Vitamin D supplementation during pregnancy has positive impact on childhood wheeze

Key takeaways:

• Higher vitamin D levels at 1 week postpartum were associated with an enriched sphingomyelin pathway.
• This profile was associated with decreased risk for recurrent wheeze and wheeze exacerbations.

The benefits of gestational exposure to vitamin D for respiratory health in children is characterized by specific alterations to the mother’s metabolism, according to a study published in The Journal of Allergy and Clinical Immunology.

These protective effects were associated with a metabolome enriched with sphingomyelins, Min Kim, MSc, PhD, postdoctoral researcher, Copenhagen Prospective Studies on Asthma in Childhood (COPSAC), Herlev and Gentofte Hospital, University of Copenhagen, and colleagues wrote.

As part of the COPSAC 2010 cohort, 315 women received 2,800 IU of vitamin D3 supplementation and 308 received 400 IU each day from week 24 of their pregnancy through 1 week after giving birth.

The Vitamin D Antenatal Asthma Reduction Trial (VDAART) included 876 women at high risk for having children with asthma who received 4,400 IU or 400 IU of vitamin D each day starting between weeks 10 and 18 of their pregnancy.

The COPSAC cohort also included 672 plasma metabolic profiles that were available 1 week after birth, including 276 from the group with low doses of vitamin D, 286 from the group with high doses of vitamin D and 110 who did not take vitamin D.

These datasets yielded 753 annotated metabolites from nine super metabolic pathways. Also, 565 children provided metabolic profiles at age 6 months. VDAART included 779 women whose plasma metabolic profiles were measured between weeks 32 and 38 of their pregnancy.

There were no significant differences between the metabolic profiles of the women on standard and high doses of vitamin D₃ in the COPSAC 2010 cohort 1 week after giving birth, the researchers said.

Similarly, the researchers said there were no significant separations in calibrated levels of 25-hydroxyvitamin D (25(OH)D) 1 week after birth in an orthogonal partial least square-Y (OPLS-Y) model.

But in a univariate approach with linear regression, 153 metabolites were nominally significant (P < .05) with 42 metabolites at a false discovery rate of 5% (FDR 5%), indicating that associations with 25(OH)D may be limited to specific pathways, the researchers said.

Using 46 metabolites with variable influence on projection (VIP) scores of less than 2, the researchers built a principal component analysis (PCA) model that found sphingomyelins to be the metabolites that contributed most to principal components 1 and 2.

Maternal calibrated 25(OH)D had positive associations with principal component 1 (B = 0.02; P = 1.93 × 10^–8) and principal component 2 (B = 0.01; P = 7.86 × 10^–7). Significant separation after cross-validation (P = .01) in a new OPLS-Y model also indicated that 25(OH)D exposure affects the metabolic profile of the 46 selected metabolites.

Sphingomyelins and phosphatidylcholine both had significant enrichment at a nominal level in the 24 sub-metabolic pathways that the 46 selected metabolites are involved in as well, but only the sphingomyelin sub-pathway with 12 of these metabolites showed significant enrichment at FDR 5%.

Additionally, primary component 2 was significantly associated with recurrent wheeze (HR = 0.92; 95% CI, 0.84-0.97) and wheeze exacerbations (HR = 0.92; 95% CI, 0.84-0.97), the researchers said.

But when the researchers stratified these results by child 17q21 rs12936231 genotype, the associations between primary component 2 and recurrent wheeze (HR = 0.87; 95% CI, 0.76-0.99) and wheeze exacerbation (HR = 0.79; 95% CI, 0.64-0.95) only were significant in children with the low-risk GG genotype.

The 12 sphingomyelins that belonged to the pathway showed significant enrichment, the researchers said, but none of them had any individual associations with recurrent wheeze, persistent wheeze or asthma, wheeze exacerbations or the number of troublesome lung symptoms among children aged 0 to 3 years.

The researchers had measurements for 45 of the 46 selected metabolites in COPSAC 2010 available in VDAART from weeks 32 to 38 of gestation. Asthma and wheeze were associated with primary components 1 (OR = 0.92; 95% CI, 0.85-0.99) and 2 (OR = 0.88; 95% CI, 0.78-0.99; P = .03) at age 0 to 3 years.

Primary component 2 was associated with asthma status at age 3 years (OR = 0.88; 95% CI, 0.77-0.99). Primary component 1 was associated with the total number of infections (incidence rate ratio = 0.97; 95% CI, 0.94-0.99) from age 3 months to age 3 years.

Consistent with the COPSAC 2010 results, the researchers said that sphingomyelin was the most significantly enriched metabolic pathway in a pathway enrichment analysis of the 38 metabolites with a VIP score greater than 2.

The researchers further determined that 25(OH)D levels had a minimal effect on associations between the maternal metabolic profiles 1 week after giving birth and clinical endpoints in COPSAC 2010 in a model adjusted for the effect of 25(OH)D levels in the children at age 6 months and other confounder variables.

Additionally, primary components 1 and 2 of a PCA based on the 38 metabolites available in the children’s metabolome showed no effects toward recurrent wheeze or wheeze exacerbations, the researchers said.

There were significant increases in levels of sphingosine -1- phosphate when human bronchial epithelial cells were treated with high doses of 25(OH)D3, including 0nM vs. 1nM (P < .05) and 0nM vs. 10nM (P < .001) as well, the researchers said.

Overall, increased levels of maternal 25(OH)D 1 week after birth were characterized by sphingomyelins in an enriched sphingolipid pathway, the researchers said, with decreased risk for recurrent wheeze and wheeze exacerbations through age 3 years among children even after adjusting for levels of 25(OH)D in the children at age 6 months.

There also were no significant associations between the metabolic profile related to 25(OH)D and recurrent wheeze and wheeze exacerbations in the metabolome for children aged 6 months, the researchers continued, underscoring the importance of exposure to vitamin D during pregnancy to promote respiratory health in children.

The researchers additionally concluded that their findings indicated a link between treatment with 25(OH)D3 and the cytoplasmatic production of sphingolipids in bronchial epithelial cells.

Considering these beneficial effects of high gestational 25(OH)D levels on the asthma phenotypes of children, the researchers said that strategies for preventing childhood asthma may include therapies that target maternal sphingomyelin metabolism.