Hanke. 2014. Risk factors for the development of atopic dermatitis and early wheeze. Allergy Asthma Proc 35(5):382-389.

von Berg, A., B. Filipiak-Pittroff, U. Kramer, B. Hoffmann, E. Link, C. Beckmann, U. Hoffmann, D. Reinhardt, A. Grubl, J. Heinrich, H. E. Wichmann, C. P. Bauer, S. Koletzko, D. Berdel, and G. I. s. group. 2013. Allergies in high-risk schoolchildren after early intervention with cow’s milk protein hydrolysates: 10-year results from the German Infant Nutritional Intervention (GINI) study. J Allergy Clin Immunol 131(6):1565-1573.

Wawro, N., J. Heinrich, E. Thiering, J. Kratzsch, B. Schaaf, B. Hoffmann, I. Lehmann, C. P. Bauer, S. Koletzko, A. von Berg, D. Berdel, and J. Linseisen. 2014. Serum 25(OH)D concentrations and atopic diseases at age 10: Results from the GINIplus and LISAplus birth cohort studies. BMC Pediatr 14:286.

Weisse, K., S. Winkler, F. Hirche, G. Herberth, D. Hinz, M. Bauer, S. Roder, U. Rolle-Kampczyk, M. von Bergen, S. Olek, U. Sack, T. Richter, U. Diez, M. Borte, G. I. Stangl, and I. Lehmann. 2013. Maternal and newborn vitamin D status and its impact on food allergy development in the German LINA cohort study. Allergy 68(2):220-228.

West, C. E., J. Dunstan, S. McCarthy, J. Metcalfe, N. D’Vaz, S. Meldrum, W. H. Oddy, M. K. Tulic, and S. L. Prescott. 2012. Associations between maternal antioxidant intakes in pregnancy and infant allergic outcomes. Nutrients 4(11):1747-1758.

West, C. E., M. L. Hammarstrom, and O. Hernell. 2013. Probiotics in primary prevention of allergic disease—follow-up at 8-9 years of age. Allergy 68(8):1015-1020.

Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"Appendix C: Risk Determinants Literature Search Strategy." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Next: Appendix D: Acronyms and Abbreviations »
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Over the past 20 years, public concerns have grown in response to the apparent rising prevalence of food allergy and related atopic conditions, such as eczema. Although evidence on the true prevalence of food allergy is complicated by insufficient or inconsistent data and studies with variable methodologies, many health care experts who care for patients agree that a real increase in food allergy has occurred and that it is unlikely to be due simply to an increase in awareness and better tools for diagnosis. Many stakeholders are concerned about these increases, including the general public, policy makers, regulatory agencies, the food industry, scientists, clinicians, and especially families of children and young people suffering from food allergy.

At the present time, however, despite a mounting body of data on the prevalence, health consequences, and associated costs of food allergy, this chronic disease has not garnered the level of societal attention that it warrants. Moreover, for patients and families at risk, recommendations and guidelines have not been clear about preventing exposure or the onset of reactions or for managing this disease.

Finding a Path to Safety in Food Allergy examines critical issues related to food allergy, including the prevalence and severity of food allergy and its impact on affected individuals, families, and communities; and current understanding of food allergy as a disease, and in diagnostics, treatments, prevention, and public policy. This report seeks to: clarify the nature of the disease, its causes, and its current management; highlight gaps in knowledge; encourage the implementation of management tools at many levels and among many stakeholders; and delineate a roadmap to safety for those who have, or are at risk of developing, food allergy, as well as for others in society who are responsible for public health.

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