opment and mineral content (Maxwell and Miles, 1925; Congdon et al., 1983) and no radiological evidence of rickets at birth (Pereira and Zucker, 1986; Campbell and Fleischman, 1988; Specker et al., 1992; Specker, 1994; Beck-Nielsen et al., 2009) in severe vitamin D deficiency, or even in the absence of 1α-hydroxylase or the VDR (Silver et al., 1985; Takeda et al., 1997; Teotia and Teotia, 1997; Kitanaka et al., 1998; Bouillon et al., 2006). In contrast, four associational studies reported lower maternal serum 25OHD levels associated with craniotabes (Reif et al., 1988), lower tibia BMC and cross–sectional area, maternal serum 25OHD level below 42.6 nmol/L (Viljakainen et al., 2010), and higher fetal femur metaphyseal cross–sectional area and splaying (Mahon et al., 2010).
Regarding the developmental programming of later skeletal health in older offspring, one observational study, using 33 percent of the initial infants in a cohort, reported an association of lower whole-body and lumbar spine BMC and areal BMD at age 9 years in children whose mothers had low serum 25OHD levels late in gestation, even though no skeletal parameters differed at birth or nine months of age (Javaid et al., 2006). In offspring of mothers whose serum 25OHD levels late in gestation were less than 27.5 nmol/L or between 27.5 and 50.0 nmol/L, whole-body BMC was reduced compared with those whose mothers had serum 25OHD levels above 50.0 nmol/L. The definition of developmental programming as an indicator per se is questionable; in any case, the evidence for developmental programming of offspring skeletal health outcomes is insufficient to permit the committee to draw any conclusions, but it may be considered within the larger context of fetal skeletal BMD.
Although the congruence of the limited RCT data and majority of the observational data in humans suggests that fetal skeletal outcomes are not adversely affected by maternal vitamin D intake or serum 25OHD concentrations, fetal BMD and related skeletal outcomes may still be of some utility for DRI development. Little evidence could be identified for maternal BMD, making it unclear as to this measure’s utility for DRI development.
Neonatal rickets The AHRQ-Ottawa report included neonatal rickets infants 0 to 6 months of age and young children 1 to 6 years of age and found fair evidence for an association between low serum 25OHD levels and rickets identified as early as 2 months, but inconsistent evidence about the threshold level of 25OHD in serum above which rickets does not occur. AHRQ-Tufts identified no additional studies. Generally, the available observational studies do not report the development of vitamin D–deficiency rickets