Vitamin
PREGNANCY RECOMMENDATION: Compatible
BREASTFEEDING RECOMMENDATION: Compatible
PREGNANCY SUMMARY
Vitamin D analogs are a group of fat-soluble nutrients essential for human life with antirachitic and hypercalcemic activity (1). The National Academy of Sciences’ recommended dietary allowance (RDA) for normal pregnant women in the United States is 400 IU (1). However, based on evidence that vitamin D deficiency is very common in pregnancy, a much higher dose is required to prevent and treat the deficiency. Although the required pregnancy dose is still under investigation, it may be in the range of 1000–2000 IU of vitamin D3/day or 50,000 IU of vitamin D2 every 2 weeks (see reference 37).
FETAL RISK SUMMARY
The two natural biologically active forms of vitamin D are 1,25-dihydroxyergocalciferol and calcitriol (1,25-dihydroxyvitamin D3) (1). A third active compound, 25-hydroxydihydrotachysterol, is produced in the liver from the synthetic vitamin D analog, dihydrotachysterol.
Ergosterol (provitamin D2) and 7-dehydrocholesterol (provitamin D3) are activated by ultraviolet light to form ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3), respectively. These, in turn, are converted in the liver to 25-hydroxyergocalciferol and calcifediol (25-hydroxyvitamin D3), the major transport forms of vitamin D in the body. Activation of the transport compounds by enzymes in the kidneys results in the two natural active forms of vitamin D.
The commercially available forms of vitamin D are ergocalciferol, cholecalciferol, calcifediol, calcitriol, and dihydrotachysterol. Although differing in potency, all of these products have the same result in the mother and fetus. Thus, only the term vitamin D, unless otherwise noted, will be used in this monograph.
High doses of vitamin D are known to be teratogenic in experimental animals, but direct evidence for this is lacking in humans. Because of its action to raise calcium levels, vitamin D has been suspected in the pathogenesis of the supravalvular aortic stenosis syndrome, which is often associated with idiopathic hypercalcemia of infancy (2–4). The full features of this rare condition are characteristic elfin facies, mental and growth restriction, strabismus, enamel defects, craniosynostosis, supravalvular aortic and pulmonary stenosis, inguinal hernia, cryptorchidism in males, and early development of secondary sexual characteristics in females (2). Excessive intake or retention of vitamin D during pregnancy by mothers of infants who develop supravalvular aortic stenosis (SAS) syndrome has not been consistently found (2,3,5). However, it is now known that SAS syndrome is a feature of a severe genetic affliction, Williams syndrome, and is not caused by vitamin D (see reference 36).
Very high levels of vitamin D have been used to treat maternal hypoparathyroidism during pregnancy (6–9). In two studies, 15 mothers were treated with doses averaging 107,000 IU/day throughout their pregnancies to maintain maternal calcium levels within the normal range (6,7). All of the 27 children were normal at birth and during follow-up examinations ranging up to 16 years. Calcitriol, in doses ≤3 mcg/day, was used to treat another mother with hypoparathyroidism (8). The high dose was required in the latter half of pregnancy to prevent hypocalcemia. The infant had no apparent adverse effects from this exposure. In a similar case, a mother received 100,000 IU/day throughout gestation, resulting in a healthy, term infant (9). In contrast, a 1965 case report described a woman who received 600,000 IU of vitamin D and 40,000 IU of vitamin A daily for 1 month early in pregnancy (10). The resulting infant had a defect of the urogenital system, but this was probably caused by ingestion of excessive vitamin A (see Vitamin A).
Vitamin D deficiency can be induced by decreased dietary intake or lack of exposure to sunlight. The conversion of provitamin D3 to vitamin D3 is catalyzed by ultraviolet light striking the skin (1). Severe deficiency during pregnancy, resulting in maternal osteomalacia, leads to significant morbidity in the mother and fetus (11–21). Pitkin (22), in a 1985 article, reviewed the relationship between vitamin D and calcium metabolism in pregnancy.
The peak incidence of vitamin D deficiency occurs in the winter and early spring when exposure to sunlight is at a minimum. Certain ethnic groups, such as Asians, seem to be at greater risk for developing this deficiency because of their dietary and sun exposure habits (11–21). In the pregnant woman, osteomalacia may cause, among other effects, decreased weight gain and pelvic deformities that prevent normal vaginal delivery (11,12). For the fetus, vitamin D deficiency has been associated with the following:
Reduced fetal growth (11,12)
Neonatal hypocalcemia without convulsions (12–14,20)
Neonatal hypocalcemia with convulsions (tetany) (15–17)
Neonatal rickets (18,19)
Defective tooth enamel (21,23)
Long-term use of heparin may induce osteopenia by inhibiting renal activation of calcifediol to the active form of vitamin D3 (calcitriol or 1,25-dihydroxyvitamin D3) (22). The decreased levels of calcitriol prevent calcium uptake by bone and result in osteopenia (see reference 23 for detailed review of calcium metabolism in pregnancy). One investigator suggests that these patients may benefit from treatment with supplemental calcitriol (22).
Numerous investigators have measured vitamin D levels in the mother during pregnancy and in the newborn (24–34). Although not universal, most studies have found a significant correlation between maternal serum and cord blood levels (24–28). In one study, a close association between both of the transport vitamin D forms in maternal and cord serum was discovered (29). No significant correlation could be demonstrated, however, between the two biologically active forms in maternal and cord blood.
Using a perfused human placenta, a 1984 report confirmed that calcifediol and calcitriol were transferred from the mother to the fetus, although at a very slow rate (35). Binding to vitamin D3-binding protein was a major rate-limiting factor, especially for calcifediol, the transport form of vitamin D3. The researchers concluded that placental metabolism of calcifediol was not a major source of fetal calcitriol (35).
Maternal levels of vitamin D at term are usually higher than those in the newborn because the fetus has no need for intestinal calcium absorption (24–30). Maternal levels are elevated in early pregnancy and continue to increase throughout pregnancy (32). During the winter months a weak correlation may exist between maternal vitamin D intake and serum levels, with exposure to ultraviolet light the main determinant of maternal concentrations (33,34). A Norwegian study, however, was able to increase maternal concentrations of active vitamin D significantly during all seasons with daily supplementation of 400 IU (29).
A 2004 review discussed vitamin D requirements during pregnancy and lactation (36). The daily recommended dose of 200–400 IU was based on erroneous data and was thought to be too low, especially for persons with darkly pigmented skin. Although the appropriate dose in pregnancy and lactation as a function of latitude and race is unknown, the authors thought that daily doses exceeding 1000 IU vitamin D, such as 2000–10,000 IU, were required to overcome vitamin D deficiency and/or to maintain normal blood concentrations of vitamin D. They also cited published evidence showing that the cause of supravalvular aortic stenosis syndrome was actually a severe genetic disorder, Williams syndrome, and was not associated with high concentrations of vitamin D (36).
In a 2007 review of vitamin D deficiency, the recommended doses of vitamin D to prevent and maintain vitamin D concentrations to avoid deficiency in pregnancy or lactation caused by fetal utilization, inadequate sun exposure, or supplementation were vitamin D3: 1000–2000 IU/day, up to 4000 IU/day is safe for 5 months; vitamin D2: 50,000 IU every 2 or 4 weeks (37). To treat deficiency caused by the above three conditions, the recommended dose of vitamin D2 was 50,000 IU every week for 8 weeks and, if the 25-hydroxyvitamin D concentration was <30 ng/mL, repeated for another 8 weeks (37).
In a study reported in 2010, vitamin D levels were measured in 928 pregnant women and 5173 nonpregnant women (38). The mean concentrations in the two groups were 65 and 59 nmol/L (26 and 24 ng/mL), respectively, with a prevalence of <75 nmol/L (<30 ng/mL) in 69% and 78%, respectively. Based on recent evidence, the investigators considered 75 or 100 nmol/L (30 or 40 ng/mL) to be required for optimal health. The clinical implications from this research were: (a) current recommendations for vitamin D supplementation of 200–400 IU/day are inadequate for many women and their infants; (b) vitamin D supplementation should begin a few months before pregnancy; and (c) further studies are required to determine the dose for vitamin D supplementation (38).
A 2010 report noted that vitamin D deficiency was estimated to occur in up to 50% of pregnant women and, compared with other groups African American women had a much higher risk (39). The authors described the effects of vitamin D deficiency on the mother and newborn based on serum concentrations of vitamin D. The maternal effects of severe deficiency (defined as <10 ng/mL) were an increased risk of preeclampsia, calcium malabsorption, bone loss, poor weight gain, myopathy, and higher parathyroid hormone levels, whereas those in the newborn included small for gestational age, hypocalcemia with possible seizures, heart failure, enamel defects, large fontanelle, congenital rickets, and rickets of infancy if breastfed. For serum concentrations (11–32 ng/mL) considered insufficient, the maternal effects were bone loss and subclinical myopathy, whereas those in the newborn were hypocalcemia, decreased bone mineral activity, and rickets if breastfed. There were no maternal or newborn adverse effects if the vitamin D concentration was 32–100 ng/mL, but levels >100 ng/mL could cause maternal hypercalcemia and increased urine calcium loss, and hypercalcemia in the newborn (39).
BREASTFEEDING SUMMARY
Vitamin D is excreted into breast milk in limited amounts (40). A direct relationship exists between maternal serum levels of vitamin D and the concentration in breast milk (41). Chronic maternal ingestion of large doses may lead to greater than normal vitamin D activity in the milk and resulting hypercalcemia in the infant (42). In the lactating woman who was not receiving supplements, controversy exists about whether her milk contained sufficient vitamin D to protect the infant from vitamin deficiency. Several studies had supported the need for infant supplementation during breastfeeding (12,40,43–45). Other investigators had concluded that supplementation is not necessary if maternal vitamin D stores are adequate (28,46–48).
The National Academy of Sciences’ RDA for vitamin D in the lactating woman is 400 IU (1). However, recent evidence suggests that vitamin D supplementation of lactating women with much higher doses is necessary to increase the nutritional vitamin D status of the mother and her breastfeeding infant (36,37). This is especially true for darkly pigmented individuals and those having limited exposure to ultraviolet light. Although the required dose has not been adequately studied, doses identical to those described for pregnancy (see Fetal Risk Summary section) have been suggested (37).
A study published in 1977 measured high levels of a vitamin D metabolite in the aqueous phase of milk (49). Although two other studies supported these findings, the conclusions were in direct opposition to previous measurements and have been vigorously disputed (50,51). The argument that human milk is low in vitamin D is supported by clinical reports of vitamin D deficiency-induced rickets and decreased bone mineralization in breastfed infants (44,45,52–54). Moreover, one investigation measured the vitamin D activity of human milk and failed to find any evidence for significant activity of water-soluble vitamin D metabolites (55). Vitamin D activity in the milk was 40–50 IU/L, with 90% of this accounted for by the usual fat-soluble components.
The Committee on Nutrition, American Academy of Pediatrics, recommends vitamin D supplements for breastfed infants if maternal vitamin D nutrition is inadequate or if the infant lacks sufficient exposure to UV light (56). A second committee of the American Academy of Pediatrics classifies vitamin D as compatible with breastfeeding, but recommends monitoring the serum calcium levels of the infant if the mother is receiving pharmacologic doses (57).
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