Vitamin D Supplementation During Pregnancy for Prevention of Asthma in Childhood (ABCvitaminD)

• ClinicalTrials.gov Identifier: NCT00856947
• Recruitment Status: Active, not recruiting
• First Posted: March 6, 2009
• Last Update Posted: February 11, 2020
• Sponsor: Copenhagen Studies on Asthma in Childhood
• Information provided by (Responsible Party): Copenhagen Studies on Asthma in Childhood

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Asthma	Dietary Supplement: Cholecalciferol D3; Other: Placebo tablet	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 600 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Vitamin D Supplementation During Pregnancy for Prevention of Asthma in Childhood: An Interventional Trial in the ABC (Asthma Begins in Childhood) Cohort
• Study Start Date: March 2009
• Estimated Primary Completion Date: July 2027
• Estimated Study Completion Date: July 2027

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Vitamin D; Dietary supplement: 2400 IU Vitamin D3 (2 tablets of 1200 IU) from week 24 of gestation to 1 week after delivery	Dietary Supplement: Cholecalciferol D3; 2 tablets of 1200 IU daily from week 24 of gestation to 1 week after delivery; Other Name: Vitamin D from Camette, Denmark
Placebo Comparator: Placebo; Placebo: 2 placebo tablets with no active substance, identical to the active tablets, from week 24 of gestation to 1 week after delivery	Other: Placebo tablet; 2 tablets containing no active substance; Other Name: Placebo tablets from Camette, Denmark

Outcome Measures

Primary Outcome Measures :

1. Persistent wheeze [ Time Frame: 0 to 3 years of age ]
   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

Secondary Outcome Measures :

1. Infections [ Time Frame: 0 to 3 years of age ]

   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
2. Allergic sensitization [ Time Frame: 6 and 18 months of age ]
   Allergic sensitization at 6 and/or 18 months assessed by skin prick test and specific IgE in blood
3. Eczema [ Time Frame: 0 to 3 years of age ]
   Age at onset of eczema diagnosed prospectively by research doctors according to predefined algorithm based upon Hanifin and Rajka criteria
4. Mothers levels of 25-OH-Vitamin D, PTH, Calcium, alkaline phosphatase [ Time Frame: 1 week after delivery ]
5. Growth [ Time Frame: 0 to 3 years of age ]
6. Asthma exacerbations [ Time Frame: 0 to 3 years of age ]
   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
7. Neurological development [ Time Frame: 0-3 years ]

   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)
8. Growth [ Time Frame: 0-3 years ]

   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

9. Systemic immune status [ Time Frame: 18 months ]

   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

10. Airway mucosal immune status [ Time Frame: 4 weeks and 2 years ]
    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)
11. 17q21 genotype and sphingolipid metabolites [ Time Frame: 6 months ]
    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.
12. Dental health [ Time Frame: 6 year ]
    Caries and enamel defects (molar incisor hypomineralization, MIH) determined at a dental examination at age 6 years.

Other Outcome Measures:

1. Asthma [ Time Frame: 3-10 years of age ]
   Asthma diagnosed from age 3 to 10 years based on the same predefined algorithm of recurrent troublesome lung symptoms, response to treatment after withdrawal of treatment, which was used for persistent wheeze at age 0-3 in phase 1 of the study. Primary outcome in phase 2 is current asthma at specific visits till age 10 years, which is diagnosed in children fulfilling the persistent wheeze algorithm at any point during the first 10 years of life and still needing inhaled corticosteroids at specific visits (3, 4, 5, 6, 8 and 10 years of age) to control the symptoms.
2. Lung function measurements [ Time Frame: 5-10 years of age ]
   Spirometry measuring airflow assessed by FEV1, MMEF and FEV1/FVC ratio at age 5, 6, 8 and 10 years.
3. Infections [ Time Frame: 3-10 years of age ]
   Prescribed medicine for infections. Types and length of infections
4. Growth [ Time Frame: 3- 10 years of age ]

   Anthropometrics:

   Clinical follow up on the development of weight in kg (calibrated digital weight scales), height in cm (Harpenden stadiometer), waist-, thorax- and head circumference in cm (using tape; 3 times each) at every visit till age 10 years assessed longitudinally in the research clinic.

5. Cognitive function [ Time Frame: 10 years of age ]
   A 2,5 hours cognitive evaluation at 10 years of age. Cognitive functions from a broad spectrum of cognitive domains will be assessed with subtests both using paper pencil tests and Cambridge Neuropsychological Test Automated Battery .
6. Behavioral and psychopathological dimensions. [ Time Frame: 6- 10 years of age ]
   Questionnaires will be administered to the parents.
7. MRI scanning of the Brain [ Time Frame: 10 years of age ]
   MRI scanning of the Brain
8. Eczema [ Time Frame: 3-10 years of age ]
   Age at onset of eczema diagnosed prospectively by research doctors according to predefined algorithm based upon Hanifin and Rajka criteria
9. Allergic sensitization/atopy [ Time Frame: 6-10 years of age ]
   Allergic sensitization at 6 and 10 years of age assessed by skin prick test (ALK-Abelló, Denmark) and specific IgE in blood (ImmunoCAP, PHarmacia Diagnostics AB, Sweden).
10. Airway mucosal immune status [ Time Frame: 3-10 years of age ]
    Immune status measured in airway mucosal lining fluid at 3, 6 and 10 years of age (combined assessments by principal component analyses for each age point).
11. The diagnose allergic rhinitis [ Time Frame: 3-10 years of age ]
    Allergic rhinitis will be diagnosed by combining allergic sensitization with symptom recording of troublesome congestion or sneezing or runny nose upon relevant exposure to allergens at age 3, 4, 5, 6, 8 and 10 years.
12. Asthma exacerbations: [ Time Frame: 3-10 years of age ]
    Age at onset and number of severe asthma exacerbation diagnosed by predefined criteria of acute severe asthma requiring oral/ high dose inhaled steroids or acute hospital contact
13. Airway resistance [ Time Frame: 3-10 years of age ]
    Measured by plethysmography (sRaw) at age 3, 4, 5, 6, 8 and 10 years.
14. Airway resistance [ Time Frame: 3-5 years of age ]
    Multiple breath wash-out using SF6 and N2 as inert gasses to determined LCI, Scond and Sacin at ages 3, 4 and 5 years.
15. Bronchial reactivity: [ Time Frame: at 6 years of age ]
    Provocative dose of methacholine leading to a 20% drop in FEV1 from baseline (PD20 value) at age 6 years.
16. Airway inflammation: [ Time Frame: 6-10 years of age ]
    Measurement of fractional exhaled nitric oxide (FeNO) at age 6, 8 and 10 years
17. Body composition [ Time Frame: 3-10 years of age ]

    Body composition measured as fat mass, lean mass, bone mineral content (BMC) and bone mineral density assessed (BMD) through DXA scans at 3 and 6 years of age.

    Body impedance measurements at 10 years of age.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

Mother:

• Pregnant in week 22-26 of gestation
• Participating in the ABC-cohort
• Living in Sealand, Denmark
• Fluent in Danish
• Willing to let the child participate in the study

Exclusion Criteria:

Mother:

• Intake of more than 400 IU of vitamin D during the last 6 months
• Endocrinological disease such as calcium metabolic disorder, parathyroid disorder, thyroid disorder or Diabetes type 1
• Tuberculosis
• Sarcoidosis
• In need of diuretics or heart medication including calcium channel blockers

Contacts and Locations

Locations

Denmark

Copenhagen University Hospital of Copenhagen

Gentofte, Denmark, 2820

Næstved Hospital, Pediatric Department

Næstved, Denmark, 4700

Sponsors and Collaborators

Copenhagen Studies on Asthma in Childhood

Investigators

• Principal Investigator: Hans Bisgaard, MD, DMSc; Copenhagen Studies on Asthma in Childhood

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Sass L, Vinding RK, Stokholm J, Bjarnadóttir E, Noergaard S, Thorsen J, Sunde RB, McGrath J, Bønnelykke K, Chawes B, Bisgaard H. High-Dose Vitamin D Supplementation in Pregnancy and Neurodevelopment in Childhood: A Prespecified Secondary Analysis of a Randomized Clinical Trial. JAMA Netw Open. 2020 Dec 1;3(12):e2026018. doi: 10.1001/jamanetworkopen.2020.26018.

Brustad N, Garland J, Thorsen J, Sevelsted A, Krakauer M, Vinding RK, Stokholm J, Bønnelykke K, Bisgaard H, Chawes BL. Effect of High-Dose vs Standard-Dose Vitamin D Supplementation in Pregnancy on Bone Mineralization in Offspring Until Age 6 Years: A Prespecified Secondary Analysis of a Double-Blinded, Randomized Clinical Trial. JAMA Pediatr. 2020 May 1;174(5):419-427. doi: 10.1001/jamapediatrics.2019.6083.

Nørrisgaard PE, Haubek D, Kühnisch J, Chawes BL, Stokholm J, Bønnelykke K, Bisgaard H. Association of High-Dose Vitamin D Supplementation During Pregnancy With the Risk of Enamel Defects in Offspring: A 6-Year Follow-up of a Randomized Clinical Trial. JAMA Pediatr. 2019 Aug 5. doi: 10.1001/jamapediatrics.2019.2545. [Epub ahead of print]

Wolsk HM, Chawes BL, Litonjua AA, Hollis BW, Waage J, Stokholm J, Bønnelykke K, Bisgaard H, Weiss ST. Prenatal vitamin D supplementation reduces risk of asthma/recurrent wheeze in early childhood: A combined analysis of two randomized controlled trials. PLoS One. 2017 Oct 27;12(10):e0186657. doi: 10.1371/journal.pone.0186657. eCollection 2017.

Chawes BL, Bønnelykke K, Stokholm J, Vissing NH, Bjarnadóttir E, Schoos AM, Wolsk HM, Pedersen TM, Vinding RK, Thorsteinsdóttir S, Arianto L, Hallas HW, Heickendorff L, Brix S, Rasmussen MA, Bisgaard H. Effect of Vitamin D3 Supplementation During Pregnancy on Risk of Persistent Wheeze in the Offspring: A Randomized Clinical Trial. JAMA. 2016 Jan 26;315(4):353-61. doi: 10.1001/jama.2015.18318.

• Responsible Party: Copenhagen Studies on Asthma in Childhood
• ClinicalTrials.gov Identifier: NCT00856947
• Other Study ID Numbers: 2008-007871-26
• First Posted: March 6, 2009
• Last Update Posted: February 11, 2020
• Last Verified: February 2020

Keywords provided by Copenhagen Studies on Asthma in Childhood:

wheeze; infections; allergy; eczema; vitamin D

Additional relevant MeSH terms:

Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Vitamin D; Vitamins; Asthma; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Immune System Diseases; Cholecalciferol; Micronutrients; Nutrients; Growth Substances; Physiological Effects of Drugs; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents