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This is related to a concomitant increase in plasma vitamin D binding protein (DBP) (Bikle et al., 1984; Ardawi et al., 1997). Free calcitriol levels do not increase until the third trimester (Bikle et al., 1984; Specker, 2004; Kovacs, 2008). The main source of calcitriol is from the maternal renal 1α-hydroxylase, with little contribution from the placenta even though it expresses 1α-hydroxylase, based on the case report of a pregnant anephric woman whose low levels of calcitriol increased less than 15 percent by the beginning of the third trimester (Turner et al., 1988). Despite the increased synthesis of calcitriol during pregnancy and the passage of 25OHD across the placenta to the fetus, maternal serum 25OHD levels are relatively unaffected by pregnancy (Hillman et al., 1978; Brooke et al., 1980; Cross et al., 1995; Ardawi et al., 1997; Morley et al., 2006; Papapetrou, 2010), although one report noted a significant decline by the third trimester in Saudi women (Ardawi et al., 1997). Even when baseline serum 25OHD level was in the severely deficient range (mean 20.1 ± 1.9 nmol/L), the serum levels did not change significantly by the end of pregnancy (Brooke et al., 1980).

The increase in maternal intestinal calcium absorption has been positively associated with the increase in maternal serum calcitriol levels in observational studies in humans (Cross et al., 1995; Ritchie et al., 1998). Certain results from studies in animal models are relevant to understanding the changes in vitamin D physiology that occur during human pregnancy. Intestinal calcium absorption is markedly up-regulated in pregnant vitamin D–deficient rats and in mice lacking the VDR (Vdr-null mice) to the same high rate achieved in pregnant vitamin D–replete rats and wild-type mice, respectively (Halloran and DeLuca, 1980a; Brommage et al., 1990; Fudge and Kovacs, 2010). This suggests that factors other than vitamin D (e.g., estrogen, placental lactogen, and prolactin) stimulate intestinal calcium absorption during pregnancy.

Very few clinical trials of vitamin D supplementation during pregnancy have been conducted. The work of Wagner et al. (2010a, b), reported currently in abstract form, has focused on high doses of vitamin D (4,000 versus 2,000 and 400 IU/day) in intervention trials in which the focus was on non-skeletal outcomes. A final report from these studies is expected soon. To date, the available intervention studies have shown little effect of vitamin D supplementation on maternal, fetal, or neonatal outcomes, although it would be expected that higher serum 25OHD levels in the newborn should protect against neonatal hypocalcemia (Specker, 2004; Kovacs, 2008). In a study of Asian women with initially low 25OHD levels (mean of 20 nmol/L) at baseline, daily supplementation with 1,000 IU of vitamin D per day did not affect cord blood calcium level or the newborns’ crown–heel length, forearm length, triceps skinfold thickness, or head circumference, but it did reduce the fontanelle area by 32.7 percent (Brooke et al.,

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