Epidemiology

Vitamin D deficiency is one of the most common nutritional deficiency worldwide in both children and adults.[1][2][11][12][13]​​​ The burden of vitamin D deficiency and inadequacy varies by world regions.​​​​[1][11]​ It has been estimated worldwide that 40% of children and adults are vitamin D deficient and 60% are deficient or insufficient.[1]​ In National Health and Nutrition Examination Survey (NHANES) data from 2011 to 2014, 5% of the US population aged ≥1 year was at risk of vitamin D deficiency and 18% was at risk of inadequacy.[14]

​In Europe, more than 40% of the population is vitamin D-deficient, with differences between European regions.[15] In the UK, around 30% to 40% of the population has a vitamin D concentration consistent with deficiency in winter, compared to 2% to 13% in the summer.[16]​ The prevalence of vitamin D deficiency in the Middle East varies between 30% and 90%.[15]

​Vitamin D deficiency affects individuals in all age groups worldwide.[13]​ The vitamin D status of infants depends on maternal prenatal vitamin D status. Globally, vitamin D deficiency is present in 54% of pregnant women and 75% of newborns.[13]​ Levels of serum 25-hydroxyvitamin D consistent with vitamin D deficiency (<50 nanomoles/L [<20 nanograms/mL]) have been reported in 48% of pre-teen white girls, 52% of adolescent Hispanic and black American boys and girls, and 32% of healthy young adults.[17][18][19][20] Dark-skinned ethnic groups have a higher prevalence of vitamin D deficiency than white groups.[11][12][13][14]​ However, multiple factors (age, diet, season, geographical latitude, cultural/lifestyle factors, skin pigmentation, differences in vitamin D metabolism) affect an individual’s risk of vitamin D deficiency and regional prevalence.[13]

Fortification of foods with vitamin D and use of vitamin supplements have greatly reduced the incidence of clinically significant vitamin D deficiency; however, vitamin D deficiency persists despite fortification policies that aim to ensure adequate intake.[13]​ In many regions, vitamin D deficiency still occurs with the consumption of unfortified foods, especially in the setting of limited sunlight exposure.

It is now recognised that vitamin D deficiency increases the risk of many chronic diseases, including cancer, autoimmune diseases, type 2 diabetes, heart disease and hypertension, neurocognitive dysfunction, and infectious diseases (including respiratory tract infections, tuberculosis, and COVID-19).[1][2][21][22]​​​

​A strong association of vitamin D deficiency with an increased risk of prostate, colon, breast, ovarian, and pancreatic cancers, among many others, has been reported.[23]​ Meta-analysis concluded that vitamin D supplementation significantly reduced total cancer mortality, but did not reduce total cancer incidence.[24][25]

​Finland has the highest incidence of type 1 diabetes in the world, which is postulated to be associated with the high rate of vitamin D deficiency.[21]​ A study in Finland found that infants who had received 2000 IU of vitamin D per day for the first year of life reduced their risk of type 1 diabetes by 78% 31 years later.[26] Lower vitamin D levels are associated with an increased risk of multiple sclerosis.[27] Furthermore, it has been shown that women with a high intake of vitamin D reduce their risk of developing multiple sclerosis by more than 40%.[28]​ Epidemiological studies confirm a high prevalence of vitamin D deficiency in several autoimmune rheumatic diseases, including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, systemic sclerosis, and systemic lupus erythematosus.[29]​ A study of patients with juvenile-onset systemic lupus erythematosus suggested that vitamin D3 supplementation for 24 weeks was effective in decreasing disease activity and improving fatigue.[30]

Results from the Third National Health and Nutrition Examination Survey (NHANES 3) revealed that, for adults who had the highest levels of serum 25-hydroxyvitamin D, the relative risk of developing type 2 diabetes was reduced by 33%.[31][32]​ In a study using 2011–2018 NHANES data, adults in the lowest serum 25-hydroxyvitamin D quartile had 2 times greater odds of being insulin-resistant, compared with the other three quartiles combined.[33]

​In a meta-analysis, a significantly lower proportion of participants in the vitamin D supplementation group had one or more acute respiratory infections.[34]​ This is consistent with the observation from NHANES 3 demonstrating that children and adults with the highest serum levels of 25-hydroxyvitamin D were less likely to develop respiratory tract infections throughout the year.​​[35]​ School children in Mongolia who ingested milk fortified with 300 IU of vitamin D3 reduced their risk of having an acute respiratory infection by approximately 50%.[36] Furthermore, a study showed that children in Japan who received 1200 IU vitamin D3 from December to the end of March demonstrated a reduced risk for influenza infection of almost 50%.[37]

Improvement in vitamin D status of children and adults has become a high priority in the COVID-19 era. One retrospective observational study of more than 191,000 blood samples from COVID-19 positive patients revealed that those who had a blood level of 25-hydroxyvitamin D of at least 85 nanomoles/L (34 nanograms/mL) in the preceding 12 months had a 54% reduced risk of being infected with severe acute respiratory syndrome coronavirus-2 compared with those who had a serum concentration of 25-hydroxyvitamin D of less than 50 nanomoles/L (20 nanograms/mL).[38]​ There continued be a further decline in infectivity with increasing concentrations up to a serum concentration of 25-hydroxyvitamin D of 37.5 nanomoles/L (55 nanograms/mL).[38]

​In a study of US veterans who were hospitalised with COVID-19, after adjusting for all covariates including race/ethnicity and poverty, there was a significant independent inverse dose-response relationship between increasing serum concentrations of 25-hydroxyvitamin D from 38-150 nanomol/L (15-60 nanograms/mL) and decreasing hospitalisation by 23% and mortality by 48%.[39]​ Another observational study reported similar results in patients hospitalised with COVID-19; severe disease infection was less prevalent in patients with vitamin D sufficiency and they had a reduced risk for mortality.[40]​ Vitamin D deficiency/insufficiency was associated with higher C-reactive protein and a lower lymphocyte percentage, which is consistent with the immunomodulatory effect of vitamin D.[40]​ Being vitamin D sufficient (defined as a serum concentration of 25-hydroxyvitamin D of at least 75 nmol/L [30 nanograms/mL])​, substantially reduced infectivity, morbidity, and mortality from COVID-19.[41]​ Increased continuous serum concentrations of 25-hydroxyvitamin D up to 150 nanomol/L (60 nanograms/mL) are considered preferable to minimise risk from COVID-19 infection.[41]

​Vitamin D deficiency has been linked with increased risk of cardiovascular disease.[42]​ An umbrella review of observational studies, RCTs, and Mendelian randomisation studies reported consistent results demonstrating that lower concentrations of vitamin D were associated with a higher risk for all-cause mortality, Alzheimer's disease, hypertension, schizophrenia, and type 2 diabetes.[43]

Some studies have raised questions about the value and effectiveness of vitamin supplementation for preventing cancers, cardiovascular events, and cognitive decline and treating hypertension.[44]​​[45]​​​[46] The VITamin D and OmegA-3 TriaL (VITAL) study, a large randomised controlled trial evaluating vitamin D3 supplementation for the prevention of cancer and cardiovascular disease, concluded that 2000 IU of vitamin D daily did not lower the incidence of major cardiovascular events.[47] However, it found that vitamin D supplementation significantly reduced the risk of mortality associated with cancer.[48]​ The umbrella review showed that vitamin D supplementation was associated with a decreased risk for all-cause mortality, but not associated with the risk for Alzheimer's disease, hypertension, schizophrenia, or type 2 diabetes.[43]

​It has also been observed that vitamin D deficiency is linked to pre-eclampsia, low birth weight and preterm birth, and an increased risk of having a caesarean section.​[49][50][51]​​​ Vitamin D3 supplementation during the third trimester enhanced prenatal linear growth.[52]​​​ One meta-analysis revealed on the basis of available evidence that there was an association with vitamin D status and several outcomes in children including birth weight and dental caries.[53]

Furthermore, it has been suggested that many of the health disparities in black Americans are due to vitamin D deficiency.[54] Black Americans have a higher risk of developing hypertension and type 2 diabetes than white Americans. They also have a higher incidence of prostate, colon, and breast cancer that tends to be more aggressive. In addition, black Americans are at higher risk for contracting tuberculosis, particularly more aggressive disease, which is thought to be in part due to vitamin D deficiency.[55]

One meta-analysis concluded that vitamin D supplementation safely and substantially reduced the rate of moderate/severe COPD exacerbations in patients with baseline 25-hydroxyvitamin D concentrations <25 nanomoles/L (<10 nanograms/mL), but not in those with higher levels.[56][Evidence A]​ One Cochrane review did not find evidence to support a role for vitamin D supplementation to reduce risk of asthma exacerbations or improve asthma control.[57]

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