2021 Nicklas Brustad – MD

In this thesis, the effect of high-dose vitamin D supplementation (2800 IU/d) vs. standard recommended intake (400 IU/d) during pregnancy on common childhood health outcomes such as asthma, allergy, growth and bone health was investigated in children from the Danish population based COPSAC2010 mother-child cohort in a double-blinded randomized controlled trial (RCT). The children were followed longitudinally in a clinical setting with 12 scheduled visits from age 1 week until age 6 years to assess asthma, allergy and anthropometrics outcomes and 2 dual-energy x-ray absorptiometry (DXA) scans of the children were performed at age 3 and 6 years to assess body composition and bone mineralization. The children were diagnosed with asthma if they fulfilled the criteria of a pre-defined detailed algorithm of recurrent episodes of troublesome lung symptoms and a need for asthma medication during the first 6 years of childhood. The term “persistent wheeze” was used before the age of 3 years and hereafter the diagnosis was termed “asthma”.

In Paper I the effect of high-dose vitamin D on the child’s risk of asthma, allergy and related clinical measurements at age 6 years was analyzed in relation to the placebo group. We found no supplementation effect on asthma or allergy, and no effect on related outcomes such as lung function measurements, bronchial reactivity, airway inflammation and sensitization.

In Paper II the high-dose vitamin D supplementation in pregnancy improved the children’s bone mineralization status during the first 6 years of childhood compared with the placebo group. Additionally, a trend toward a reduced risk of developing childhood fractures was observed in the intervention group. There was no effect on any of the childhood growth parameters by age 6 years.

In Paper III the effect of vitamin D supplementation was investigated on the children’s risk of developing persistent wheeze during the first 3 years by maternal and child vitamin D pathway single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) gene and GC gene, encoding vitamin D binding protein (VDBP). The analyses were performed in two RCTs; the COPSAC2010 for discovery and the North American VDAART for replication. The study revealed that the effect of intervention on the children’s risk of persistent wheeze was significantly influenced by VDR genotype in the COPSAC2010 RCT, but not in VDAART. There was no effect modification by the GC gene in any of the RCTs.

In conclusion, a high-dose vitamin D RCT in the COPSAC2010 cohort with deep clinical phenotyping of the children was performed where a 7-fold increased dose was compared with the national recommended intake in search of a preventive strategy against common childhood diseases, which could have an impact on adulthood health as well.

The bone mineralization status already in childhood have been suggested to influence peak bone mass in early adulthood and might play a role in the risk of developing osteoporosis later in life. The positive finding of an intervention effect on bone mineralization in preschool-age children is plausible due to the effect of vitamin D on calcium and phosphate homeostasis in the body and act as two key components in forming the bone structure. The trend of fewer fractures registered in children from the vitamin D group during the follow-up period support this finding.

A targeted supplementation effect was assessed and revealed the strongest supplementation effect on bone mineralization in children born to mothers having initial low vitamin D levels or born during the winter period suggesting these pregnant women and their children to benefit most from the intervention. From a clinical perspective, these results could provide evidence for a future precision prevention strategy.