VITAMIN D

Fetal Risk Summary

Vitamin D analogues 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).

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 analogue, 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 (2,3 and 4). The full features of this rare condition are characteristic elfin facies, mental and growth retardation, 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 syndrome has not been consistently found (2,3,5). Although the exact cause is unknown, it is possible that the syndrome results from abnormal vitamin D metabolism in the mother, the fetus, or both.

Very high levels of vitamin D have been used to treat maternal hypoparathyroidism during pregnancy (6,7,8 and 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 up to 3 µg/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, full-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 (11,12,13,14,15,16,17,18,19,20 and 21). Pitkin, in a 1985 article, reviewed the relationship between vitamin D and calcium metabolism in pregnancy (22).

Although rare in the United States, 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 (11,12,13,14,15,16,17,18,19,20 and 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 (12,13 and 14,20,) Neonatal hypocalcemia with convulsions (tetany) (15,16 and 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).

A number of investigators have measured vitamin D levels in the mother during pregnancy and in the newborn (24,25,26,27,28,29,30,31,32,33 and 34). Although not universal, most studies have found a significant correlation between maternal serum and cord blood levels (24,25,26,27 and 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 at term are usually higher than those in the newborn because the fetus has no need for intestinal calcium absorption (24,25,26,27,28,29 and 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).

[*Risk Factor D if used in doses above the RDA.]

Breast Feeding Summary

Vitamin D is excreted into breast milk in limited amounts (36). A direct relationship exists between maternal serum levels of vitamin D and the concentration in breast milk (37). Chronic maternal ingestion of large doses may lead to greater than normal vitamin D activity in the milk and resulting hypercalcemia in the infant (38). In the lactating woman who is not receiving supplements, there is considerable controversy about whether her milk contains sufficient vitamin D to protect the infant from vitamin deficiency. Several studies have supported the need for infant supplementation during breast feeding (12,36,39,40 and 41). Other investigators have concluded that supplementation is not necessary if maternal vitamin D stores are adequate (28,42,43 and 44).

A study published in 1977 measured high levels of a vitamin D metabolite in the aqueous phase of milk (45). Although two other studies supported these findings, the conclusions were in direct opposition to previous measurements and have been vigorously disputed (46,47). 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 breast-fed infants (40,41,48,49,50). 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 (51). Vitamin D activity in the milk was 40–50 IU/L, with 90% of this accounted for by the usual fat-soluble components.

The National Academy of Sciences' RDA for vitamin D in the lactating woman is 400 IU (1). The Committee on Nutrition, American Academy of Pediatrics, recommends vitamin D supplements for breast-fed infants if maternal vitamin D nutrition is inadequate or if the infant lacks sufficient exposure to ultraviolet light (52). A second committee of the American Academy of Pediatrics considers maternal consumption of vitamin D to be compatible with breast feeding (53). However, the serum calcium levels of the infant should be monitored if the mother is receiving pharmacologic doses (53).

References

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5. Anita AU, Wiltse HE, Rowe RD, Pitt EL, Levin S, Ottesen OE, Cooke RE. Pathogenesis of the supravalvular aortic stenosis syndrome. J Pediatr 1967;71:431–41.
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