We found 25(OH)D levels < 20 ng/mL to be common in the cord blood of infants in a southern climate in the United States representing about 60% of the infants in our study, with about 20% of the infants having values ≤ 10 ng/mL. However, we did not identify any specific physiological consequences of these cord 25(OH)D levels for bone mineralization at birth as evidenced by initial DXA measurements. Supplementation with 400 IU/day of vitamin D to these infants led to a relatively greater increase in those who were born with the lowest vitamin D status and there was no suggestion of any bone mineral outcome deficits at one week or three months of age in infants with low cord 25(OH)D levels. We also did not find any significant relationship between cord 25(OH)D values and growth outcomes. We note that our study was of limited size however, and that larger studies are needed in diverse global populations. Our study did not have the ability to identify the effects of small amounts of formula or other nutritional differences between groups.
The close relationships between weight and length and initial BMC imply that calcium transfer across the placenta is closely related to overall nutrient transfer and not to vitamin D status (7). Of note is that few subjects had a cord 25(OH)D < 6 ng/mL, a value found in studies in pregnant women and newborns in the Middle East [9
]. Neonatal rickets and hypocalcemia have been reported in some, but not all infants with cord or maternal 25(OH)D values < 6-10 ng/mL from the Middle East. These extremely low values are not commonly reported in the United States, although we speculate that an increasing number of cases may be reported in the future due to increased awareness of vitamin D deficiency.
There are very few data on 25(OH)D in cord blood in the Hispanic population and no data looking specifically at the relative increase over time based on cord 25(OH)D [11
]. We did not have PTH values on the cord blood but PTH values at three months of age were not correlated significantly with 25(OH)D values at birth or three months or with bone mineral outcomes. Differences in 25(OH)D between Hispanic and Caucasian infants may be related to lifestyle including sunshine exposure. These were not evaluated in this study but there are no clear cultural reasons to expect a substantial difference in Houston.
In a European population, 64% of infants had a serum 25(OH)D at 3-6 days of age that was below 12 ng/mL [12
]. Of note is that in that study, about 10% of infants with these very low 25(OH)D levels had evidence of hypocalcemia although none had physical symptoms and it is not clear if there was a true cause and effect in this group. Although there was a trend in that study towards a relative increase in 25(OH)D in infants with lower baseline values who received supplementation, this was not clearly demonstrated. In the United States, median values for 25(OH)D in a northern setting in the first days of life were 17 ng/mL with 58% of infants < 20 ng/mL, results very similar to those seen in our study [13
We found similar ionized calcium levels in Hispanic and Caucasians at birth. There is some suggestion that late hypocalcemic tetany is more common in Hispanic infants, although this is not well demonstrated due to the limited published data [14
]. Regardless, serum calcium in the cord blood and in the first days of life is likely controlled by a variety of factors, of which vitamin D is only one factor.
Limited previous research is generally consistent with our findings. Park et al [15
] studied Korean infants at 2 to 5 months of age and found no relationship between 25(OH)D level and BMC assessed by DXA even though many of the infants had very low 25(OH)D levels. They speculated that this is due primarily to passive absorption of calcium at this age. It has been suggested but is not proven that early life calcium absorption is primarily non-vitamin D dependent [2
]. However, it is likely that by three months of age, vitamin D has a key role in calcium absorption, especially in breast-fed infants with a relatively low calcium intake compared to formula-fed infants. Whether the greater bioavailability of calcium from human milk compared to formula affects the needed level of 25(OH)D by infants is unknown.
Greer et al [16
] found an increase in 25(OH)D from 24 to 39 ng/mL at three months of age with the provision of 400 IU/day of vitamin D to breast-fed infants. These results are similar to ours, with slightly higher 25(OH)D values found in the Greer study. Direct comparisons however of 25(OH)D values between studies conducted in the past and recent studies should be done with caution due to well-documented variations in assay techniques.
Therefore, in considering early vitamin D supplementation, the question becomes whether there is physiological benefit to rapid replenishment with vitamin D (e.g. high doses of vitamin D in early life) with or without monitoring of 25(OH)D levels or whether the 400 IU/day dose is adequate. Our data, from this small dataset, can only be used to partially answer this question specifically related to bone health. However, it appears that, at least in a southern US setting, 400 IU/day is adequate for infants regardless of vitamin D status at birth. We cannot rule out the possibility that a small number of infants will be hypocalcemic in the first weeks of life with this approach, but, this appears to be uncommon and may be more related to PTH function than vitamin D. Further research is needed relative to the etiology of symptomatic hypocalcemia in the first weeks of life.
Studies in adults have found a greater increase in 25(OH)D levels in subjects who started at a lower level before supplementation [17
]. Similar data are not readily available in pediatric populations. Caution should be used in interpreting any results for changes in 25(OH)D based on baseline levels. It has been suggested that these results may reflect a regression to the mean phenomenon or may be related in part to measurement variability (8). However, the findings in our study appear meaningful in that the provision of vitamin D at a dose of 400 IU/day led to mean values that were above 30 ng/mL regardless of starting value or ethnicity. The 30 ng/mL target is well above that likely to be needed for adequate vitamin D status in the newborn based upon the recent recommendations of the Institute of Medicine [2
The effects of maternal vitamin D deficiency are complex and may extend beyond bone health effects in infants. Provision of all pregnant and lactating women with the Recommended Daily Allowance of 600 IU/day is an important public health strategy. Nonetheless, such supplements are not universally consumed by the population. The Hispanic community may be at higher risk due to darker skin pigmentation, greater obesity, lower dairy intake and less supplement use. It has been suggested that all Hispanics and all pregnant and lactating women have their 25(OH)D levels monitored [4
Of note is that 25(OH)D levels in a southern United States climate are low despite sunshine exposure year round at the latitude in Houston. Furthermore, there is a seasonal dependence of 25(OH)D levels although we did not have enough subjects to identify the degree to which this seasonal dependence was affected by ethnicity. We had previously shown a seasonal dependence of 25(OH)D levels in prepubertal girls in Houston [18
] with no differences in calcium absorption or kinetics between Hispanic and Caucasian prepubertal girls. Thus, it is clear that a southern US location is not protective against seasonal deficiency of vitamin D or low cord 25(OH)D levels.