Because the preliminary results of this arm of the trial are important for decision-making in the current clinical environment, we report here the interim results of an ongoing vitamin D supplementation trial of lactating women and their infants. In this ongoing study of lactating women and their infants who were randomized to one of three treatment groups, we sought to determine whether the one drop per day of an oil emulsion vitamin D3
preparation is effective in raising the infants' levels to the desired target of >30
nmol/L). Infant's 25(OH)D levels consistently and significantly increased to a plateau by three months of therapy on the daily oil emulsion preparation dispensed as one drop per day to deliver 400 IU. Overall, the infant's circulating 25(OH)D levels increased 37% above baseline. There were no adverse events associated with the prescribed vitamin D supplementation. While not powered to assess safety at this juncture, it is important to note that, thus far, there have been no increased rates of infection in the infants or adverse health effects that could be attributed to vitamin D supplementation in this cohort.
Another important finding in this study is that the majority of infants enrolled in this cohort of exclusively breastfed infants had vitamin D deficiency (defined as circulating 25(OH)D levels <20
ng/mL) at one month of age. Infant vitamin D levels in exclusively breastfed infants reflect maternal vitamin D status, and given that the majority of the mothers in this cohort present with circulating 25(OH)D levels <30
ng/mL, it is not surprising that the infants who are almost solely dependent on the mother for their vitamin D have corresponding deficiency. Until it can be determined what amount of vitamin D supplementation in mothers will effectively and safely increase and/or maintain the vitamin D status in her breastfed infant, we must rely on vitamin D supplementation of the infant to prevent deficiency. Thus, our findings in this study and our earlier studies [4
] support the recent AAP recommendation of starting vitamin D supplementation in all breastfed infants within the first few days after delivery [26
Concerns about dosing infants with any medication, particularly as a single drop, are warranted. The greatest risk appears when a parent is not instructed on how to give a medication or does not receive the full instruction on proper dispensing. We have found in our study of lactating women that demonstrating how to give the drop is the best method of teaching proper dispensing. Mothers are asked to demonstrate how to give the drop prior to leaving the research outpatient clinic, and this method has been found to be effective.
Our findings support the premise that an oil emulsion delivered as a single drop is well-tolerated and absorbed with a consistent increase in circulating 25(OH)D on the vitamin D supplementation during a three-month interval that was sustained during the next three-month interval. While prescription of a vitamin or medication and changes in blood levels of that vitamin or medication, in this case, vitamin D does not prove direct causality, the change in circulating 25(OH)D status was independent of season. In addition, despite the normal growth of the infants during this six-month period, on a per kilogram basis, the 400
IU/day dose was adequate in helping the infant maintain adequate vitamin D status during the six-month study period.
Limitations of this study include its small sample size. This study is designed to enroll 126 subjects into the control arm. To date, 54 subjects have been enrolled and 33 have completed the study. We acknowledge that this interim report is based on the first 33 to have completed this ongoing trial and that while this represents ~ 61% of the 54 enrolled and 26% of the total projected cohort, we believe that the results are generalizable since timing of enrollment is random. There would be no underlying systematic bias that would suggest that the results of the first 33 subjects would differ from the middle 33 or the last 33, especially when seasonality is controlled as a potential confounder, which was done.
Another limitation of this study is the lack of a placebo control group. While a group of infants that received placebo would allow for more refined statistical analyses, it is deemed unethical by the investigators and the IRB not to supplement the infants with what is now the standard of care for vitamin D supplementation of infants and children in both the U.S. and Canada (see AAP statement 2008 [5
] and Canadian Paediatric Society statement 2007 [33
]). The direct effect of the vitamin D supplementation is supported by the following: in this trial, of the mothers who were randomized to receive 2400
IU vitamin D/day, there was insufficient transfer of vitamin D in their milk and 31% of those breastfed infants required open label vitamin D supplementation at the 4th month visit compared with 6% in the control group and 5% in the 6400
IU vitamin D supplementation group. As a result, the 2400
IU arm of the study was stopped in February 2008 (unpublished data). Clearly, the 400
IU/day group of infants (presented here) had improved vitamin D status based on their therapy that was not seen in the 2400
IU group of infants, who were receiving placebo and whose only source of vitamin D was maternal breast milk that has significantly lower levels than that of the 6400 IU group.
In summary, a single drop oil emulsion vitamin D preparation appears to be an effective method to deliver vitamin D3 to a breastfed infant. The safety of this regimen beyond this small cohort remains to be determined. Further evaluation of this method also is warranted in infants who have underlying disease states.