The aim of this study is to prevent asthma symptoms (recurrent wheeze) in childhood by supplementation with high dose vitamin D to the mother during pregnancy. Participants are mothers and children of the ABC (Asthma Begins in Childhood) cohort. Mothers are recruited during pregnancy and receive daily supplement with 2400 IU of Vitamin D3 or placebo from week 24 og gestation to 1 week after delivery. In addition all mothers are advised to take the recommended dose of 400 IU vitamin D daily. The mothers in ABC also participate in an interventional trial with fish oil supplementation, and the vitamin D randomization is stratified by fish oil treatment group. The child is followed with acute and planned vits at the research unit, and wheeze is diagnosed according to predefined algorithms.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
QUADRUPLE
Enrollment
600
2 tablets of 1200 IU daily from week 24 of gestation to 1 week after delivery
2 tablets containing no active substance
Copenhagen University Hospital of Copenhagen
Gentofte Municipality, Gentofte, Denmark
Næstved Hospital, Pediatric Department
Næstved, Næstved, Denmark
Persistent wheeze
Age at onset of persistent wheeze diagnosed according to predefined algorithm of recurrent troublesome lung symptoms, response to treatment and relapse after withdrawal of treatment
Time frame: 0 to 3 years of age
Infections
Main analysis: • Number of lower respiratory tract infections registered in daily diaries Secondary analyses: * Acute otitis media * Number of upper respiratory tract infections * Number of other infections * Total number of infections
Time frame: 0 to 3 years of age
Allergic sensitization
Allergic sensitization at 6 and/or 18 months assessed by skin prick test and specific IgE in blood
Time frame: 6 and 18 months of age
Eczema
Age at onset of eczema diagnosed prospectively by research doctors according to predefined algorithm based upon Hanifin and Rajka criteria
Time frame: 0 to 3 years of age
Mothers levels of 25-OH-Vitamin D, PTH, Calcium, alkaline phosphatase
Time frame: 1 week after delivery
Growth
Time frame: 0 to 3 years of age
Asthma exacerbations
Age at onset of severe asthma exacerbation diagnosed by predefined criteria of acute severe asthma requiring oral/high dose inhaled steroids or acute hospital contact
Time frame: 0 to 3 years of age
Neurological development
Main analysis: • Cognitive development assessed at 2½ years using the cognitive part of Bayley Scales of Infant and Toddler Development, third edition Secondary analyses: * Milestone development monitored prospectively by the parents using a registration form based on The Denver Development Index and WHO milestones registration (combined assessment by principal component analysis) * Language development assessed at 1 and 2 years of age with the Danish version of The MacArthur Bates Communicative Developmental Inventory (CDI) * The child´s general development (language, fine and gross motor, social and problem solving) at 3 years of age assessed with Ages and stages Questioner, third edition (ASQ-3)
Time frame: 0-3 years
Growth
Main analysis: • Body composition (fat mass and bone mineral density) assessed by DEXA scan at 3 years of age Secondary analysis • Development of BMI from birth to 3 years assesses longitudinally in the research clinic
Time frame: 0-3 years
Systemic immune status
Main analysis Immune status at 18 months measured in stimulated whole blood as cytokine release (combined assessments by prinicipal component analyses) Secondary analyses Composition of immune cell subsets in whole blood at birth and at 18 months of age
Time frame: 18 months
Airway mucosal immune status
Immune status measured in airway mucosal lining fluid at 4 weeks and 2 years of age (combined assessments by prinicipal component analyses for each age point)
Time frame: 4 weeks and 2 years
17q21 genotype and sphingolipid metabolites
In a secondary analyses, we will determine the effect of 17q21 genotype on the efficacy of vitamin D supplementation in the prevention of asthma/wheeze. We will compute hazard ratios for the reduction in asthma/wheeze risk associated with prenatal supplementation, stratified by rs12936231. rs12936231 is a functional SNP influencing expression of ORMDL3, and given the role of ORMDL3 as a key sphingolipid biosynthesis regulator, we will subsequently investigate the relative abundance of sphingolipids between those in the vitamin D Intervention arm and those in the placebo group, stratified by 17q21 genotype. Finally we will identify interactions between prenatal vitamin D supplementation, rs12936231 genotype and sphingolipid metabolism in the risk of asthma/wheeze by age three.
Time frame: 6 months
Dental health
Caries and enamel defects (molar incisor hypomineralization, MIH) determined at a dental examination at age 6 years.
Time frame: 6 year
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