Relationship Between Vitamin D During Perinatal Development and Health

Current Vitamin D Recommendations and Target Levels for Serum 25(OH)D

In 1997, the Institute of Medicine's Food and Nutrition Board (FNB) recommended that the daily vitamin D intake for pregnant and lactating women be 200 IU (5 mcg).^[6] However, most clinicians recommend a daily vitamin D supplement of 400 IU per day (10 mcg), because this amount is included in most prenatal multivitamins in the United States.^[7] A dose of 400 IU per day raises serum 25(OH)D by 2.8 to 4.8 ng/mL (7–12 nmoL/L)^[60] but is often ineffective for resolving vitamin D deficiency.

Measuring serum 25(OH)D concentrations will identify vitamin D deficiency in pregnancy. Levels of less than 10 ng/mL (<25 nmoL/L) indicate severe vitamin D deficiency that can result in rickets or have adverse effects on overall health.^[6] Concentrations between 10 to 20 ng/mL (25–50 nmoL/L) reflect vitamin D inadequacy and are common in northern regions that have low sun exposure. Higher concentrations—those above 32 ng/mL (>80 nmoL/L)—are proposed as adequate for overall health and disease prevention. Ultra high concentrations of 25(OH)D >200 ng/mL (>500 nmoL/L) are considered potentially toxic, although human data are limited. Vitamin D toxicity may lead to nonspecific symptoms, such as nausea, vomiting, poor appetite, constipation, weakness, and weight loss, or more serious conditions, such as hypercalcemia and hyperphosphatemia.

The National Health and Nutrition Examination Survey (1988–2004) found that 4% of white and 42% of black women of childbearing age residing in the United States have serum 25(OH)D levels less than 10 ng/mL, consistent with a diagnosis of severe vitamin D deficiency.^[61] A more recent study (2007) revealed similar trends,^[26] indicating that the widespread problem of vitamin D deficiency still persists. Emerging research suggests that more than 1000 IU per day (25 mcg/day) may be needed during pregnancy and lactation to achieve adequate levels of serum 25(OH)D.^[12,62] However, the tolerable upper intake limit of 2000 IU per day that was set by the FNB in 1997 (based on a report by Narang et al.^[63]) has impeded the ability to change policy.^[6] The report, by Narang et al.,^[63] showed that mean serum calcium concentrations were abnormally high in six healthy subjects who consumed 3800 IU per day for 3 months.^[63] However, this study did not report data on serum 25(OH)D concentrations that would verify the vitamin D dose used, and without other studies being able to replicate these findings, the quality of data is highly questionable. A recent risk assessment study that evaluated 21 available clinical trials of vitamin D supplementation concluded that 10,000 IU per day may be a more appropriate upper limit for vitamin D supplementation.^[64] A pilot clinical trial in childbearing women revealed that maternal vitamin D supplementation of 6400 IU per day for 6 months can ensure that both the mother and the infant have adequate 25(OH)D status, and that their serum and urinary calcium are in the normal range.^[7]

If ongoing research confirms these results, it may help to change policy on vitamin D intake during pregnancy and lactation. In 2008, the FNB established an expert committee to reevaluate adequate vitamin D intakes for healthy populations and reassess indicators of adequacy, hazard, health outcomes, and risk factors (i.e., skin pigmentation, age, sex, and sunlight exposure). The new report on vitamin D intake is expected in late 2010. As of 2009, however, only the Canadian Paediatric Society has made a recommendation for higher doses of vitamin D (2000 IU daily) to be taken by women during pregnancy.^[65]

The high incidence of vitamin D deficiency among mothers is reflected in their newborn infants, with 10% of white and 46% of black neonates having 25(OH)D concentrations below 15 ng/mL.^[26] Low concentrations of 25(OH)D will impair neonatal development and pose a threat to adult health. Serum 25(OH)D concentrations that are greater than 10 ng/mL are necessary in infants 0 to 12 months of age to avoid vitamin D–induced rickets and osteomalacia. A lactating mother who consumes a daily vitamin D dose of 200 to 400 IU will have approximately 20 to 70 IU/L in her breast milk, which is inadequate for infant development. Moreover, infants are typically not exposed to ample amounts of sunlight. Therefore, to achieve adequate serum concentrations of 25(OH)D, an infant must consume a minimum of 200 IU (5 mcg) of vitamin D per day. Although this level is deemed adequate by the FNB to minimize the risk of developing diseases, the American Academy of Pediatrics recommends that breastfed, healthy term infants receive a daily vitamin D supplement of 400 IU (10 mcg).^[66] For nonbreastfed infants, formulas and baby food products are fortified with 400 IU of vitamin D per litre of formula.^[67] However, if an infant is not consuming at least one liter (32 oz) of formula per day, these recommendations for vitamin D intake will not be met because vitamin D is scarce in other sources of an infant's diet. Vitamin D supplementation should begin at birth and continue until the infant's diet includes at least 400 IU (10 μg) of vitamin D per day.

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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