Background We conducted a literature review on the studies that investigated the relationship of preterm birth, including spontaneous preterm birth (sPTB), with vitamin D status. Overall, these studies demonstrated that the incidence of sPTB was associated with maternal vitamin D insufficiency in early pregnancy. However, the potential mechanisms and biological pathways are unknown. Objectives To investigate early pregnancy gene expression signatures associated with both vitamin D insufficiency and sPTB. We further constructed a network of these gene signatures and identified the common biological pathways involved. Study design We conducted peripheral blood transcriptome profiling at 10-18 weeks of gestation in a nested case-control cohort of 24 pregnant women who participated in the Vitamin D Antenatal Asthma Reduction Trial (VDAART). In this cohort, 8 women had spontaneous preterm delivery (21-32 weeks of gestation) and 17 women had vitamin D insufficiency (25-hydroxyvitamin D < 30 ng/mL). We separately identified vitamin D-associated and sPTB gene signatures at 10 to 18 weeks and replicated the overlapping signatures in the mid-pregnancy peripheral blood of an independent cohort with sPTB cases. Result At 10-18 weeks of gestation, 146 differentially expressed genes (25 upregulated) were associated with both vitamin D insufficiency and sPTB in the discovery cohort (FDR < 0.05).

We hypothesized metabolomic profiling could be utilized to identify children who scored poorly on the communication component of the Ages and Stages Questionnaire (ASQ); which assesses development in childhood, and to provide candidate biomarkers for autism spectrum disorders (ASD). In a population of three-year-old children, 15 plasma metabolites, were significantly (p < 0.05) different between children who were categorized as having communication skills that were “on schedule” (n = 365 (90.6%)) as compared to those “requiring further monitoring/evaluation” (n = 38 (9.4%)) according to multivariable regression models. Five of these metabolites, including three endocannabinoids, were also dysregulated at age one (n = 204 “on schedule”, n = 24 “further monitoring/evaluation”) in the same children. Stool metabolomic profiling identified 11 significant metabolites. Both the plasma and stool results implicated a role for tryptophan and tyrosine metabolism; in particular, higher levels of N-formylanthranilic acid were associated with an improved communication score in both biosample types. A model based on the significant plasma metabolites demonstrated high sensitivity (88.9%) and specificity (84.5%) for the prediction of autism by age 8. These results provide evidence that ASQ communication score and metabolomic profiling of plasma and/or stool may provide alternative approaches for early diagnosis of ASD, as well as insights into the pathobiology of these conditions.

Autism Spectrum Disorders (ASD) are complex and multifactorial. Previous investigations have revealed associations between allergic disease and ASD, which are characterized by impaired communication skills. In this study we observed an association between allergic disease and communication skills development as assessed by the Ages and Stages Questionnaire (ASQ) communication score, as a proxy for ASD, among children who participated in the Vitamin D Antenatal Asthma Reduction Trial (VDAART). In particular, we observed significant associations between both a diagnosis of eczema at age 3 years (OR=1.87; confidence interval [CI]: 0.97-3.47; p=0.054) and a diagnosis of food allergy at age 6 years (OR=3.61; 95% CI: 1.18-9.85; p=0.015) with ASQ communication score. Plasma metabolomics analyses suggest that dysregulated tryptophan metabolism may contribute to the pathogenesis of these co-morbidities.