High-Dose Neonatal Vitamin A Supplementation Transiently Decreases Thymic Function in Early Infancy

Abstract

Background: Vitamin A deficiency (VAD) impairs T-cell-mediated immunity. In regions where VAD is prevalent, vitamin A supplementation (VAS) reduces child mortality, perhaps by improving immune function.

Objective: Our objective was to determine if neonatal VAS would improve thymic function in Bangladeshi infants, and to determine if such effects differed by sex or nutritional status (i.e., birth weight above/below the median).

Methods: Three hundred and six infants were randomly assigned to 50,000 IU vitamin A (VA) or placebo (PL) within 48 h of birth. Primary outcomes were measured at multiple ages and included 1) thymic index (TI) at 1, 6, 10, and 15 wk; 2) T-cell receptor excision circles (TREC), an index of thymic output of naïve T cells; and 3) total/naïve T cells in peripheral blood at 6 wk, 15 wk, and 2 y. A mixed linear model for repeated measures was used to assess group differences at each age and identify interactions with sex and birth weight.

Results: VAS did not significantly (P = 0.21) affect TI overall (i.e., at all ages) but decreased TI by 7.8% (P = 0.029) at 6 wk: adjusted TI means for the PL and VA groups at 1, 6, 10, and 15 wk were 4.09 compared with 3.80 cm2, 7.78 compared with 7.18 cm2, 8.11 compared with 7.84 cm2, and 7.91 compared with 7.97 cm2, respectively. VAS did not significantly (P = 0.25) affect TREC overall but decreased TREC by 19% (P = 0.029) at 15 wk: adjusted TREC means for the PL and VA groups at 6 wk, 15 wk, and 2 y were 13.6 compared with 16.1 copies/pg DNA, 19.4 compared with 15.7 copies/pg DNA, and 11.8 compared with 10.0 copies/pg DNA, respectively. VAS did not significantly affect overall total (P = 0.10) or naïve (P = 0.092) T cells: adjusted naïve T-cell means for the PL and VA groups at 6 wk, 15 wk, and 2 y were 3259 compared with 3109 cells/µL, 3771 compared with 3487 cells/µL, and 1976 compared with 1898 cells/µL, respectively.

Conclusion: In contrast to our hypothesis, VAS decreased thymic function early in infancy but health effects are presumably negligible owing to the transience and small magnitude of this effect. This trial was registered at clinicaltrials.gov as NCT01583972 and NCT02027610.

Keywords: Bangladesh; T-cell receptor excision circle; T-lymphocyte; infant; neonate; thymus; vitamin A; vitamin A deficiency.

Published by Oxford University Press on behalf of the American Society for Nutrition 2019.

Figures

FIGURE 1

Mean ± SE thymic index between 1 and 15 wk of age by treatment group (A), treatment group adjusted for body weight at each age (B), and sex (C) in study infants receiving vitamin A (50,000 IU) or placebo capsules within 48 h of birth. P values indicate overall effect of treatment (A, B) or sex (C). Interaction P values (Pixn) are shown if P < 0.10 and indicate interactions of age with treatment group or sex. *,#Statistical significance of group differences at each age: *P < 0.05; #P < 0.10. (A, C) Values are mean ± SE, n = 146, 143, 142, and 143 for boys and n = 145, 146, 146, and 146 for girls at 1, 6, 10, and 15 wk, respectively. (B, D) Values are mean ± SE, n = 146, 147, 146, and 145 for the placebo group and n = 145, 142, 142, and 144 for the vitamin A group at 1, 6, 10, and 15 wk, respectively. Least-square means derived from the statistical analysis models (see Supplemental Table 4 and Methods) were used and the means shown here (back-transformed from square root) are thus adjusted for all covariates in the model.

FIGURE 2

Mean ± SE TREC concentrations in peripheral blood mononuclear cells at 6 wk, 15 wk, and 2 y of age by treatment group (A) and sex (B) in study infants receiving vitamin A (50,000 IU) or placebo capsules within 48 h of birth. P values indicate overall effect of (A) treatment or (B) sex. Interaction P values (Pixn) are shown if < 0.10 and indicate interactions of age with treatment group or sex. *,#Statistical significance of group differences at each age: *P < 0.05; #P < 0.10. (A) Values are mean ± SE, n = 124, 124, and 127 for the placebo group and n = 114, 119, and 128 for the vitamin A group at 6 wk, 10 wk, and 2 y, respectively. (B) Values are mean ± SE, n = 117, 120, and 125 for boys and n = 121, 123, and 133 for girls at 6 wk, 15 wk, and 2 y, respectively. Least-square means derived from the statistical analysis models (see Supplemental Table 4 and Methods) were used and the means shown here (back-transformed from square root) are thus adjusted for all covariates in the model. TREC, T-cell receptor excision circle.

FIGURE 3

Mean ± SE peripheral blood total naïve T-cell concentrations (A, B) and naïve CD4 T-cell concentrations (C, D) by treatment group (B, D) and sex (A, C) at 6 wk, 15 wk, and 2 y of age in study infants receiving vitamin A (50,000 IU) or placebo capsules within 48 h of birth. P values indicate overall effect of sex (A, C) or treatment (B, D). Interaction P values (Pixn) are shown if < 0.10 and indicate interactions of age with treatment group or sex. (A, C) Values are mean ± SE, n = 142, 140, and 132 for girls and n = 134, 143, and 126 for boys at 6 wk, 15 wk, and 2 y, respectively. (B, D) Values are mean ± SE, n = 140, 144, and 131 for the vitamin A group and n = 136, 139, and 127 for the placebo group at 6 wk, 15 wk, and 2 y of age, respectively. Least-square means derived from the statistical analysis models (see Supplemental Table 4 and Methods) were used and the means shown here (back-transformed from square root) are thus adjusted for all covariates in the model.