High-Dose Vitamin D Does Not Improve Outcomes In Infants

Increasing the dose of vitamin D3 supplementation to 1200 IU/day does not bolster bone strength or reduce infection risk compared with 400 IU/day in healthy term infants receiving supplementation from age 2 weeks to 24 months, a randomized controlled trial (RCT) indicates.

"We hypothesized that higher dosages of vitamin D supplementation [might] improve bone strength and reduce infections in early childhood in a northern European population with limited sunlight exposure," Jenni Rosendahl, MD, University of Helsinki, Finland, and colleagues observe. But they found that "in vitamin D–sufficient healthy infants, daily supplementation with 1200 IU vitamin D3 compared with 400 IU provides no additional benefits for bone strength or for parent reported incidence of infections during the first 2 years of life," researchers add.

The researchers published their findings online May 29 in JAMA Pediatrics.

The Vitamin D Intervention Infants (VIDI) study randomly assigned 489 infants to daily oral vitamin D3 at a dose of 400 IU and another 486 infants to a dose of 1200 IU starting at age 2 weeks. "Vitamin D supplements were administered orally once daily in a volume of 5 drops for both concentrations," the authors note. Infants were all healthy term babies and they were all of Northern European descent to exclude contamination of treatment effects resulting from skin pigmentation.

Almost 85% (84.4%) of the cohort completed the 24-month study and mean adherence to vitamin D supplementation across the study was similar at 88% in both groups. At birth, the mean serum 25-hydroxyvitamin D [25(OH)D] concentration was almost identical in both groups at 32.73 ng/mL in the 400-IU group and 32.57 ng/mL in the 1200-IU group — a sign that most mothers had adequate vitamin D supplementation during pregnancy, the authors write.

Not unexpectedly, mean serum 25(OH)D concentrations were higher in the 1200-IU group than in the 400-IU group at both 12 and 24 months of age.

Table. Mean Serum 25(OH)D Concentrations at 12 and 24 Months

Study Group	25(OH)D at Age 12 mo (ng/mL)	25(OH)D at Age 24 mo (ng/mL)
400 IU	33.13	34.70
1200 IU	46.07	47.16

No infant had a 25(OH)D concentration higher than 100.16 ng/mL, the investigators observe. Nor did any infant develop severe hypercalcemia at any point. Both of these might be a sign of vitamin D toxicity, the researchers explain.

Mean ionized calcium levels also did not differ between the two groups, and all were within age-specific reference limits at both 12 and 24 months of age.

Bone Strength Similar at Age 24 Months

Bone scans of the left tibia were obtained in 783 children who attended the 24-month follow-up visit. Of 704 evaluable scans, bone strength measurements between the two groups did not differ for total bone or cortical bone. Similarly, of 8458 parent-reported infectious episodes that occurred during the study, infants in the 400-IU group had a mean of 9.18 infections (95% confidence interval [CI], 8.73 - 9.63) during the first 24 months of age, whereas infants in the 1200-IU group had a mean of 9.14 infections (95% CI, 8.68 - 9.60) at the same endpoint.

"Infection characteristics were similar," the authors add, the majority being respiratory infections. The only difference in infections between the 400-IU and the 1200-IU group was the use of antibiotics, which was 17% higher among infants in the 1200-IU group (incidence rate ratio, 1.17; 95% CI, 1.00 - 1.36). Since 2010, vitamin D intake has improved across the Finnish population as certain foods are now fortified with vitamin D.

For example, milk products are fortified with 40 IU of vitamin D3 per 100 mL, whereas fat spreads are fortified with 800 IU per 100 g. Public health officials have also promoted the use of vitamin D supplementation and guidelines recommend pregnant and breast-feeding women as well as children under age 2 years receive 400 IU of vitamin D supplementation a day. A dose of 300 IU vitamin D supplementation is recommended for older children and adolescents.

"These public health actions have recently improved vitamin D status in Finland," the authors observe. "In a country where sunlight exposure is limited but food fortification with vitamin D is common, supplementation with 400 IU of vitamin D₃ daily seems adequate to ensure vitamin D sufficiency in children younger than 2 years," they conclude.

Systematic Review and Meta-analysis

In an unrelated systematic review and meta-analysis published online in the same issue of JAMA Pediatrics, Wei Guang Bi, BSc, University of Montreal, Quebec, Canada, and colleagues identified 24 studies that evaluated the effect of vitamin D supplementation during pregnancy on infant growth, morbidity, and mortality. The clinical trials involved 5405 participants. Six RCTs found infants born to mothers who took a vitamin D supplement during pregnancy had a 28% lower risk of being born small for gestational age (relative risk, 0.72; 95% CI, 0.52 - 0.99).

Fourteen RCTs found that newborns who had been exposed to vitamin D supplementation in utero also had higher 25(OH)D levels than did those in the control groups (mean difference, 13.50 ng/mL; 95% CI, 10.12 - 16.87 ng/mL). Seven RCTs found that neonates exposed to prenatal vitamin D were almost three times more likely to have adequate vitamin D levels at birth (20 ng/mL). Vitamin D supplementation during pregnancy was also associated with greater birth weight and greater height at 3, 6, and 9 months of age, as well as greater skinfold thickness at birth.

Importantly, in utero exposure to vitamin D supplementation did not increase the risk for fetal or neonatal mortality or congenital abnormality. The researchers also suggest that vitamin D supplementation at doses of 2000 IU/day or lower during pregnancy may reduce the risk for fetal or neonatal mortality, on the basis of their systematic review of the literature.

Rosendahl and colleagues' study was supported by the Foundation for Pediatric Research, Finska Läkaresällskapet, Finnish Medical Foundation, Governmental Subsidy for Clinical Research, Päivikki and Sakari Sohlberg Foundation, Stiftelsen Dorothea Olivia, Karl Walter och Jarl Walter Perkléns minne, Academy of Finland, Sigrid Jusélius Foundation, Folkhälsan Research Foundation, Novo Nordisk Foundation, Orion Research Foundation, and Barncancerfonden. Orion Pharmaceuticals is acknowledged for providing the vitamin D supplements gratis for the study. For Bi and colleagues' meta-analysis, Weiler is supported by an award from Canada Research Chair in Nutrition and Development and a research award from the Fonds de Recherche en Santé du Quebec. The authors have disclosed no relevant financial relationships.

JAMA Pediatrics. Published online May 29, 2018. Rosendahl study abstract, Bi meta-analysis abstract

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