Relationship Between Vitamin D During Perinatal Development and Health

Vitamin D Metabolism

Vitamin D belongs to a group of sterols, with the two most important sterols being vitamin D₂ and vitamin D₃. The major difference between the two vitamin D sterols is the source from which they are obtained. When skin is exposed to ultraviolet sunlight, it synthesizes vitamin D₃, the most readily available form.^[3] However, the ability of skin to synthesize vitamin D₃ from sunlight exposure is adversely affected by factors that diminish the intensity of the exposure, such as poor air quality, extreme latitudes, and the winter season.^[4] In addition, factors that limit the skin's absorption of sunlight, such as increased pigmentation, the use of sunscreen, and advanced age, can also limit vitamin D₃ synthesis.^[4] Foods such as oily fish are an additional source of vitamin D₃, whereas plant sources provide vitamin D₂.^[3] However, the amount of vitamin D obtained through diet is often low and limited by malabsorption syndromes. Therefore, many people rely on fortified foods and dietary supplements to meet their vitamin D needs during times of insufficient sunlight. Vitamin D₃ supplements may be more effective at increasing serum levels of 25-hydroxyvitamin D (25(OH)D) than vitamin D₂ supplements.^[5] This may be because vitamin D₃ has a stronger affinity for vitamin D–binding protein, a transporter that mediates its delivery to muscle or fat for storage, or liver and kidney for bioactivation.

Both forms of vitamin D are biologically inert and must undergo two metabolic steps before becoming physiologically active. The first step occurs in the liver, which converts vitamin D to 25(OH)D, the main circulating form and the usual measure of vitamin D status. This conversion to 25(OH)D is impeded in those with liver disease. According to a recent study, 92% of patients with chronic liver disease are vitamin D deficient. Vitamin D deficiency is defined by serum 25(OH)D concentrations below 10 ng/mL (25 nmol/L), because values below this cut-off are associated with rickets and myopathy.^[6]

The second metabolic step occurs in the kidney and many other tissues (i.e., heart, brain, skin, reproductive tissue, skeletal muscle, spinal cord, and the placenta) and forms the physiologically active hormone 1,25-dihydroxyvitamin D [1,25(OH)₂D].^[7] The 1,25(OH)₂D is released into the circulatory system and can stimulate target cells in close proximity through its autocrine and paracrine functions.^[7,8] Moreover, 1,25(OH)₂D can bind to vitamin D receptor (VDR) and modulate many cellular and immunologic processes.^[9] The expression of VDR has been identified in most organs and several types of white blood cells, indicating that the vitamin D endocrine system is essential for the development and maintenance of tissue structure and function.

Table 1. Epidemiologic Evidence Linking Vitamin D and Disease
Disease Relationship	Variables Used in Epidemiology to Infer a Relationship to Vitamin D
Sun Exposure	Migration Away From High Sun Exposure	Season of Birth	Skin Pigmentation	Dietary Vitamin D
Osteomalacia and rickets	Decreased sun exposure in third trimester is associated with decreased bone mass²⁹	Afro-Caribbean immigrants in the UK are associated with an increased incidence of rickets⁶⁸	To our knowledge, no epidemiologic studies have shown this relationship	Children with darker skin have a higher prevalence of having poor bone health and rickets^17,69,70	Low maternal 25(OH)D concentrations during pregnancy are associated with decreased bone mineral content in children at 9 years of age²⁹ Vitamin D deficiency in early life is associated with rickets, mild respiratory distress, weak muscle tone, decreased calcium and increased parathyroid hormone levels⁷¹
Multiple sclerosis (MS)	Increased sun exposure during early life is associated with a decreased risk of MS⁷² MS relapse is inversely associated with UV exposure and 25(OH)D levels⁷³	Indian and Pakistani immigrants who enter the UK between 0–4 years of age are at increased risk of having MS⁷⁴ Second-generation Afro-Caribbean immigrants in the UK are associated with an increased MS risk⁷⁵	Data pooled from 4 countries shows that spring births are associated with an increased MS risk and fall births are associated with a decreased MS risk⁷⁶	Having white skin lowers the prevalence of MS disability⁷⁷	Consumption of fish 3–4 times a week is associated with a decreased MS risk⁷² Diets low in fish but high in meat and dairy products are associated with an increased prevalence of MS⁷⁸ Intake of vitamin D from supplements is inversely associated with MS risk⁷⁹
Schizophrenia	Increased sun exposure is associated with decreased risks of having schizophrenia, and schizophrenia-induced symptoms are weaker and less regular⁸⁰	Second-generation immigrants from Morocco and Surinam to the Netherlands are associated with an increased risk of schizophrenia⁸¹ Afro-Caribbean immigrants to the UK are associated with an increased risk of schizophrenia⁸²	Data pooled from 6 countries shows that winter births are associated with an increased incidence of schizophrenia^{83, 84}	Having black skin may be associated with an increased incidence of schizophrenia⁸⁵	Vitamin D supplementation during the first year of life lowered the risk of developing schizophrenia in males, but not females⁸⁶ Maternal 25(OH)D was not a risk factor for schizophrenia. But the results in the black subgroup raise the possibility that below a certain threshold low levels of 25(OH)D may be associated with an increased risk of schizophrenia⁸⁵
Type 1 diabetes	Monthly sunshine availability is inversely associated with having type 1 diabetes⁸⁷	Children who migrated to an area prevalent in diabetes (northern region) had a greater risk of developing type 1 diabetes⁸⁸	Winter and spring births are associated with higher frequency of type 1 diabetes^89–91 than summer births⁹¹	Children with black skin are at a higher risk of having type 1 diabetes than children with white skin⁹²	In a meta-analysis, vitamin D supplementation was associated with a decreased risk of type 1 diabetes⁹³ Children who consumed vitamin D supplements had an 80% lower risk of having type 1 diabetes⁵⁵ Use of cod liver oil by mothers during pregnancy and infants in the first year of life lowered the infants' risk of developing type 1 diabetes⁵⁶

Table 1. Epidemiologic Evidence Linking Vitamin D and Disease

Disease Relationship

Variables Used in Epidemiology to Infer a Relationship to Vitamin D

Sun Exposure

Migration Away From High Sun Exposure

Season of Birth

Skin Pigmentation

Dietary Vitamin D

Osteomalacia and rickets

Decreased sun exposure in third trimester is associated with decreased bone mass²⁹

Afro-Caribbean immigrants in the UK are associated with an increased incidence of rickets⁶⁸

To our knowledge, no epidemiologic studies have shown this relationship

Children with darker skin have a higher prevalence of having poor bone health and rickets^17,69,70

Low maternal 25(OH)D concentrations during pregnancy are associated with decreased bone mineral content in children at 9 years of age²⁹
Vitamin D deficiency in early life is associated with rickets, mild respiratory distress, weak muscle tone, decreased calcium and increased parathyroid hormone levels⁷¹

Multiple sclerosis (MS)

Increased sun exposure during early life is associated with a decreased risk of MS⁷²
MS relapse is inversely associated with UV exposure and 25(OH)D levels⁷³

Indian and Pakistani immigrants who enter the UK between 0–4 years of age are at increased risk of having MS⁷⁴
Second-generation Afro-Caribbean immigrants in the UK are associated with an increased MS risk⁷⁵

Data pooled from 4 countries shows that spring births are associated with an increased MS risk and fall births are associated with a decreased MS risk⁷⁶

Having white skin lowers the prevalence of MS disability⁷⁷

Consumption of fish 3–4 times a week is associated with a decreased MS risk⁷²
Diets low in fish but high in meat and dairy products are associated with an increased prevalence of MS⁷⁸
Intake of vitamin D from supplements is inversely associated with MS risk⁷⁹

Schizophrenia

Increased sun exposure is associated with decreased risks of having schizophrenia, and schizophrenia-induced symptoms are weaker and less regular⁸⁰

Second-generation immigrants from Morocco and Surinam to the Netherlands are associated with an increased risk of schizophrenia⁸¹
Afro-Caribbean immigrants to the UK are associated with an increased risk of schizophrenia⁸²

Data pooled from 6 countries shows that winter births are associated with an increased incidence of schizophrenia^{83, 84}

Having black skin may be associated with an increased incidence of schizophrenia⁸⁵

Vitamin D supplementation during the first year of life lowered the risk of developing schizophrenia in males, but not females⁸⁶
Maternal 25(OH)D was not a risk factor for schizophrenia. But the results in the black subgroup raise the possibility that below a certain threshold low levels of 25(OH)D may be associated with an increased risk of schizophrenia⁸⁵

Type 1 diabetes

Monthly sunshine availability is inversely associated with having type 1 diabetes⁸⁷

Children who migrated to an area prevalent in diabetes (northern region) had a greater risk of developing type 1 diabetes⁸⁸

Winter and spring births are associated with higher frequency of type 1 diabetes^89–91 than summer births⁹¹

Children with black skin are at a higher risk of having type 1 diabetes than children with white skin⁹²

In a meta-analysis, vitamin D supplementation was associated with a decreased risk of type 1 diabetes⁹³
Children who consumed vitamin D supplements had an 80% lower risk of having type 1 diabetes⁵⁵
Use of cod liver oil by mothers during pregnancy and infants in the first year of life lowered the infants' risk of developing type 1 diabetes⁵⁶

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Relationship Between Vitamin D During Perinatal Development and Health

Vitamin D Metabolism

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