Correction of neonatal vitamin D status using 1000 IU vitamin D/d increased lean body mass by 12 months of age compared with 400 IU/d: a randomized controlled trial

Abstract

Background: Intrauterine exposure to maternal vitamin D status <50 nmol/L of serum 25-hydroxyvitamin D [25(OH)D] may adversely affect infant body composition. Whether postnatal interventions can reprogram for a leaner body phenotype is unknown.

Objectives: The primary objective was to test whether 1000 IU/d of supplemental vitamin D (compared with 400 IU/d) improves lean mass in infants born with serum 25(OH)D <50 nmol/L.

Methods: Healthy, term, breastfed infants (Montréal, Canada, March 2016-2019) were assessed for serum 25(OH)D (immunoassay) 24-36 h postpartum. Infants with serum 25(OH)D <50nmol/L at 24-36 h were eligible for the trial and randomly assigned at baseline (1 mo postpartum) to 400 (29 males, 20 females) or 1000 IU/d (29 males, 20 females) of vitamin D until 12 mo. Infants (23 males, 18 females) with 25(OH)D ≥50 nmol/L (sufficient) formed a nonrandomized reference group provided 400 IU/d. Anthropometry, body composition (DXA), and serum 25(OH)D concentrations were measured at 1, 3, 6, and 12 mo.

Results: At baseline, mean ± SD serum 25(OH)D concentrations in infants allocated to the 400 and 1000 IU/d vitamin D groups were 45.8 ± 14.1 and 47.6 ± 13.4, respectively; for the reference group it was 69.2 ± 16.4 nmol/L. Serum 25(OH)D concentration increased on average to ≥50 nmol/L in the trial groups at 3-12 mo. Lean mass varied differently between groups over time; at 12 mo it was higher in the 1000 IU/d vitamin D group than in the 400 IU/d group (mean ± SD: 7013 ± 904.6 compared with 6690.4 ± 1121.7 g, P = 0.0428), but not the reference group (mean ± SD: 6715.1 ± 784.6 g, P = 0.19). Whole-body fat mass was not different between the groups over time.

Conclusions: Vitamin D supplementation (400 or 1000 IU/d) during infancy readily corrects vitamin D status, whereas 1000 IU/d modestly increases lean mass by 12 mo. The long-term implications require further research. This trial was registered at clinicaltrials.gov as NCT02563015.

Keywords: infant; lean mass; randomized controlled trial; vitamin D status; vitamin D supplementation.

© Her Majesty the Queen in Right of Canada, as represented by the Minister of Health Canada, 2022.

Figures

FIGURE 1

Consolidated Standards of Reporting Trials (CONSORT) flow diagram. BF, breastfeed; LGA, large for gestational age; SGA, small for gestational age; 25(OH)D, 25-hydroxyvitamin D.

FIGURE 2

Infant body composition over time. (A) Lean mass and lean mass accretion, (B) percentage lean mass, (C) LMI, (D) fat mass and fat mass accretion, (E) percentage fat mass, and (F) FMI among groups over time. Data are mean ± SD. Sample sizes are as follows: reference group (baseline, n = 39; 3 mo, n = 34; 6 mo, n = 34; 12 mo, n = 30); 400 IU/d group (baseline, n = 49; 3 mo, n = 43; 6 mo, n = 39; 12 mo, n = 30); and 1000 IU/d group (baseline, n = 49; 3 mo, n = 44; 6 mo, n = 41; 12 mo, n = 37). Data were compared using a mixed-effect model (SAS PROC MIXED) for fixed effects of group × time, sex, skin tone, infant actual age at each visit, gravida, parental age at delivery, maternal BMI preconception, and family income. Participant (ID) modeled as a random effect. P values reflect Tukey's post hoc tests with Tukey-Kramer adjustment for multiple comparisons. The shaded area reflects reference ± SD. *P < 0.05, 1000 IU/d group compared with 400 IU/d group at 12 mo for lean mass; no other differences between groups over time were observed. FMI, fat mass index; LMI, lean mass index.

FIGURE 3

Infant growth over time. (A) Weight, (B) crown to heel length, and (C) head circumference measurements, (D) weight-for-age, (E) length-for-age, and (F) head-circumference-for-age z scores, among groups over time. Data are mean ± SD. Sample sizes are as follows: reference group (baseline, n = 41; 3 mo, n = 35; 6 mo, n = 34; 12 mo, n = 32); 400 IU/d group (baseline, n = 49; 3 mo, n = 44; 6 mo, n = 40; 12 mo, n = 36); and 1000 IU/d group (baseline, n = 49; 3 mo, n = 44; 6 mo, n = 43; 12 mo, n = 42). Data were compared for weight, length, and head circumference measurements using a mixed-effect model (SAS PROC MIXED) tested for fixed effects of group × time, sex, skin tone, infant actual age at each visit, gravida, parental age at delivery, maternal BMI preconception, and family income. Participant (ID) modeled as a random effect; and for weight-, length-, and head-circumference-for-age z scores sex and infant actual age at each visit were removed from the mixed model. P values reflect Tukey's post hoc tests with Tukey-Kramer adjustment for multiple comparisons. The shaded area reflects reference ± SD. *P < 0.05, 1000 IU/d compared with 400 IU/d at 12 mo for body weight; no other differences in growth between groups over time were observed.

FIGURE 4

Infant serum 25(OH)D concentrations of the reference group (n = 41) and those in the pool for the trial (n = 98) at birth (24–36 h postpartum) (A), infant serum 25(OH)D concentrations among groups over the first 12 mo of life (baseline, 3, 6, and 12 mo) (B), infant whole-blood ionized calcium among groups (C), and proportions of infants in the reference, trial 400 IU/d, and trial 1000 IU/d groups achieving the cutoff for sufficiency for vitamin D status [25(OH)D ≥50 nmol/L] at each time point (D). (A–C) Data are mean ± SD, (D) data are mean and 95% CIs. Sample sizes are as follows: reference group (baseline, n = 41; 3 mo, n = 35; 6 mo, n = 34; 12 mo, n = 32); 400 IU/d group (baseline, n = 49; 3 mo, n = 44; 6 mo, n = 40; 12 mo, n = 36); and 1000 IU/d group (baseline, n = 49; 3 mo, n = 44; 6 mo, n = 43; 12 mo, n = 42). Continuous data were compared using a mixed-effect model (SAS PROC MIXED) tested for fixed effects of group × time, sex, skin tone, infant actual age at each visit, gravida, parental age at delivery, maternal BMI preconception, and family income. Participant (ID) modeled as a random effect. P values reflect Tukey's post hoc tests with Tukey-Kramer adjustment for multiple comparisons. The shaded area is reference ± SD. #P < 0.05, reference group compared with trial 400 and 1000 IU/d groups; *P < 0.05, trial 1000 IU/d compared with the trial 400 IU/d and reference groups. Categorical data were compared at each time point using chi-square analyses: ^P < 0.05, reference group compared with the trial 400 IU/d and 1000 IU/d groups at baseline only. 25(OH)D, 25-hydroxyvitamin D.

FIGURE 5

Infant plasma IGF-1 (A), IGFBP-3 concentrations (B), Δ IGF-1 (C), and Δ IGFBP-3 (D). Data are mean ± SD. Sample sizes are as follows: reference group (baseline, n = 41; 3 mo, n = 35; 6 mo, n = 34; 12 mo, n = 32); 400 IU/d group (baseline, n = 49; 3 mo, n = 44; 6 mo, n = 40; 12 mo, n = 36); and 1000 IU/d group (baseline, n = 49; 3 mo, n = 44; 6 mo, n = 43; 12 mo, n = 42). Data were compared using a mixed-effect model (SAS PROC MIXED) tested for fixed effects of group × time, sex, skin tone, infant actual age at each visit, gravida, parental age at delivery, maternal BMI preconception, and family income. Participant (ID) modeled as a random effect. P values reflect Tukey's post hoc tests with Tukey-Kramer adjustment for multiple comparisons. The shaded area is reference ± SD. #P < 0.05, baseline compared with 3 mo and 6 mo for all groups; ^P < 0.05, 3 mo compared with 6 mo for all groups except trial 1000 IU/d; *P < 0.05, baseline to 3 mo compared with 3 mo–6 mo for all groups. IGFBP-3, insulin-like growth factor binding protein 3; IGF-1, insulin-like growth factor 1.