Background
Methods
Protocol and registration
Selection criteria
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Types of studies: cohort studies. We excluded case–control studies and cross sectional studies.
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Types of participants: children less than 18 years old and free of asthma at the time of inclusion in the cohort. We did not consider other kinds of allergic conditions.
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Types of exposure: serum vitamin D levels in the child. We excluded studies of vitamin D levels in the pregnant mother or in the cord blood at the time of delivery and studies of vitamin D intake or supplementation.
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Types of outcome measures: asthma diagnosed based on doctor’s diagnosis, questionnaires, or spirometry measures.
Search strategy
Selection of studies
Data collection
Assessment of risk of bias in included studies
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Failure to develop and apply appropriate eligibility criteria (e.g., selection of exposed and unexposed in cohort studies from different populations).
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Flawed measurement of exposure (i.e., serum vitamin D levels).
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Flawed measurement of outcome (i.e., asthma diagnosis).
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Failure to adequately control confounding variables (e.g., failure of accurate measurement of all known prognostic factors, failure to match for prognostic factors and/or adjustment in statistical analysis).
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Incomplete follow-up.
Data analysis and synthesis
Results
Description of study selection
Study characteristics
Study name, Funding | Study design | Participants | Exposure | Outcome | Notes |
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• Hollams [13] | • Prospective birth cohort started in 1989 | • Conducted as part of West Australian Pregnancy Cohort (Raine Study): a longitudinal birth cohort, in which mothers (2900 volunteers) were enrolled for antenatal care at the main local tertiary maternity hospital | • Serum 25-hydroxyvitamin D levels measured at the age of 6 years | • Current asthma; defined as wheeze plus use of any asthma medication in the last 12 months, in children with a prior doctor diagnosis of asthma | • Vitamin D levels at age 6 years (Continuous outcome) analyzed as a predictor of subsequent clinical phenotypes at 14 years of age |
Source of funding not reported | |||||
• Follow up: 8 years | |||||
• Measured using the enzyme immunoassay kit from Immunodiagnostic Systems Ltd (Scottsdale, AZ, USA) | |||||
• 8 years period between the point of measuring vitamin D levels and the assessment of asthma | • Reference group: sufficient level of vit D (> 75) | ||||
• Included in this study: 989 children assessed at the age of 6 (no further details provided about selection criteria or process); 693 were included in the analysis. | |||||
• Vitamin D values were ‘deseasonalized’ | |||||
• Lung function; assessed by spirometry | |||||
• Bronchial hyperrsponsiveness (BHR); assessed by methacholine challenge. | |||||
• Perth, Western Australia, Australia | |||||
• Outcomes assessed at the age of 14 years | |||||
Van Oeffelen [12] | • Prospective birth cohort started in 1996 | • Conducted as part of PIAMA birth cohort of 3963 newborns; pregnant women recruited from the general population when visiting one of 52 prenatal clinics | • Serum 25-hydroxyvitamin D levels measured at the age of 4 years | • Asthma and severe asthma diagnosed using the (ISAAC) [29] questionnaire answered by parents annually until 8 year of age | • Vitamin D levels categorized into tetriles (Reference: tertile 1) |
Funded by the Netherlands Organisation for Health Research and Development, the Netherlands Asthma Foundation, the Netherlands Ministry of Health, Welfare and Sport, and the National Institute of Public Health and the Environment. | • Follow up: 5 years | ||||
• Serum extracted and directly stored in a refrigerator at -20C, and defrosted in 2008 to measure of vit. D levels | |||||
• Measured using a competitive enzyme immunoassay in microtiter plates (OCTEIA; IDS, Boldon, UK). | |||||
• 4 years period between the point of measuring vitamin D levels and the assessment of asthma | |||||
• Included in this study: 372 “selected” 4-year-old children (no further details provided about selection criteria or process); all were included in the analysis | |||||
• Storage time of serum samples proved to be no confounder and was therefore not added to the models. | |||||
• Categorized into tertiles (range; median): | |||||
• Bronchial hyperrsponsiveness (BHR) measured at 8 years of age; assessed by methacholine challenge | |||||
o Tertile 1: 23.1–60.2; 52.0 | |||||
o Tertile 2: 60.7–78.8; 68.3 | • Vitamin D values were ‘deseasonalized’ | ||||
Netherlands | |||||
Tertile 3: 79.0–303.8; 97.0 | |||||
Tolppanen [22] | • Prospective birth cohort started in 1991 | • Conducted as part of the Avon longitudinal Study of Parents and children (ALSPAC): 14,062 live births from 14,541 enrolled pregnant women who were expected to give birth between 1st of April 1991 and 31st of December 1992 | • Serum 25-hydroxyvitamin D2 and D3 levels measured at a mean age of 9.8 years | • Asthma and wheezing assessed (questionnaire to children) at the age of 15-16 years. | • Asthma and wheezing also assessed on a yearly basis (questionnaire to caregiver); not clear whether those data were included in the analysis |
Funded by the UK Medical Research Council, the Wellcome trust, and the University of Bristol | |||||
• Follow up: 6 years | |||||
• 5-6 years period between the point of measuring vitamin D levels and the assessment of asthma | |||||
• Measured using high pressure liquid chromatography tandem mass spectrometer in the multiple reaction mode | |||||
• The exposures are standardized for age and sex and 25(OH)D3 is adjusted for season and ethnicity | |||||
• Interassay coefficients of | |||||
• Variation for 25(OH)D2 and 25(OH)D3 were < 10% across a working range of 1–250 ng/ml | |||||
• Lung function measured at a mean age of 15.5 years by spirometry according to the American Thoracic Society/European respiratory Society criteria. The best measurements from three reproducible flow-volume curves were used for analyses | |||||
• Included in this study (mean age of 9.8): 3323 children for the asthma outcome and 2,259 for spirometry (inclusion based on completeness of data on exposures, confounders, and outcome) | |||||
• South West England |
Risk of bias
Study name | Developing and applying appropriate eligibility criteria | Measurement of exposure | Measurement of outcome | Controlling for confounding | Completeness of data |
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• Hollams [13] | • Uncertain risk | • High risk | • Low risk | • High risk | • High Risk |
• Although the risk of bias is low for the original cohort, no further details were provided about selection criteria or process for participants in this current study | • “Vit D levels was measured in thawed serum cryobanked at age 6 years” (number of years since blood draw not mentioned) | • Low for lung function and BHR | • Did not match or adjust for maternal atopy, maternal asthma, maternal age, education or household smoking | • Outcome data were missing for 30% of the enrolled cohort | |
• The used enzyme immunoassay kit “method appeared to overestimate the vitamin D levels at age 6 years” | |||||
• Measuring Vitamin D levels at one point only may not be a reliable measure of integrated 25(OH) D levels over time | |||||
Van Oeffelen [12] | • High risk | • High risk | • Low risk | • Low risk | • Uncertain Risk |
• Out of the larger cohort, a small “selected” sample included in this study, with no further details about selection provided | • Serum samples were defrosted to measure concentrations of Vitamin D (number of years since blood draw not mentioned) | for asthma (ISAAC score) Low risk for BHR | • Confounders were added to all models (gender, maternal atopy, paternal atopy, smoking by anyone in the house, and serum magnesium) | • Outcome data were missing for 12% of the enrolled cohort | |
• Measured using a competitive enzyme immunoassay in microtiter plates | |||||
• Measuring Vitamin D levels at one point only may not be a reliable measure of integrated 25(OH) D levels over time | • Also considered playing outside and overweight as potential confounders | ||||
Tolppanen [22] | • Uncertain risk | • High risk | • Uncertain risk for asthma, using spirometry & bronchidilatory responsiveness with non-validated questionnaires to diagnose asthma | • Low risk | • High risk |
• Except for the loss of follow up, the cohort was from a single community and followed specific eligibility criteria | • The exposures are standardized for age and sex and 25-hydroxyvitamin D3 is adjusted for season and ethnicity | • Model 1 unadjusted | • Of 5765 participants in the assessment of the wheezing and asthma outcome 3323 where included (42% missing data) | ||
• Measured using high pressure liquid chromatography tandem mass spectrometer in the multiple reaction mode (number of years since blood draw not mentioned) | • High risk for wheezing | • Models 2 and 3 adjusted for respectively 8 and 9 potential confounders | |||
• Recall bias | • And of 4488 participants in the spirometric assessment 2259 where included (50% missing data). | ||||
• Measuring Vitamin D levels at one point only may not be a reliable measure of integrated 25(OH) D levels over time | • Proportion of incident wheezing, and asthma was higher among children excluded owing to missing data |