Effect of Maternal Vitamin D3 Supplementation on Iron Status During Pregnancy and Early Infancy

The risk of both low iron and vitamin D status have been recognized as public health concerns among pregnant women and young children, with high rates of deficiency in low-and middle-income countries. Through its involvement in regulation of the hepcidin-ferroportin axis, as well as its potential to increase the expression of the erythropoietin receptor, vitamin D has been suggested as a modulator of iron homeostasis. Vitamin D supplementation may therefore represent a candidate facilitator for the management of iron deficiency, yet few intervention trials have directly assessed the effect of vitamin D supplementation on biomarkers of iron status.

To examine the effect of vitamin D supplementation on iron status during pregnancy and early infancy, data and blood samples will be drawn from a completed double-blind, dose-ranging trial of maternal prenatal and postpartum vitamin D supplementation. Women at 17-24 weeks' gestation were randomized to 1 of 5 dose groups comprising a prenatal; postpartum regimen of placebo; placebo, 4200;0, 16800;0, 28000;0 or 28000;28000 IU vitamin D3/week until 26 weeks postpartum. Enrolment (n=1300) was completed in September 2015, and all infants were delivered by February 2016. The MDIG trial was primarily designed to determine the effect of maternal vitamin D on infant length at 12 months of age (with follow-up continuing until infants reached 24 months of age; completed in March 2018).

Analyses of serum ferritin and related iron biomarkers (serum iron, transferrin, soluble transferrin receptor, hepcidin), and inflammatory makers (e.g. CRP), will be conducted using previously collected stored blood samples. Linear regression models will be used to assess the effect of vitamin D supplementation on the biomarkers of interest among pregnant women and their infants at 6 months of age.

To examine the potential dose-response relation between prenatal vitamin D treatment dose (i.e., across all 4 assigned prenatal vitamin D doses by combining the 2 high-dose prenatal vitamin D treatment groups) and the biomarker of interest, linear regression models will be fitted using the assigned prenatal vitamin D treatment group as the categorical exposure variable and the specified biomarker as the (continuous) outcome variable. Data will be reported as mean differences (or mean % differences, if applicable) and 95% CIs.

To explore potential effects of prenatal only versus prenatal plus postpartum vitamin D supplementation on Hb and ferritin concentrations among infants at 6 months of age, a similar dose-response analysis will be conducted across all 5 treatment groups (i.e., disaggregation of the 2 high-dose prenatal vitamin D groups), for which the investigators will regress the biomarker (Hb as a continuous variable) on the vitamin D treatment group assigned during the prenatal and postpartum periods (as a categorical variable). Differences in each supplementation group will therefore be compared to the placebo group, and expressed as mean differences (or geometric means, or mean % differences, if applicable) and 95% CIs.

Given the influence of inflammation on serum ferritin concentrations, secondary analyses will include inflammatory markers (e.g. CRP) as covariates to test the role of inflammation in mediating the association between the vitamin D intervention and serum ferritin concentrations.