According to the latest Cochrane review on the subject6 and other recent meta-analyses,7 supplementation with 400 IU/day in infants aged less than 1 year has been found to be safe and effective in improving vitamin D status and decreasing the percentage of infants with calcifediol levels below 20 ng/mL. However, this improvement in serum levels is not always associated with an improvement in bone health assessed by means of bone density scans. One of the main limitations is the lack of well-designed studies, as only three clinical trials comparing the use of vitamin D against placebo have been published in infants, all of them with a very small number of patients.

The most severe form of vitamin D deficiency is rickets, the incidence of which has been increasing in recent years in Europe, mainly in at-risk groups. Observational studies have shown that the use of vitamin D supplementation, as well as the use of fortified foods as a public health policy, reduces the prevalence of rickets.8,9 There is also evidence from large case series of healthy infants who received prophylaxis with 400 UI/day in which there were no diagnosed cases of rickets.10

There have been several clinical trials comparing the administration of various doses of vitamin D in the first year of life (from 400 to 2000 IU/day), although they were dose-response studies without comparison with placebo. They showed that administration of doses greater than 400 IU/day did not provide any benefit in terms of body composition, gross motor skills or bone density at 3 years of follow-up.11,12 In a recent trial, a group of healthy breastfed infants with calcifediol levels below 20 ng/mL at age 1 month were randomly assigned to receive 400 or 800 IU/day. At 12 months of follow-up, there were no differences in bone health assessed by means of bone density scans or in serum calcifediol levels between the two groups. These studies show that, in healthy infants, supplementation at doses greater than 400 IU/day does not seem to provide additional benefits, and that, in the absence of risk factors, serum levels should not be monitored, given that, regardless of the calcifediol level, a dose of 400 IU/day seems sufficient to achieve the nutritional target for adequate bone health in this age group.

In this age group, there is even less evidence. In a recent published meta-analysis, vitamin D supplementation for one year in children with calcifediol levels greater than 8 ng/mL has a minimal effect on the bone mineral density of the hips in densitometry, increasing 6.8 mg/cm2 (95% CI, 0.7-1.9),13 without evidence of changes in any of the other regions. In consequence, the authors did not support universal vitamin D supplementation, although they cautioned that the results could not be extrapolated to children with vitamin D levels outside the studied range. There is also no evidence that supplementation is effective in reducing the incidence of fractures in this age group.

One of the extraskeletal benefits for which there is the most evidence is its role in antimicrobial activity: several clinical trials and meta-analyses14 have shown that supplementation with vitamin D can, in certain circumstances, reduce the risk of developing respiratory infections (Table 1). One of the most recent meta-analyses15 showed that, vitamin D supplementation reduced the overall risk of respiratory infection (OR, 0.92; 95% CI, 0.86-0.99) and was most effective in patients aged 1 to 18 years who received low doses of vitamin D (between 400-800 IU/day), with no underlying disease and with calcifediol levels of less than 35 ng/mL (OR, 0.56; 95% CI, 0.38-0.82). Considering that very heterogeneous methods were used for the definition of the different types of respiratory infection (otitis, pneumonia, upper respiratory tract infection…), that the improvement was limited to a specific group and that the magnitude of the effect was low (OR, 0.9; CI of almost 1), these results still seem insufficient to recommend universal vitamin D supplementation.

There is no evidence that vitamin D supplementation decreases the incidence or severity of other types of infection. Moreover, studies in developing countries have shown that the use of high-dose vitamin D supplementation in malnourished infants increases the risk of recurrent pneumonia.16 These findings could be due to the sharp rises and falls in vitamin D levels, which can suppress adaptive responses to infection, boost innate responses and block the activity of enzymes that synthesize and catabolize calcitriol in extrarenal tissues. This could result in reduced concentrations of this active metabolite in disease foci. There is also no evidence that vitamin D supplementation in healthy pediatric population decreases the risk of atopy, autoimmune diseases or cancer, among other diseases.17,18

In infants (age < 1 year), nearly every guideline recommends universal supplementation with 400 IU a day of vitamin D, independently of infant feeding modality.3,19–24 Foregoing supplementation is only considered in the small group of infants who reach a daily intake of at least 1 liter of adapted infant formula (equivalent to 400 IU/day).1,2 These recommendations are mainly based on the impossibility of reaching the recommended daily intakes through diet, the low sun exposure in this age group, the role of vitamin D supplementation as a public health strategy for prevention of rickets end, evidence from multiple safety studies supporting the use of this dose25 and the ethical issues involved in conducting a placebo controlled trial in infants, chiefly in relation to those who are breastfed.

In children aged more than 1 year, most guidelines do not recommend universal supplementation, but individualization based on the presence of risk factors, sun exposure and dietary vitamin D intake. Only specific countries in the northern hemisphere recommend universal supplementation or supplementation during the winter months (Table 2).

n spite of the heterogeneity of the recommendations on vitamin D supplementation (mainly in children aged more than 1 year), all guidelines are against monitoring vitamin D levels in healthy children without risk factors who are asymptomatic. The strategy has not been found to be cost-effective, and in addition to the scarce evidence on supplementation in this population, there is no consensus on the cut-off points for defining deficiency. All of this can lead to inadequate prescription of vitamin D supplementation and unnecessary blood tests.26 The main scientific societies agree in considering that measurement of calcifediol levels is only indicated in select cases (Table 3). In children who require monitoring, measurement in the last months of winter is recommended.

In Spain, the adherence to clinical practice guidelines is poor,27 and, based on recent studies conducted in Europe and the United States, adherence in some countries is below 15%. To address this issue, some health care organizations have implemented a series of measures to try to improve their performance (promoting training of health care professionals, prescribing in the labor and delivery ward with provision of written information for families on the importance of supplementation, outpatient monitoring of adherence through electronic prescribing systems…).28

In most of the cases of vitamin D toxicity reported in the literature, children received very high doses (total cumulative intake over days or weeks ranging from 240 000 to 4 500 000 IU).29 A recent meta-analysis that included 32 clinical trials in patients aged 0 to 6 years who received between 1200 and 10 000 IU/day found no differences in the number of serious adverse events (death or hospital admission) compared to children who received lower doses.30 However, it is important to be cautious, as there is a subset of children with specific polymorphisms or carrying CYP24A1 variants who are at increased risk of developing hypercalcemia and vitamin D toxicity at lower doses. In addition, an excess of vitamin D could have a negative impact on bone mineralization during childhood and adolescence, which are considered critical periods for bone health.

The established tolerable upper intake level (UL) varies between scientific societies; thus, the European Food Safety Authority (EFSA) has set it at 1000 IU/day for infants and 2000 IU/day for children aged 1 to 10 years, while the Institute of Medicine (IOM) has set it at 1000 IU/day for infants aged less than 6 months and 1500 IU/day for infants aged 6 to 12 months.5,31 No cases of toxicity have been reported in association with smaller doses, so the recommendation for supplementation with 400 IU/day in infants up to 1 year of age is completely safe and does not require lowering the dose of vitamin D supplementation as dietary intake increases in the infant.

Notwithstanding, in recent years there has been an increase in the incidence of vitamin D toxicity32 that can probably be attributed to the increased frequency of prescribing and the commercialization of vitamin D supplements at widely varying concentrations that may give rise to administration errors. In consequence, it is recommended that directions always be given in writing, including the timing, preparation, concentration and dose, in addition to verifying during primary care visits that supplementation is being administered correctly. The use of electronic prescribing systems may be useful to check on the number of packages ordered and dispensed to the patient.