Towards evidence-based vitamin D supplementation in infants: vitamin D intervention in infants (VIDI) — study design and methods of a randomised controlled double-blinded intervention study

Serum calcium and phosphate concentrations are tightly regulated by parathyroid hormone (PTH) and 1,25-OH₂D by negative feedback. Rickets is caused by insufficient vitamin D supply resulting in the lack of sufficient calcium and phosphate for bone mineralization at the growth plates [11]. The worldwide incidence of rickets is increasing [11]. Vitamin D deficiency is associated with low bone mineral density (BMD) and an unfavourable bone development in children aged 6–16 years and in newborns [12, 13]. However, data on the relationship between vitamin D and BMD in children are somewhat contradictory. In healthy children aged 8–17 years with S-25-OHD levels above 50 nmol/L, no effect of vitamin D supplementation on BMD is seen [14], and the relationship between BMD and S-25-OHD is inconsistent in infants and young children [15].

In infants, severe vitamin D deficiency (<25 nmol/L) associates with poor linear growth and delayed motor development possibly due to muscle weakness [16, 17]. In vitamin D deficient children, vitamin D supplementation improved growth velocity and prevented stunted growth [18, 19]. The increase in S-25-OHD concentration increased circulating IGF-1 level [18].

Rickets commonly presents with comorbidities such as continuous or recurrent respiratory infections [20, 21]. Vitamin D has profound effects on the immune system by promoting immune responses and inducing innate immune defences. Immune cells express vitamin D receptor (VDR) and respond to vitamin D [22, 23]. On innate immunity, vitamin D inhibits the expression of pattern-recognition receptors, induces autophagy in macrophages and induces endogenous antimicrobial peptides, such as cathelicidin. On adaptive immunity, for example, vitamin D acts by regulating the release of pro-inflammatory cytokines from mononuclear cells and inhibits T-cell proliferation through decreased Th1 cytokine secretion [24‐26]. Therefore, vitamin D does not only have a role in modulating host defence to infections, but is likely to control factors in autoimmunity, also in allergic disease.

Vitamin D modifies response to both bacterial and viral infections [24, 27]. In adults, vitamin D insufficiency increases the risk of severe infections [28], but the results from intervention trials are conflicting [29]. Vitamin D deficiency may contribute to increased occurrence of lower respiratory tract infections in children [30]. In 167 Japanese children aged 6–16 years a supplemental vitamin D3 of 1 200 IU for a period of 4 months resulted in a significant reduction in influenza A infections [31]. In addition, vitamin D deficiency is associated with upper respiratory tract, gastrointestinal and ear infections in children [32, 33]. Identification, treatment, and prevention of vitamin D deficiency in early childhood may therefore have widespread health effects throughout childhood.

In Finland, the prevalence of asthma among children aged 7–16 years is 7% [34]. Based on epidemiological studies, low maternal intake of vitamin D at pregnancy and low cord blood 25-OHD concentration have been associated with a higher risk for asthma, allergic rhinitis and atopic eczema in the offspring, as assessed at 5 years of age [35‐38]. However, findings have not been consistent [39] and recent studies on prenatal vitamin D supplementation have not demonstrated an effect on wheezing at 3 years of age [40, 41]. Vitamin D may, however, have a protective effect against childhood wheezing and asthma, but the evidence is inconclusive [42]. In adults, IgE concentrations are higher for those adults with low or very high concentration of serum 25-OHD (S-25-OHD) [43].

The association between concentrations of S-25-OHD and cognitive abilities has been widely studied among middle-aged and older individuals [44‐46]. Vitamin D trials are rare and they have not been able to support beneficial effects of vitamin D supplementation on cognitive functions among adults [47, 48]. Little evidence exists on the effects of vitamin D on the cognitive development among children and adolescents. Low concentrations of cord blood 25-OHD increased the risk for delayed mental and psychomotor development in 363 16–18-months-old children with severe vitamin D deficiency [49]. Surprisingly, also the children with the highest S-25-OHD concentrations had deficits in psychomotor development. However, S-25-OHD concentrations were not associated with cognitive performance in adolescents after controlling for ethnicity [50‐52]. Although preliminary results point to importance of early life exposure, the role of vitamin D in cognitive development during childhood and adolescence remains largely unstudied.

S-25-OHD concentration has high heritability (28–80%), which explains differences in responses to vitamin D supplementation [53]. Genome-wide association studies on vitamin D insufficiency identified a number of common genetic variants that influence 25-OHD concentrations and the risk of insufficiency [54]. These included single nucleotide polymorphisms in the GC gene encoding vitamin D binding protein, locus near the 7-dehydrocholesterol reductase involved in vitamin D synthesis in the skin, and CYP2R1 coding cytochrome P450 responsible for 25-hydroxylation. We have studied GC polymorphisms in relation to vitamin D metabolism and bone strength in children [55] and observed differences in S-25-OHD and PTH concentrations between GC genotypes and that variation exists in BMD and bone strength index as well. The variation in S-25-OHD between GC genotypes suggests differences in vitamin D utilisation. Polymorphisms of the vitamin D receptor gene VDR associate with growth pattern in infancy [56, 57] and with bone strength [58]. VDR polymorphisms together with vitamin D supplementation affect bone mineral accrual suggesting that vitamin D supplementation could be used to change the developmental trajectory and induce phenotype with lowered risk for chronic disease or disorder [59, 60]. Other possible candidate genes include CYP24A1 that encodes 24-hydroxylase initiating degradation of both 25-OHD and 1,25-OHD [54].