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Importance: Limited access to healthy foods, resulting from residence in neighborhoods with low food access, is a public health concern. The contribution of this exposure in early life to child obesity remains uncertain., Objective: To examine associations of neighborhood food access during pregnancy or early childhood with child body mass index (BMI) and obesity risk., Design, Setting, and Participants: Data from cohorts participating in the US nationwide Environmental Influences on Child Health Outcomes consortium between January 1, 1994, and March 31, 2023, were used. Participant inclusion required a geocoded residential address in pregnancy (mean 32.4 gestational weeks) or early childhood (mean 4.3 years) and information on child BMI., Exposures: Residence in low-income, low-food access neighborhoods, defined as low-income neighborhoods where the nearest supermarket is more than 0.5 miles for urban areas or more than 10 miles for rural areas., Main Outcomes and Measures: BMI z score, obesity (age- and sex-specific BMI ≥95th percentile), and severe obesity (age- and sex-specific BMI ≥120% of the 95th percentile) from age 0 to 15 years., Results: Of 28 359 children (55 cohorts; 14 657 [51.7%] male and 13 702 [48.3%] female; 590 [2.2%] American Indian, Alaska Native, Native Hawaiian, or Other Pacific Islander; 1430 [5.4%] Asian; 4034 [15.3%] Black; 17 730 [67.2%] White; and 2592 [9.8%] other [unspecified] or more than 1 race; 5754 [20.9%] Hispanic and 21 838 [79.1%] non-Hispanic) with neighborhood food access data, 23.2% resided in low-income, low-food access neighborhoods in pregnancy and 24.4% in early childhood. After adjusting for individual sociodemographic characteristics, residence in low-income, low-food access (vs non-low-income, low-food access) neighborhoods in pregnancy was associated with higher BMI z scores at ages 5 years (β, 0.07; 95% CI, 0.03-0.11), 10 years (β, 0.11; 95% CI, 0.06-0.17), and 15 years (β, 0.16; 95% CI, 0.07-0.24); higher obesity risk at 5 years (risk ratio [RR], 1.37; 95% CI, 1.21-1.55), 10 years (RR, 1.71; 95% CI, 1.37-2.12), and 15 years (RR, 2.08; 95% CI, 1.53-2.83); and higher severe obesity risk at 5 years (RR, 1.21; 95% CI, 0.95-1.53), 10 years (RR, 1.54; 95% CI, 1.20-1.99), and 15 years (RR, 1.92; 95% CI, 1.32-2.80). Findings were similar for residence in low-income, low-food access neighborhoods in early childhood. These associations were robust to alternative definitions of low income and low food access and additional adjustment for prenatal characteristics associated with child obesity., Conclusions: Residence in low-income, low-food access neighborhoods in early life was associated with higher subsequent child BMI and higher risk of obesity and severe obesity. We encourage future studies to examine whether investments in neighborhood resources to improve food access in early life would prevent child obesity.

Vitamin D 3 's role in mineral homeostasis through its endocrine function, associated with the main circulating metabolite 25-hydroxyvitamin D 3 , is well characterized. However, the increasing recognition of vitamin D 3 's paracrine and autocrine functions-such as cell growth, immune function, and hormone regulation-necessitates examining vitamin D 3 levels across different tissues post-supplementation. Hence, this review explores the biodistribution of vitamin D 3 in blood and key tissues following oral supplementation in humans and animal models, highlighting the biologically active metabolite, 1,25-dihydroxyvitamin D 3 , and the primary clearance metabolite, 24,25-dihydroxyvitamin D 3 . While our findings indicate significant progress in understanding how circulating metabolite levels respond to supplementation, comprehensive insight into their tissue concentrations remains limited. The gap is particularly significant during pregnancy, a period of drastically increased vitamin D 3 needs and metabolic alterations, where data remains sparse. Within the examined dosage ranges, both human and animal studies indicate that vitamin D 3 and its metabolites are retained in tissues selectively. Notably, vitamin D 3 concentrations in tissues show greater variability in response to administered doses. In contrast, its metabolites maintain a more consistent concentration range, albeit different among tissues, reflecting their tighter regulatory mechanisms following supplementation. These observations suggest that serum 25-hydroxyvitamin D 3 levels may not adequately reflect vitamin D 3 and its metabolite concentrations in different tissues. Therefore, future research should aim to generate robust human data on the tissue distribution of vitamin D 3 and its principal metabolites post-supplementation. Relating this data to clinically appropriate exposure metrics will enhance our understanding of vitamin D 3 's cellular effects and guide refinement of clinical trial methodologies., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: The determinants of preterm birth remain unknown. Excessive maternal inflammation during pregnancy may play an important role in the pathogenesis of preterm birth. Our objective was to describe the association of prenatal levels of proinflammatory C-reactive protein (CRP) and interleukin-8 (IL-8) with preterm birth in participants of the Vitamin D Antenatal Asthma Reduction Trial., Study Design: Five hundred and twenty-eight patients with available samples of both first- and third-trimester plasma were included in this analysis. CRP and IL-8 were measured from maternal prenatal samples. We examined the association between prenatal CRP and IL-8 with maternal health characteristics and the outcome of preterm birth. We also described the patterns of change in CRP and IL-8 from first to third trimester and their association with preterm birth. A subgroup analysis comparing only those with a spontaneous preterm birth phenotype to those with term birth was also performed., Results: Maternal characteristics including lower educational attainment, higher prepregnancy body mass index, gestational diabetes, lower vitamin D, and an unhealthy diet were associated with elevated levels of prenatal CRP and IL-8. Higher third trimester CRP and an increase in CRP from first to third trimester were associated with an increased odds of preterm birth when compared to lower levels of CRP (adjusted odds ratio [aOR] = 1.49, 95% confidence interval: 1.02, 2.23, p  = 0.04) or a decrease in CRP over pregnancy (aOR = 3.06, 95% CI = 1.31,7.55, p  = 0.01), after adjusting for potential confounders. These associations were strengthened when comparing only patients with spontaneous preterm birth ( n  = 22) to those with term births., Conclusion: Higher levels of the proinflammatory markers CRP and IL-8 are associated with indicators of poor maternal health and preterm birth. Prenatal CRP levels may reflect maternal prenatal health status and serve as a predictor of preterm birth, especially among those with spontaneous preterm birth., Key Points: · Elevated prenatal CRP is associated with poor maternal health.. · High prenatal CRP may predict premature birth, especially spontaneous premature birth phenotypes.. · Vitamin D insufficiency may be a modifiable risk factor for prenatal inflammation.., Competing Interests: A.A.L. has received author royalties from UpToDate, Inc. S.T.W. has received royalties from UpToDate, Inc. H.M. has received research support from NHLBI. K.L.-S., N.L., Y.S.C., R.S.K., and H.K. have nothing to disclose., (Thieme. All rights reserved.)

Vitamin D possesses immunomodulatory functions and vitamin D deficiency has been associated with the rise in chronic inflammatory diseases, including asthma (Litonjua and Weiss, 2007). Vitamin D supplementation studies do not provide insight into the molecular genetic mechanisms of vitamin D-mediated immunoregulation. Here, we provide evidence for vitamin D regulation of two human chromosomal loci, Chr17q12-21.1 and Chr17q21.2, reliably associated with autoimmune and chronic inflammatory diseases. We demonstrate increased vitamin D receptor ( Vdr ) expression in mouse lung CD4+ Th2 cells, differential expression of Chr17q12-21.1 and Chr17q21.2 genes in Th2 cells based on vitamin D status and identify the IL-2/Stat5 pathway as a target of vitamin D signaling. Vitamin D deficiency caused severe lung inflammation after allergen challenge in mice that was prevented by long-term prenatal vitamin D supplementation. Mechanistically, vitamin D induced the expression of the Ikzf3 -encoded protein Aiolos to suppress IL-2 signaling and ameliorate cytokine production in Th2 cells. These translational findings demonstrate mechanisms for the immune protective effect of vitamin D in allergic lung inflammation with a strong molecular genetic link to the regulation of both Chr17q12-21.1 and Chr17q21.2 genes and suggest further functional studies and interventional strategies for long-term prevention of asthma and other autoimmune disorders., Competing Interests: AK, AH, MD, EM, MD, TB, JR, RC, HM, AS, JK, TN, HP, NK, RA, KG, AL, MD, HR, BL No competing interests declared, SW receives royalties from UpToDate and is an investor in Histolix, (© 2023, Kilic, Halu et al.)

This article provides an overview of the findings obtained from the Vitamin D Antenatal Asthma Reduction Trial (VDAART) spanning a period of 15 years. The review covers various aspects, including the trial's rationale, study design, and initial intent-to-treat analyses, as well as an explanation of why those analyses did not achieve statistical significance. Additionally, the article delves into the post hoc results obtained from stratified intent-to-treat analyses based on maternal vitamin D baseline levels and genotype-stratified analyses. These results demonstrate a statistically significant reduction in asthma among offspring aged 3 and 6 years when comparing vitamin D supplementation (4400 IU/d) to the standard prenatal multivitamin with vitamin D (400 IU/d). Furthermore, these post hoc analyses found that vitamin D supplementation led to a decrease in total serum IgE levels and improved lung function in children compared to those whose mothers received a placebo alongside the standard prenatal multivitamin with vitamin D. Last, the article concludes with recommendations regarding the optimal dosing of vitamin D for pregnant women to prevent childhood asthma as well as suggestions for future trials in this field., (Copyright © 2023. Published by Elsevier Inc.)

Fetal exposures can induce epigenetic modifications, particularly DNA methylation, potentially predisposing individuals to later health issues. Cord blood (CB) DNA methylation provides a unique window into the fetal epigenome, reflecting the intrauterine environment's impact. Maternal factors, including nutrition, smoking and toxin exposure, can alter CB DNA methylation patterns, associated with conditions from obesity to neurodevelopmental disorders. These epigenetic changes underscore prenatal exposures' enduring effects on health trajectories. Technical challenges include tissue specificity issues, limited coverage of current methylation arrays and confounding factors like cell composition variability. Emerging technologies, such as single-cell sequencing, promise to overcome some of these limitations. Longitudinal studies are crucial to elucidate exposure-epigenome interactions and develop prevention strategies. Future research should address these challenges, advance public health initiatives to reduce teratogen exposure and consider ethical implications of epigenetic profiling. Progress in CB epigenetics research promises personalized medicine approaches, potentially transforming our understanding of developmental programming and offering novel interventions to promote lifelong health from the earliest stages of life.

Background: Preeclampsia has been associated with maternal epigenetic changes, in particular DNA methylation changes in the placenta. It has been suggested that preeclampsia could also cause DNA methylation changes in the neonate. We examined DNA methylation in relation to gene expression in the cord blood of offspring born to mothers with preeclampsia., Methods: This study included 128 mother-child pairs who participated in the Vitamin D Antenatal Asthma Reduction Trial (VDAART), where assessment of preeclampsia served as secondary outcome. We performed an epigenome-wide association study of preeclampsia and cord blood DNA methylation (Illumina 450 K chip). We then examined gene expression of the same subjects for validation and replicated the gene signatures in independent DNA methylation datasets. Lastly, we applied functional enrichment and network analyses to identify biological pathways that could potentially be involved in preeclampsia., Findings: In the cord blood samples (n = 128), 263 CpGs were differentially methylated (FDR <0.10) in preeclampsia (n = 16), of which 217 were annotated. Top pathways in the functional enrichment analysis included apelin signaling pathway and other endothelial and cardiovascular pathways. Of the 217 genes, 13 showed differential expression (p's < 0.001) in preeclampsia and 11 had been previously related to preeclampsia (p's < 0.0001). These genes were linked to apelin, cGMP and Notch signaling pathways, all having a role in angiogenic process and cardiovascular function., Interpretation: Preeclampsia is related to differential cord blood DNA methylation signatures of cardiovascular pathways, including the apelin signaling pathway. The association of these cord blood DNA methylation signatures with offspring's long-term morbidities due to preeclampsia should be further investigated., Funding: VDAART is funded by National Heart, Lung, and Blood Institute grants of R01HL091528 and UH3OD023268. HMK is supported by Jane and Aatos Erkko Foundation, Paulo Foundation, and the Pediatric Research Foundation. HM is supported by K01 award from NHLBI (1K01HL146977-01A1). PK is supported by K99HL159234 from NIH/NHLBI., Competing Interests: Declaration of interests AAL reports personal fees from UpToDate, Inc., outside the submitted work. STW reports income from UpToDate, outside the submitted work. The remaining authors declare no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: MicroRNAs (miRNAs) have been implicated in the pathobiology of preeclampsia, a common hypertensive disorder of pregnancy. In a nested matched case-control cohort within the Vitamin D Antenatal Asthma Reduction Trial (VDAART), we previously identified peripheral blood mRNA signatures related to preeclampsia and vitamin D status (≤30 ng/mL) during gestation from 10 to 18 weeks, using differential expression analysis., Methods: Using quantitative PCR arrays, we conducted profiling of circulating miRNAs at 10-18 weeks of gestation in the same VDAART cohort to identify differentially expressed (DE) miRNAs associated with preeclampsia and vitamin D status. For the validation of the expression of circulating miRNA signatures in the placenta, the HTR-8/SVneo trophoblast cell line was used. Targets of circulating miRNA signatures in the preeclampsia mRNA signatures were identified by consensus ranking of miRNA-target prediction scores from four sources. The connected component of target signatures was identified by mapping to the protein-protein interaction (PPI) network and hub targets were determined. As experimental validation, we examined the gene and protein expression of IGF1R, one of the key hub genes, as a target of the DE miRNA, miR-182-5p, in response to a miR-182-5p mimic in HTR-8/SVneo cells., Results: Pregnant women with preeclampsia had 16 circulating DE miRNAs relative to normal pregnancy controls that were also DE under vitamin D insufficiency (9/16 = 56% upregulated, FDR < .05). Thirteen miRNAs (13/16 = 81.3%) were detected in HTR-8/SVneo cells. Overall, 16 DE miRNAs had 122 targets, of which 87 were unique. Network analysis demonstrated that the 32 targets of DE miRNA signatures created a connected subnetwork in the preeclampsia module with CXCL8, CXCL10, CD274, MMP9 and IGF1R having the highest connectivity and centrality degree. In an in vitro validation experiment, the introduction of an hsa-miR-182-5p mimic resulted in significant reduction of its target IGF1R gene and protein expression within HTR-8/SVneo cells., Conclusions: The integration of the circulating DE miRNA and mRNA signatures associated preeclampsia added additional insights into the subclinical molecular signature of preeclampsia. Our systems and network biology approach revealed several biological pathways, including IGF-1, that may play a role in the early pathophysiology of preeclampsia. These pathways and signatures also denote potential biomarkers for the early stages of preeclampsia and suggest possible preventive measures., (© 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

The early life microbiome plays an important role in developmental and long-term health outcomes. However, it is unknown whether adverse pregnancy complications affect the offspring's gut microbiome postnatally and in early years. In a longitudinal cohort with a five-year follow-up of mother-child pairs affected by preeclampsia (PE) or spontaneous preterm birth (sPTB), we evaluated offspring gut alpha and beta diversity as well as taxa abundances considering factors like breastfeeding and mode of delivery. Our study highlights a trend where microbiome diversity exhibits comparable development across adverse and normal pregnancies. However, specific taxa at genus level emerge with distinctive abundances, showing enrichment and/or depletion over time in relation to PE or sPTB. These findings underscore the potential for certain adverse pregnancy complications to induce alterations in the offspring's microbiome over the course of early life. The implications of these findings on the immediate and long-term health of offspring should be investigated in future studies., Competing Interests: R.S.Z. reports grants from the NHLBI for the present work. Other grants and personal fees from MERCK & Co; MedImmune/AstraZeneca, Genentech/Novartis, and GSK. Personal fees from Regeneron Pharmaceuticals, UpToDate, and DBV Technologies. Grants from ALK Pharma. TEVA, and Quest. The other authors report no conflicts., (© 2023 The Author(s).)

Problem: Promotion of a healthy pregnancy is dependent on a coordinated immune response that minimizes inflammation at the maternal-fetal interface. Few studies investigated the effect of fetal sex on proinflammatory biomarkers during pregnancy and whether maternal race could impact this association. We aimed to examine whether fetal sex could, independently of maternal race/ethnicity and the condition of pregnancy (normal vs. complicated), impact inflammatory markers (C-reactive protein [CRP] and interleukin-8 [IL-8] levels) in early and late pregnancy., Methods of Study: This study was a cohort analysis using prospectively collected data from pregnant women who participated in the Vitamin Antenatal Asthma Reduction Trial (VDAART, N = 816). Maternal serum CRP and IL-8 levels were measured in early and late pregnancy (10-18 and 32-38 weeks of gestation, respectively). Five hundred and twenty-eight out of 816 pregnant women who participated in the trial had available CRP and IL-8 measurements at both study time points. We examined the association of fetal sex with early and late CRP and IL-8 levels and their paired sample difference. We further investigated whether maternal race/ethnicity, pregnancy complications (i.e., preeclampsia and gestational diabetes), and early pregnancy body mass index (BMI) could affect the association between these two biomarkers and fetal sex adjusting for potential confounders. For this purpose, we used generalized linear and logistic regression models on log-normalized early and late CRP and IL-8 levels as well as their split at median to form high and low groups., Results: Women pregnant with male fetuses (266/528 = 56.5%) had higher CRP levels in early to mid-pregnancy (β = .18: 95% confidence interval [CI]: CI = 0.03-0.32; p = .02). Twenty-seven percent (143/528) of the study subjects were Hispanic. Hispanic African American [AA] women and women of races other than White and AA had higher levels of CRP at early to mid-pregnancy compared with White women (β = .57; 95% CI: 0.17-0.97; p < .01 and β = .27; 95% CI: 0.05-0.48; p = .02, respectively). IL-8 levels were not associated with fetal sex in early and late pregnancy (p's > .05). Other factors such as gestational diabetes and early pregnancy BMI were associated with higher CRP levels and higher CRP and IL-8 levels, respectively. Dichotomizing log-normalized cytokine levels at the median in a sensitivity analysis, women with male fetuses had lower odds of high (above-median) IL-8 levels at early pregnancy. Also, women with races other than AA and White carrying male fetuses had higher odds of having high (above-median) late-pregnancy CRP and early-pregnancy IL-8 levels (adjusted odds ratio [aOR] = 3.80, 95% CI: 0.24-1.23; p = .02 and aOR = 3.57; 95% CI: 0.23-1.03; p = .02, respectively). Of the pregnancy complications, women with gestational diabetes mellitus had a higher paired difference of early and late pregnancy CRP levels (β = .38; 95% CI: 0.09-0.68; p = .01), but no difference in IL-8 levels (p's > .05). No associations between the inflammatory markers and preeclampsia were found., Conclusion: Fetal sex is associated with CRP in early pregnancy and an association with IL-8 in early pregnancy is implied. Our study further indicates that maternal race/ethnicity could be a contributing factor in the relationship between fetal sex and inflammatory responses during pregnancy. However, the specificity and level of the contribution might vary by type of cytokine, pregnancy stage, and other confounding factors such as BMI that may impact these associations., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Excessive weight is associated with the development of childhood asthma. However, trends among preterm and term offspring may differ., Objective: To assess whether the association of longitudinal weight for age (WFA) and odds of asthma/recurrent wheeze in early life differs between children born preterm and those born at term., Methods: This study used prospectively collected data from the Vitamin D Antenatal Asthma Reduction Trial. Children (n = 804) were followed-up and anthropometric measurements, including WFA, were taken at birth and annually until the age of 6 years. The primary outcome was asthma/recurrent wheeze by age 3 and 6 years., Results: Among the offspring, 71 (8.8%) were premature. In all the children, the odds of asthma/recurrent wheeze increased by 15% (adjusted odds ratio [aOR], 1.15; 95% CI, 1.10-1.20; P < .001) by age 3 years and 9% (aOR, 1.09; 95% CI, 1.07-1.11; P < .001) by age 6 years for each unit increase in WFA z score. Odds were different between term and preterm offspring (P interaction < .001). In term offspring, the odds of having asthma/recurrent wheeze by age 3 and 6 years increased by 22% and 15%, respectively (aOR, 1.22, 95% CI, 1.16-1.27, P < .001, and aOR, 1.15, 95% CI, 1.11-1.18, P < .001). In preterm offspring, by age 3 years, odds of asthma/recurrent wheeze decreased by 10% for each unit increase in WFA z score (aOR, 0.90; 95% CI, 0.81-0.99; P = .030) and decreased by 27% by age 6 years (aOR, .73; 95% CI, 0.61-0.86; P < .001)., Conclusions: During early life, increasing standardized WFA is associated with higher odds of asthma/recurrent wheeze in term children. In contrast, in preterm children, a higher standardized WFA during catch-up growth may decrease the odds of asthma/recurrent wheeze associated with prematurity., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Prenatal vitamin D deficiency is associated with asthma or recurrent wheezing in offspring. However, evidence from randomized trials on the efficacy of vitamin D supplementation is inconclusive., Objectives: We aimed to examine the differential efficacy of prenatal vitamin D supplementation based on the maternal baseline vitamin D status and the starting time of supplementation to prevent early life asthma or recurrent wheezing., Methods: We conducted a secondary analysis of the Vitamin D Antenatal Asthma Reduction Trial (VDAART), a randomized double-blind trial of prenatal vitamin D supplementation initiated at 10-18 weeks (wks) of gestation (4400 IU of intervention/day compared with 400 IU of placebo/day) to prevent offspring asthma or recurrent wheezing by the age of 6 years. We assessed the effect of modification of supplementation by maternal baseline vitamin D status at enrollment and the timing of initiation of supplementation., Results: An inverse relationship was observed between maternal 25-hydroxyvitamin D (25(OH)D) levels at trial entry and 25(OH)D levels during late pregnancy (32-38 wks of gestation) in both supplementation arms (P < 0.001). Overall, supplementation efficacy was not dependent on the maternal baseline 25(OH)D status. However, a trend toward the reduction of asthma or recurrent wheezing was observed across the baseline groups in the intervention arm (P = 0.01), with the greatest reduction observed in the most severely vitamin D-deficient women (25(OH)D < 12 ng/mL; adjusted odds ratio [aOR] = 0.48; confidence interval [CI]: 0.17, 1.34). Gestational age at trial enrollment modified supplementation efficacy, showing a greater reduction of offspring asthma or recurrent wheezing with earlier intervention during pregnancy (aOR = 0.85; CI = 0.76, 0.95), particularly in women who were 9-12 wk pregnant (aOR = 0.45; CI = 0.24, 0.82)., Conclusions: Pregnant women with severe vitamin D deficiency show the greatest 25(OH)D improvement because of supplementation. In these women, a vitamin D dose of 4400 IU might have a preventive role in the development of early life offspring asthma or recurrent wheezing. Gestational age is suggested to modify the efficacy of prenatal vitamin D supplementation, showing the highest beneficial effect if supplementation is started during the first trimester of pregnancy. This study is an ancillary analysis from the VDAART, which is registered in ClinicalTrials.gov as NCT00902621., (Copyright © 2023 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Background: Prior studies suggest that vitamin D may modify the effects of environmental exposures; however, none have investigated gestational vitamin D and cumulative tobacco smoke exposure (TSE) throughout pregnancy and early life., Objectives: This study investigated the effects of early life TSE on child lung function and the modulatory effects of gestational vitamin D on this association., Methods: The VDAART (Vitamin D Antenatal Asthma Reduction Trial) recruited nonsmoking pregnant women and followed the mother-child pairs to age 6 years. TSE was assessed with questionnaires and plasma cotinine measurements in the mothers (10-18 and 32-38 gestational weeks) and children (1, 3, and 6 years). Cumulative TSE was calculated from the repeated cotinine measurements. 25-hydroxyvitamin D (25[OH]D) levels were measured at 10-18 and 32-38 gestational weeks. Lung function was assessed at 6 years with spirometry and impulse oscillometry., Results: Of the 476 mother-child pairs, 205 (43%) had increased cotinine levels at ≥1 time point. Cumulative TSE was associated with decreased FEV 1 (β = -0.043 L, P = .018) and increased respiratory resistance at 5 Hz (R5; β = 0.060 kPa/L/s, P = .002). This association persisted in subjects with insufficient (<30 ng/mL) 25(OH)D levels throughout pregnancy (β = 0.077 kPa/L/s, P = .016 for R5) but not among those with sufficient levels throughout pregnancy., Conclusions: Cumulative TSE from pregnancy to childhood is associated with dose- and duration-dependent decreases in child lung function at 6 years even in the absence of reported maternal smoking. Gestational vitamin D may modulate this effect and have therapeutic potential for minimizing the adverse effect of TSE on lung throughout early life., Randomized Trial: Maternal Vitamin D Supplementation to Prevent Childhood Asthma (VDAART); clinicaltrials.gov identifier: NCT00920621., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: The pathogenesis of childhood asthma is complex, and determinants of risk may begin in utero., Objective: To describe the association of systemic prenatal inflammation, measured by plasma C-reactive protein (CRP), with childhood asthma, eczema, and allergic rhinitis., Methods: A total of 522 maternal-offspring pairs from the Vitamin D Antenatal Asthma Reduction Trial were included. Prenatal plasma CRP level was measured between 10 and 18 weeks of gestation and between 32 and 38 weeks of gestation. Offspring asthma, eczema, and allergic rhinitis were assessed quarterly between birth and age 6 years. We performed mediation analyses of prenatal CRP on the association between several maternal characteristics and offspring asthma., Results: Elevated early and late prenatal CRP and an increase in CRP from early to late pregnancy were associated with asthma by age 6 years (early: adjusted odds ratio [aOR], 1.76, 95% CI, 1.12-2.82, P = .02; late: aOR, 2.45, 95% CI, 1.47-4.18, P < .001; CRP increase: aOR, 2.06, 95% CI, 1.26-3.39, P < .004). Prenatal CRP and childhood asthma associations were strengthened among offspring with atopic asthma (early: aOR, 3.78, 95% CI, 1.49-10.64, P = .008; late: aOR, 4.84, 95% CI, 1.68-15.50, P = .005; CRP increase: aOR, 3.01, 95% CI, 1.06-9.16, P = .04). Early and late prenatal CRP mediated 96% and 86% of the association between maternal prepregnancy body mass index and offspring asthma, respectively., Conclusions: Higher prenatal CRP and an increase in CRP from early to late pregnancy are associated with childhood asthma. Systemic inflammation during pregnancy associated with modifiable maternal characteristics may be an important determinant of childhood asthma risk., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Prior research has demonstrated bidirectional associations between gestational diabetes mellitus (GDM) and perinatal maternal depression. However, the association between GDM, prenatal depression, and postpartum depression (PPD) has not been examined in a prospective cohort longitudinally., Methods: Participants in the current analysis included 5,822 women from the National Institutes of Health's Environmental influences on Child Health Outcomes (ECHO) Research Program: N = 4,606 with Neither GDM nor Prenatal Maternal Depression (Reference Category); N = 416 with GDM only; N = 689 with Prenatal Maternal Depression only; and N = 111 with Comorbid GDM and Prenatal Maternal Depression. The PROMIS-D scale was used to measure prenatal and postnatal maternal depressive symptoms. Primary analyses consisted of linear regression models to estimate the independent and joint effects of GDM and prenatal maternal depression on maternal postpartum depressive symptoms., Results: A higher proportion of women with GDM were classified as having prenatal depression (N = 111; 21%) compared to the proportion of women without GDM who were classified as having prenatal depression (N = 689; 13%), however this finding was not significant after adjustment for covariates. Women with Comorbid GDM and Prenatal Maternal Depression had significantly increased postpartum depressive symptoms measured by PROMIS-D T-scores compared to women with Neither GDM nor Prenatal Maternal Depression (mean difference 7.02, 95% CI 5.00, 9.05). Comorbid GDM and Prenatal Maternal Depression was associated with an increased likelihood of PPD (OR 7.38, 95% CI 4.05, 12.94). However, women with GDM only did not have increased postpartum PROMIS-D T-scores or increased rates of PPD., Conclusions: Our findings underscore the importance of universal depression screening during pregnancy and in the first postpartum year. Due to the joint association of GDM and prenatal maternal depression on risk of PPD, future studies should examine potential mechanisms underlying this relation., (© 2022. The Author(s).)

Objective: To examine whether maternal race could affect the relationship between fetal sex and preeclampsia., Material and Methods: This study was a cohort analysis using prospectively collected data from pregnant women who participated in the Vitamin Antenatal Asthma Reduction Trial (VDAART). Preeclampsia was the secondary outcome of VDAART. We examined the association of fetal sex with preeclampsia and its potential interaction with maternal race in 813 pregnant women (8% with preeclampsia) in logistic regression models with adjustment for preterm birth (<37 weeks of gestation), maternal age, education, and body mass index at enrollment and clinical center. We further conducted a race stratified analysis and also examined whether any observed association was dependent on the gestational age at delivery and prematurity., Results: In an analysis of all races combined, preeclampsia was not more common among pregnant women with a male fetus compared to those with a female fetus (odds ratio [OR] = 1.3, 95% CI = 0.81, 2.24). There was an interaction between African American race and fetal sex in association with preeclampsia after adjustment for preterm delivery and other potential confounders ( p  = .014). In race stratified analyses, we observed higher odds of preeclampsia among African American pregnant women who carried male fetuses after adjustment for preterm delivery and other potential confounders (adjusted OR = 2.4, 95% CI = 1.12, 5.60)., Conclusion: We observed fetal sexual dimorphic differences in the occurrence of preeclampsia in African American women, but not in Whites. Information on fetal sex may ultimately improve the prediction of pre-eclampsia in African American mothers, who might be at higher risk for this adverse condition in pregnancy.

Background: The role of prenatal vitamin D sufficiency and supplementation in the development of childhood aeroallergen sensitization and allergic rhinitis remains uncertain., Objective: To describe the association of prenatal vitamin D sufficiency with childhood allergic outcomes in participants of the Vitamin D Antenatal Asthma Reduction Trial, a randomized controlled trial of prenatal vitamin D supplementation., Methods: We included 414 mother-offspring pairs with offspring aeroallergen sensitization data available at age 6 years in this analysis. We examined the association between prenatal vitamin D sufficiency status, based on vitamin D levels measured in the first and third trimesters, or vitamin D supplementation treatment assignment with the outcomes of aeroallergen sensitization, parent-reported clinical allergic rhinitis, parent-reported clinical allergic rhinitis with aeroallergen sensitization, food sensitization, any sensitization, eczema, and total IgE at ages 3 and 6 years., Results: Compared with early and late insufficiency, early prenatal vitamin D insufficiency with late sufficiency was associated with reduced development of clinical allergic rhinitis with aeroallergen sensitization at 3 years (adjusted odds ratio [aOR] = 0.34; 95% confidence interval [CI], 0.13-0.82; P = .02) and 6 years (aOR = 0.54; 95% CI, 0.29-0.98; P = .05). At 6 years, clinical allergic rhinitis with sensitization was significantly decreased in offspring whose mothers received high-dose vitamin D (aOR = 0.54; 95% CI, 0.32-0.91; P = .02) compared with offspring whose mothers who received low-dose vitamin D. Associations of prenatal vitamin D with aeroallergen sensitization were strengthened among children who also developed asthma or who had a maternal history of atopy., Conclusions: Among mothers with first-trimester vitamin D insufficiency, we detected a protective effect of third-trimester prenatal vitamin D sufficiency on the development of clinical allergic rhinitis with aeroallergen sensitization at ages 3 and 6 years., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

RANTES is implicated in allergic asthma and in T cell-dependent clearance of infection. RANTES receptor family comprises CCR1, CCR3, and CCR5, which are G-protein-coupled receptors consisting of seven transmembrane helices. Infections with respiratory viruses like Rhinovirus cause induction of RANTES production by epithelial cells. Here, we studied the role of RANTES in the peripheral blood mononuclear cells in cohorts of children with and without asthma and validated and extended this study to the airways of adults with and without asthma. We further translated these studies to a murine model of asthma induced by house dust mite allergen in wild-type RANTES and CCR5-deficient mice. Here we show an unpredicted therapeutic role of RANTES in the resolution of allergen-induced asthma by orchestrating the transition of effector GATA-3+CD4+ T cells into immune-regulatory-type T cells and inflammatory eosinophils into resident eosinophils as well as increased IL-10 production in the lung., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)

Background: Randomized controlled trials (RCTs) suggest a protective effect of high-dose vitamin D supplementation in pregnancy on offspring risk of persistent wheeze, but only in some individuals, which might be explained by variations in vitamin D pathway genes. This study aimed to investigate the effect of vitamin D supplementation by maternal and offspring vitamin D receptor (VDR) genotype and GC genotype, encoding vitamin D binding protein (VDBP), in two RCTs., Methods: In the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC 2010 ) RCT, we analyzed the effect of high-dose vitamin D during pregnancy on the risk of persistent wheeze age 0-3 years by variants in single nucleotide polymorphisms (SNPs) in VDR (rs1544410, rs2228570, rs7975128, rs7975232) and GC (rs4588, rs7041). Replication was sought in the Vitamin D Antenatal Asthma Reduction Trial (VDAART)., Results: In COPSAC 2010 , VDR SNP rs1544410 influenced the effect of high-dose vitamin D: maternal P interaction  = .049 and child P interaction  = .001, with the largest effect in offspring from mothers with TT genotype: hazard ratio (95% CI), 0.26 (0.10-0.68), P = .006, and no effect among CT or CC genotypes: 0.85 (0.48-1.51), P = .58 and 0.94 (0.47-1.89), P = .87, respectively. However, these findings were not replicated in VDAART. There was no significant effect modification from maternal or offspring GC genotype in either COPSAC 2010 or VDAART: all P interaction  ≥ .17., Conclusions: We found that the effect of high-dose vitamin D supplementation during pregnancy on offspring risk of persistent wheeze was significantly influenced by VDR genotype in the COPSAC 2010 RCT, but not VDAART, which may be due to population differences., (© 2021 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Of children with recurrent wheezing in early childhood, approximately half go on to develop asthma. MicroRNAs have been described as excellent non-invasive biomarkers due to their prognostic utility. We hypothesized that circulating microRNAs can predict incident asthma and that that prediction might be modified by vitamin D. We selected 75 participants with recurrent wheezing at 3 years old from the Vitamin D Antenatal Asthma Reduction Trial (VDAART). Plasma samples were collected at age 3 and sequenced for small RNA-Seq. The read counts were normalized and filtered by depth and coverage. Logistic regression was employed to associate miRNAs at age 3 with asthma status at age 5. While the overall effect of miRNA on asthma occurrence was weak, we identified 38 miRNAs with a significant interaction effect with vitamin D and 32 miRNAs with a significant main effect in the high vitamin D treatment group in VDAART. We validated the VDAART results in Project Viva for both the main effect and interaction effect. Meta-analysis was performed on both cohorts to obtain the combined effect and a logistic regression model was used to predict incident asthma at age 7 in Project Viva. Of the 23 overlapped miRNAs in the stratified and interaction analysis above, 9 miRNAs were replicated in Project Viva with strong effect size and remained in the meta-analysis of the two populations. The target genes of the 9 miRNAs were enriched for asthma-related Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathways. Using logistic regression, microRNA hsa-miR-574-5p had a good prognostic ability for incident asthma prognosis with an area under the receiver operating characteristic (AUROC) of 0.83. In conclusion, miRNAs appear to be good biomarkers of incident asthma, but only when vitamin D level is considered.

Background: Childhood asthma developmental programming is complex. Maternal asthma is a strong risk factor for childhood asthma, whereas vitamin D (VD) has emerged as a modifiable prenatal exposure., Objective: Our aim was to examine the combined effect of early and late prenatal VD status in during pregnancies in women with and without asthma on childhood asthma or recurrent wheeze development., Methods: We conducted a cohort study using prospectively collected data from the Vitamin D Antenatal Asthma Reduction Trial, a randomized, double-blinded, placebo-controlled VD supplementation trial in pregnant women at high risk of offspring asthma (N = 806 mother-offspring pairs). 25-Hydroxyvitamin-D (25(OH)D) level was measured in early and late pregnancy. Our main exposure was an ordered variable representing early and late prenatal VD sufficiency (25(OH)D level ≥ 30 ng/mL) status during pregnancy in women with and without asthma. The primary outcome was offspring with asthma or recurrent wheeze by age 3 years. We also examined the effect of prenatal VD level on early life asthma or recurrent wheeze progression to active asthma at age 6 years., Results: Among mothers with asthma versus among mothers with early and late prenatal VD insufficiency, those with early or late VD sufficiency (adjusted odds ratio = 0.56; 95% CI = 0.31-1.00) or early and late VD sufficiency (adjusted odds ratio = 0.36; 95% CI = 0.15-0.81) had a lower risk of offspring with asthma or recurrent wheeze by age 3 years (P for trend  = .008). This protective trend was reiterated in asthma or recurrent wheeze progression to active asthma from age 3 to 6 years (P for   trend  = .04)., Conclusion: This study implies a protective role for VD sufficiency throughout pregnancy, particularly in attenuating the risk conferred by maternal asthma on childhood asthma or recurrent wheeze development., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Objective: To assess whether women with a genetic predisposition to medical conditions known to increase pre-eclampsia risk have an increased risk of pre-eclampsia in pregnancy., Design: Case-control study., Setting and Population: Pre-eclampsia cases (n = 498) and controls (n = 1864) in women of European ancestry from five US sites genotyped on a cardiovascular gene-centric array., Methods: Significant single-nucleotide polymorphisms (SNPs) from 21 traits in seven disease categories (cardiovascular, inflammatory/autoimmune, insulin resistance, liver, obesity, renal and thrombophilia) with published genome-wide association studies (GWAS) were used to create a genetic instrument for each trait. Multivariable logistic regression was used to test the association of each continuous scaled genetic instrument with pre-eclampsia. Odds of pre-eclampsia were compared across quartiles of the genetic instrument and evaluated for significance., Main Outcome Measures: Genetic predisposition to medical conditions and relationship with pre-eclampsia., Results: An increasing burden of risk alleles for elevated diastolic blood pressure (DBP) and increased body mass index (BMI) were associated with an increased risk of pre-eclampsia (DBP, overall OR 1.11, 95% CI 1.01-1.21, P = 0.025; BMI, OR 1.10, 95% CI 1.00-1.20, P = 0.042), whereas alleles associated with elevated alkaline phosphatase (ALP) were protective (OR 0.89, 95% CI 0.82-0.97, P = 0.008), driven primarily by pleiotropic effects of variants in the FADS gene region. The effect of DBP genetic loci was even greater in early-onset pre-eclampsia cases (at <34 weeks of gestation, OR 1.30, 95% CI 1.08-1.56, P = 0.005). For other traits, there was no evidence of an association., Conclusions: These results suggest that the underlying genetic architecture of pre-eclampsia may be shared with other disorders, specifically hypertension and obesity., Tweetable Abstract: A genetic predisposition to increased diastolic blood pressure and obesity increases the risk of pre-eclampsia., (© 2020 John Wiley & Sons Ltd.)

Background: We recently described increased NFATc1, IRF4, and NIP45 messenger RNA (mRNA) expression in peripheral blood mononuclear cells (PBMCs) of asthmatic children and adults with multiple allergies., Objective: NFATc2 has been described to associate with IRF4 to induce interleukin-4, and to be inhibited by T-bet. Here, we analyzed the role of NFATc2 in asthmatic children and adults., Methods: PBMCs were isolated from the blood of control of asthmatics subjects. Some PBMCs were analyzed untreated and some cultured with and without phytohemagglutinin. Then, RNA was extracted from the cells and cytokines were measured in the supernatants via enzyme-linked immunosorbent assay or multiplex analysis. RNA was then reverse-transcribed and NFATc1, NFATC2, IRF4, and T-bet mRNA were analyzed by real-time polymerase chain reaction. In addition, in peripheral blood cells, NFATc2 expression was analyzed, in a population of asthmatic children and adults from the Asthma BRIDGE study., Results: In addition to NFATc1 and NIP45, also NFATc2 was found upregulated in PBMCs and peripheral blood cells from asthmatic children and adults with allergic asthma. Moreover, NFATc1 directly correlated with lymphocytes number whereas NFATc2 correlated with peripheral eosinophilia in asthma., Conclusions: In addition to NFATc1 and NIP45, NFATc2 was found upregulated in asthma. Moreover, NFATc1 mRNA correlated with lymphocytes both in control and asthma, and NFATC1 and NFATc2 mRNA showed a direct correlation with eosinophils in controls but not in asthma, indicating that NFATc1 is associated with lymphocytes and not eosinophils in asthma., Clinical Significance: Targeting NFATc2 in T lymphocytes might ameliorate the allergic phenotype in asthmatic subjects., (© 2020 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

We hypothesize that first trimester circulating micro particle (CMP) proteins will define preeclampsia risk while identifying clusters of disease subtypes among cases. We performed a nested case-control analysis among women with and without preeclampsia. Cases diagnosed < 34 weeks' gestation were matched to controls. Plasma CMPs were isolated via size exclusion chromatography and analyzed using global proteome profiling based on HRAM mass spectrometry. Logistic models then determined feature selection with best performing models determined by cross-validation. K-means clustering examined cases for phenotypic subtypes and biological pathway enrichment was examined. Our results indicated that the proteins distinguishing cases from controls were enriched in biological pathways involved in blood coagulation, hemostasis and tissue repair. A panel consisting of C1RL, GP1BA, VTNC, and ZA2G demonstrated the best distinguishing performance (AUC of 0.79). Among the cases of preeclampsia, two phenotypic sub clusters distinguished cases; one enriched for platelet degranulation and blood coagulation pathways and the other for complement and immune response-associated pathways (corrected p < 0.001). Significantly, the second of the two clusters demonstrated lower gestational age at delivery (p = 0.049), increased protein excretion (p = 0.01), more extreme laboratory derangement (p < 0.0001) and marginally increased diastolic pressure (p = 0.09). We conclude that CMP-associated proteins at 12 weeks' gestation predict the overall risk of developing early preeclampsia and indicate distinct subtypes of pathophysiology and clinical morbidity.

Several studies have linked maternal asthma, excess BMI, and low vitamin D status with increased risk of Preeclampsia (PE) development. Given prior evidence in the literature and our observations from the subjects in the Vitamin D Antenatal Asthma Reduction Trial (VDAART), we hypothesized that PE, maternal asthma, vitamin D insufficiency, and excess body mass index (BMI) might share both peripheral blood and placental gene signatures that link these conditions together. We used samples collected in the VDAART to investigate relationships between these four conditions and gene expression patterns in peripheral blood obtained at early pregnancy. We identified a core set of differentially expressed genes in all comparisons between women with and without these four conditions and confirmed them in two separate sets of samples. We confirmed the differential expression of the shared gene signatures in the placenta from an independent study of preeclampsia cases and controls and constructed the preeclampsia module using protein-protein interaction networks. CXC chemokine genes showed the highest degrees of connectivity and betweenness centrality in the peripheral blood and placental modules. The shared gene signatures demonstrate the biological pathways involved in preeclampsia at the pre-clinical stage and may be used for the prediction of preeclampsia.

Background: Few studies investigated whether late preterm infants might have developmental delays in several domains in early life and how stable the lag in developmental status might be., Aim: We aimed to examine the stability of potential delays across developmental domains at 24 and 36 months of age in late preterm (34°-36 6 weeks) and term (≥37 weeks) children and whether the risk of delays remained high at 36 months., Study Design, Subjects, and Outcome Measure: We conducted a prospective cohort analysis of the children of pregnant women participating in the Vitamin Antenatal Asthma Reduction Trial (VDAART). 652 children who were prospectively followed up and had parent-completed Ages Stages Questionnaires (ASQ-3) questionnaires at both 24 and 36 months were analyzed to assess their domain-specific developmental status., Results: 6.61 % (42/635) of children had a late preterm birth. Developmental delays were stable between 24 and 36 months on all 5 domains for the children born preterm and on 4/5 domains for those born at term. The developmental domains with the status stability at 24 and 36 months in both late preterm and term children were the gross motor, communication, personal-social skills, and problem-solving. Late preterm children compared with term children remained at higher risk of delays at 36 months for gross motor, communication, and problem-solving skills (aOR = 4.54, 95 %CI: 1.81-10.79; aOR = 8.60, 95 %CI: 3.10-23.28 and aOR = 3.80, 95 %CI: 1.58-8.73, respectively)., Conclusion: Late preterm birth is associated with suboptimal development and stability in several domains at both 24 and 36 months and compared with term birth, requiring early monitoring and assessment of the developmental lag to avoid potential long-term implications., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Precision medicine represents an evolving approach to improve treatment efficacy by modifying it to individual patient's gene variation. Pharmacogenetics, an applicable branch of precision medicine, identifies patient's predisposing genotypes that alter the clinical outcome of the drug, hence preventing serious adverse drug reactions. Pharmacogenetics has been extensively applied to various fields of medicine, but in the field of anesthesiology and preoperative medicine, it has been unexploited. Although the US Food and Drug Administration (FDA) has a table of pharmacogenomics biomarkers and pharmacogenetics, this table only includes general side effects of the included drugs. Thus, the existing FDA table offers limited information on genetic variations that may increase drug side effects. Aims: The purpose of this paper is to provide a web-based pharmacogenomics search tool composed of a comprehensive list of medications that have pharmacogenetic relevance to perioperative medicine that might also have application in other fields of medicine. Method: For this investigation, the FDA table of pharmacogenomics biomarkers in drug labeling was utilized as an in-depth of drugs to construct our pharmacogenetics drug table. We performed a literature search for drug-gene interactions using the unique list of drugs in the FDA table. Publications containing the drug-gene interactions were identified and reviewed. Additional drugs and extracted gene-interactions in the identified publications were added to the constructed drug table. Result: Our tool provides a comprehensive pharmacogenetic drug table including 258 drugs with a total of 461 drug-gene interactions and their corresponding gene variations that might cause modifications in drug efficacy, pharmacokinetics, pharmacodynamics and adverse reactions. This tool is freely accessible online and can be applied as a web-based search instrument for drug-gene interactions in different fields of medicine, including perioperative medicine. Conclusion: In this research, we collected drug-gene interactions in a web-based searchable tool that could be used by physicians to expand their field knowledge in pharmacogenetics and facilitate their clinical decision making. This precision medicine tool could further serve in establishing a comprehensive perioperative pharmacogenomics database that also includes different fields of medicine that could influence the outcome of perioperative medicine.

Vitamin D insufficiency during pregnancy is widespread. The effects of active vitamin D on the human placenta in vivo are unknown. We test the hypotheses that 25(OH)D sufficiency (arbitrarily defined as 25(OH)D ≥32 ng/mL) modulates placental structure and function in vivo in a population of women whose offspring are at risk for childhood asthma, and that placental pathology is more common in offspring that evolve asthma at age 3. Pregnant volunteers in the St. Louis, MO, cohort of the Vitamin D Antenatal Asthma Reduction Trial (VDAART, NIH grant #HL091528) participated in a nested case-control study and consented for the study of placentas after delivery. Maternal concentrations of 25(OH)D were measured at trial entry and in the third trimester. The histopathology of the placentas from women with sufficient 25(OH)D, versus insufficient, showed no clinically significant differences, but morphometry revealed villi of women with sufficient third-trimester 25(OH)D had a higher villous surface density. Notably, analyses of transcripts, extracted from formalin-fixed paraffin-embedded specimens, revealed higher expression of INTS9, vWF, MACC1, and ARMS2, and diminished expression of the CNTN5 genes in the insufficient group. A larger proportion of placentas showed chronic chorioamnionitis in offspring with versus without asthma at age 3. These findings suggest that maternal 25(OH)D insufficiency has a limited effect on human placental villous histopathology and morphometry, but attenuates a small number of placental gene expression profiles in this selected population. The association of placental chronic chorioamnionitis and offspring asthma is worthy of further study., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: We previously reported the results of a trial of prenatal vitamin D supplementation to prevent asthma and recurrent wheeze in young children, which suggested that supplementation provided a protective effect at the age of 3 years. We followed the children through the age of 6 years to determine the course of asthma and recurrent wheeze., Methods: In this follow-up study, investigators and participants remained unaware of the treatment assignments through the children's sixth birthday. We aimed to determine whether, when maternal levels of 25-hydroxyvitamin D were taken into account, children born to mothers who had received 4400 IU of vitamin D 3 per day during pregnancy (vitamin D group) would have a lower incidence of asthma and recurrent wheeze at the age of 6 years than would those born to mothers who had received 400 IU of vitamin D 3 per day (control group). Time-to-event methods were used to compare the treatment groups with respect to time to the onset of asthma or recurrent wheeze. Multivariate methods were used to compare longitudinal measures of lung function between the treatment groups., Results: There was no effect of maternal vitamin D supplementation on asthma and recurrent wheeze in either an intention-to-treat analysis or an analysis with stratification according to the maternal 25-hydroxyvitamin D level during pregnancy. There was no effect of prenatal vitamin D supplementation on most of the prespecified secondary outcomes. We found no effects of prenatal supplementation on spirometric indexes. Although there was a very small effect on airway resistance as measured by impulse oscillometry, this finding was of uncertain significance., Conclusions: Vitamin D supplementation during the prenatal period alone did not influence the 6-year incidence of asthma and recurrent wheeze among children who were at risk for asthma. (Funded by the National Heart, Lung, and Blood Institute; VDAART ClinicalTrials.gov number, NCT00920621.)., (Copyright © 2020 Massachusetts Medical Society.)

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). Of these genes, 43 (25 upregulated) were replicated in the independent cohort of sPTB cases and controls with normal pregnancies (P < 0.05). Functional enrichment and network analyses of the replicated gene signatures suggested several highly connected nodes related to inflammatory and immune responses., Conclusions: Our gene expression study and network analyses suggest that the dysregulation of immune response pathways due to early pregnancy vitamin D insufficiency may contribute to the pathobiology of sPTB., Competing Interests: The authors have declared that no competing interests exist.

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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Here we investigated the role of NFAT-interacting protein (NIP)-45, an Interleukin (IL)-4 inducing Transcription Factor, and its impact on the differentiation of Group 2 Innate -Lymphoid -Cells (ILC2s) in the pathogenesis of asthma. NIP45, a transcription factor regulating NFATc1 activity, mRNA was found to be induced in the Peripheral Blood mononuclear cells (PMBCs) of asthmatic pre-school children with allergies and in the peripheral blood CD4 + T cells from adult asthmatic patients. In PBMCs of asthmatic and control children, NIP45 mRNA directly correlated with NFATc1 but not with T-bet. Targeted deletion of NIP45 in mice resulted in a protective phenotype in experimental asthma with reduced airway mucus production, airway hyperresponsiveness and eosinophils. This phenotype was reversed by intranasal delivery of recombinant r-IL-33. Consistently, ILC2s and not GATA3 + CD4 + T-cells were decreased in the lungs of asthmatic NIP45 -/- mice. Reduced cell number spleen ILC2s could be differentiated from NIP45 -/- as compared to wild-type mice after in vivo injection of a microcircle-DNA vector expressing IL-25 and decreased cytokines and ILC2 markers in ILC2 differentiated from the bone marrow of NIP45 -/- mice. NIP45 thus emerges as a new therapeutic target for the resolution of the airway pathology, down-regulation of ILC2s and mucus production in asthma.

Objectives: Fentanyl is a potent analgesic that accounts for an increasing number of overdose deaths in the United States. This study tested whether altered pharmacokinetics plays a pivotal role in the increased fentanyl dose requirements in patients receiving the enzyme-inducing anticonvulsant, carbamazepine., Methods: Neurosurgical patients receiving carbamazepine for >6 weeks (N = 11) or no carbamazepine (N = 6, controls) received a single bolus dose of fentanyl (200 μg) intravenously. Plasma was collected before and for up to 9 h after the bolus. Fentanyl concentrations were measured using liquid chromatography-mass spectrometry. Pharmacokinetic variables were derived from plasma concentration-time curves best fitted to a two-compartment model., Key Findings: Fentanyl clearance was significantly higher in the carbamazepine group compared to controls (mean ± SD: 20.1 ± 6.8 vs 13.2 ± 4.8 ml/min per kg, P < 0.05), and area under the plasma concentration curve (AUC) was significantly lower (150 ± 65 vs 233 ± 70 ng/ml × min, P < 0.02). Volume of distribution was larger in the carbamazepine group, but the difference was not statistically significant (5.4 ± 3.1 vs 3.6 ± 1.2 l/kg, P > 0.15). The terminal elimination half-life did not differ between the two groups., Conclusions: Chronic carbamazepine therapy leads to increased fentanyl clearance and decreased AUC, which may result in decreased duration of therapeutic plasma concentrations of fentanyl and an increased dose requirement. Assuming that carbamazepine does not change fentanyl pharmacodynamics, patients on chronic carbamazepine therapy may require more frequent or higher fentanyl doses to maintain therapeutic plasma concentrations., (© 2019 Royal Pharmaceutical Society.)

Background: While familial clustering of asthma is known, few studies have reported on the relative roles of paternal and maternal asthma and the role of maternal asthma control in pregnancy on the risk for asthma in the child., Objective: We aimed to investigate the relative roles of paternal asthma, maternal asthma, and maternal asthma control during pregnancy on the risk of asthma or recurrent wheeze in 3-year-old children and how prenatal and cord blood vitamin D status might affect this risk., Methods: Data from 806 women, their partners (biologic fathers of the infants), and their children participated in the Vitamin D Antenatal Asthma Reduction Trail (VDAART, clinicaltrials.gov identification number NCT00920621) were used for this cohort analysis. The parental report of physician-diagnosed asthma or recurrent wheeze in offspring was the main outcome. Weibull regression models for interval-censored event times were used to estimate the main variables of interests and additional covariates on the outcome., Results: The highest risk was observed among children with both parents being asthmatic relative to non-asthmatic parents (aHR = 2.30, 95% CI: 1.35-3.84), and less so if only the mother was asthmatic (aHR = 1.70, 95% CI: 1.17-2.40). In the subset of children born to asthmatic mothers, the risk for asthma was higher in those who were born to mothers whose asthma was uncontrolled (aHR = 1.60, 95% CI: 1.02-2.54). Children whose mothers had sufficient vitamin D status (25Hydroxyvitamin D ≥ 30 ng/mL) at early and late pregnancy and had cord blood vitamin D sufficiency demonstrated a lower risk of asthma/recurrent wheeze than children who had insufficient cord blood vitamin D status at birth (aHR = 0.47, 95% CI: 0.27-0.83)., Conclusion and Clinical Relevance: Careful attention to maternal asthma control, monitoring vitamin D status, and correcting insufficiency at early pregnancy and maintaining the sufficiency status throughout pregnancy have potential preventive roles in offspring asthma or recurrent wheeze., (© 2018 John Wiley & Sons Ltd.)

Cord blood 25-hydroxyvitamin D (25OHD) has been reported in association with risk of early life recurrent wheeze. In a subset of infants who participated in the Vitamin D Antenatal Asthma Reduction Trial, we demonstrated that higher cord blood 25OHD at birth (>31 ng/mL) was associated with a reduced risk of recurrent wheeze in the first year of life. We then identified a module of co-expressed genes associated with cord blood 25OHD levels >31 ng/mL. Genes in this module are involved in biological and immune pathways related to development and progression of asthma pathogenesis including the Notch1 and transforming growth factor-beta signalling pathways., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Rationale: Maternal asthma and preeclampsia have independently been reported to be associated with increased asthma incidence in children of affected mothers. Maternal asthma is also associated with increased risk of preeclampsia development. However, the joint effect of these maternal conditions on child asthma risk is unknown., Objectives: To study whether development of preeclampsia among pregnant women with asthma was associated with higher risk of childhood asthma in the VDAART (Vitamin D Antenatal Asthma Reduction Trial)., Methods: A total of 806 pregnant women and their offspring at high risk of asthma or atopy, who were followed from VDAART enrollment (10-18 wk of gestation) through the child's third birthday, were included in this cohort analysis. Preeclampsia status was determined by chart review, obstetrician diagnosis, and adjudication by a panel of obstetricians. Child asthma was the main outcome as determined by parental report of a physician diagnosis, and the risk of child asthma was also examined if accompanied by recurrent wheeze. The main risk variable of interest was a four-level ordered variable defined for each mother, with values without asthma without preeclampsia, without asthma with preeclampsia, with asthma without preeclampsia, and with asthma with preeclampsia during their pregnancy. We examined the trend of outcome proportions across these categories. To account for differences in maternal and child characteristics, we used a Weibull regression model for interval-censored data to compare the incidence of child asthma by age of 3 years across the maternal variable categories., Measurements and Main Results: The incidence of asthma in 3-year-old children was 9.90% (44/445), 17.95% (7/39), 22.11% (65/294), and 32.14% (9/28) among those born to mothers without asthma and without preeclampsia, mothers without asthma with preeclampsia, mothers with asthma without preeclampsia, and mothers with asthma with preeclampsia, respectively. The incidences demonstrated an increasing trend in risk of child asthma across the maternal groups (P for trend <0.001). After accounting for potential confounders and using time to report of childhood asthma as analysis outcome, risk of asthma was greater among children born to mothers with asthma without preeclampsia, compared with mothers without asthma without preeclampsia (adjusted hazard ratio, 2.18; 95% confidence interval, 1.46-3.26). This risk was 50% greater for children born to mothers with asthma who developed preeclampsia during pregnancy (adjusted hazard ratio, 2.68; 95% confidence interval, 1.30-5.61). The trend in asthma and recurrent wheeze proportions across the maternal groups' children also indicated a higher risk for children born to mothers with asthma with preeclampsia (adjusted hazard ratio, 4.73; 95% confidence interval, 2.20-10.07; P for trend <0.001)., Conclusions: Preeclampsia is associated with increased risk of early life childhood asthma in children less than 3 years old over and above that associated with maternal asthma alone. The results implicate the interplay between maternal factors as strong predictors of offspring asthma and in utero maternal-fetal immune perturbations and developmental dysregulations associated with preeclampsia.

The genetic susceptibility to preeclampsia, a pregnancy-specific complication with significant maternal and fetal morbidity, has been poorly characterized. To identify maternal genes associated with preeclampsia risk, we assembled 498 cases and 1864 controls of European ancestry from preeclampsia case-control collections in 5 different US sites (with additional matched population controls), genotyped samples on a cardiovascular gene-centric array composed of variants from ≈2000 genes selected based on prior genetic studies of cardiovascular and metabolic diseases and performed case-control genetic association analysis on 27 429 variants passing quality control. In silico replication testing of 9 lead signals with P <10 - 4 was performed in independent European samples from the SOPHIA (Study of Pregnancy Hypertension in Iowa) and Inova cohorts (212 cases, 456 controls). Multiethnic assessment of lead signals was then performed in samples of black (26 cases, 136 controls), Hispanic (132 cases, 468 controls), and East Asian (9 cases, 80 controls) ancestry. Multiethnic meta-analysis (877 cases, 3004 controls) revealed a study-wide statistically significant association of the rs9478812 variant in the pleiotropic PLEKHG1 gene (odds ratio, 1.40 [1.23-1.60]; P meta =5.90×10 -7 ). The rs9478812 effect was even stronger in the subset of European cases with known early-onset preeclampsia (236 cases diagnosed <37 weeks, 1864 controls; odds ratio, 1.59 [1.27-1.98]; P =4.01×10 -5 ). PLEKHG1 variants have previously been implicated in genome-wide association studies of blood pressure, body weight, and neurological disorders. Although larger studies are required to further define maternal preeclampsia heritability, this study identifies a novel maternal risk locus for further investigation., (© 2018 American Heart Association, Inc.)

Background: Maternal asthma, uncontrolled asthma, and low vitamin D levels during pregnancy have been individually linked to increased risk of preeclampsia., Objective: To investigate the association of history of physician-diagnosed asthma and uncontrolled asthma status during pregnancy with the risk of preeclampsia and the effects of early pregnancy vitamin D concentrations on this relationship., Methods: A total of 816 subjects with available pregnancy outcome data and risk factors of interest were analyzed. A group of experienced obstetricians and gynecologists from 3 study centers validated the preeclampsia diagnoses. Vitamin D was measured using the DiaSorin method at 10 to 18 weeks of gestation. The Pregnancy-Asthma Control Test was used to assess asthma control during pregnancy. Criterion-based stepwise variable selection algorithm was applied to investigate the relationships of risk factors of interest (history of asthma diagnosis, uncontrolled asthma during pregnancy, and vitamin D) to preeclampsia., Results: The incidence of preeclampsia was not related to the presence of asthma diagnosis (8.9% with vs 7.4% without). The adjusted odds of preeclampsia controlled for maternal serum 25-hydroxyvitamin D (25OHD) concentrations was higher for women with a higher proportion of uncontrolled asthma months per visit during pregnancy (adjusted odds ratio, 3.55; 95% CI, 1.15-13.0). Adjusting for asthma control status during pregnancy, an additional decrease in the associated preeclampsia risk by 7% was observed for a 10-unit (ng/mL) increase in early pregnancy 25OHD levels (adjusted odds ratio 10-unit , 0.60; 95% CI, 0.43-0.82) as compared with the previous risk estimate of preeclampsia associated with low maternal 25OHD unadjusted for asthma control status., Conclusions: Uncontrolled asthma during pregnancy is associated with an increased risk of preeclampsia. Early pregnancy 25OHD contributes to the association of uncontrolled asthma status with preeclampsia., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Reduced telomere length, or its accelerated attrition, has been implicated in aging, mortality, and several human diseases, including respiratory diseases. Age dependent manifestation of telomere-mediated disease during life span indicates the role of developmental stage in these diseases and highlights the importance of fetal developmental process in utero and at earlier life stages. Environmental determinants during developmental and later stages of life could affect telomere length. Smoke exposure as one of these significant determinants have been investigated in association with telomere length in neonates at time of delivery, children and adults., Objective: We sought to investigate whether intrauterine fetal exposure to tobacco smoking characterized by placenta cotinine levels during early weeks of pregnancy might be associated with shorter relative telomere length (T/S ratio) as compared to fetuses without exposure to tobacco smoking., Study Design: 207 Human placenta and epithelial lung samples were used for both fetal lung telomere length assessment and measurement of placental cotinine levels. Tissues were obtained from two NICHD-supported tissue retrieval programs with registries for elective abortions, the University of Washington Center for Birth Defects Research (Seattle, WA) and the University of Maryland Brain and Tissue Bank for Developmental Disorders (Baltimore, MD). Cotinine levels (ng/g total placental tissue) were determined in whole cell extracts prepared from human placenta samples to characterize and confirm the cotinine exposure status associated with maternal smoking. Relative telomere length (T/S ratio) in genomic DNA extracted from fetal lung tissue was measured by use of quantitative real-time polymerase chain reaction. Multivariable linear regression was used to investigate the relationship between fetal Telomere-to-Single Copy (T/S) ratio and tobacco exposure., Results: The estimated post-conception ages for included samples in the study ranged from 54 to 137days (7-19 weeks of gestation); 47.37% of fetal samples had female sex. Of the samples included in the analysis 96 and 111 fetal samples with and without intrauterine tobacco smoking exposure were distinguished. While T/S ratio was not different between those with and without smoking exposure (1.24±0.41 and 1.27±0.48, respectively; P=0.70), a significant effect modification of post-conception age on the relationship of intrauterine smoke exposure on fetal T/S ratio was observed (adjusted coefficient=-0.008, 95% CI: -0.016, -0.0004). The smoke exposure status was associated with T/S ratio after 93-day post conception (adjusted coefficient=-0.29, 95% CI: -0.53, -0.052)., Conclusions: Our results demonstrate a significant association of smoke exposure in utero at early pregnancy with shortened fetal relative telomere length in the developing lung and suggest that the detrimental effect of smoking exposure on future disease sequelae may start at the early stages of pregnancy., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Vitamin D deficiency is implicated in a range of common complex diseases that may be prevented by gestational vitamin D repletion. Understanding the metabolic mechanisms related to in utero vitamin D exposure may therefore shed light on complex disease susceptibility. Objective: The goal was to analyze the programming role of in utero vitamin D exposure on children's metabolomics profiles. Design: First, unsupervised clustering was done with plasma metabolomics profiles from a case-control subset of 245 children aged 3 y with and without asthma from the Vitamin D Antenatal Asthma Reduction Trial (VDAART), in which pregnant women were randomly assigned to vitamin D supplementation or placebo. Thereafter, we analyzed the influence of maternal pre- and postsupplement vitamin D concentrations on cluster membership. Finally, we used the metabolites driving the clustering of children to identify the dominant metabolic pathways that were influential in each cluster. Results: We identified 3 clusters of children characterized by 1 ) high concentrations of fatty acids and amines and low maternal postsupplement vitamin D (mean ± SD; 27.5 ± 11.0 ng/mL), 2 ) high concentrations of amines, moderate concentrations of fatty acids, and normal maternal postsupplement vitamin D (34.0 ± 14.1 ng/mL), and 3 ) low concentrations of fatty acids, amines, and normal maternal postsupplement vitamin D (35.2 ± 15.9 ng/mL). Adjusting for sample storage time, maternal age and education, and both child asthma and vitamin D concentration at age 3 y did not modify the association between maternal postsupplement vitamin D and cluster membership ( P = 0.0014). Maternal presupplement vitamin D did not influence cluster membership, whereas the combination of pre- and postsupplement concentrations did ( P = 0.03). Conclusions: Young children can be clustered into distinct biologically meaningful groups by their metabolomics profiles. The clusters differed in concentrations of inflammatory mediators, and cluster membership was influenced by in utero vitamin D exposure, suggesting a prenatal programming role of vitamin D on the child's metabolome. This trial was registered at clinicaltrials.gov as NCT00920621., (© 2017 American Society for Nutrition.)

Introduction: Preeclampsia represents a major public health burden worldwide, but predictive and diagnostic biomarkers are lacking. Metabolomics is emerging as a valuable approach to generating novel biomarkers whilst increasing the mechanistic understanding of this complex condition., Objectives: To summarize the published literature on the use of metabolomics as a tool to study preeclampsia., Methods: PubMed and Web of Science were searched for articles that performed metabolomic profiling of human biosamples using either Mass-spectrometry or Nuclear Magnetic Resonance based approaches and which included preeclampsia as a primary endpoint., Results: Twenty-eight studies investigating the metabolome of preeclampsia in a variety of biospecimens were identified. Individual metabolite and metabolite profiles were reported to have discriminatory ability to distinguish preeclamptic from normal pregnancies, both prior to and post diagnosis. Lipids and carnitines were among the most commonly reported metabolites. Further work and validation studies are required to demonstrate the utility of such metabolites as preeclampsia biomarkers., Conclusion: Metabolomic-based biomarkers of preeclampsia have yet to be integrated into routine clinical practice. However, metabolomic profiling is becoming increasingly popular in the study of preeclampsia and is likely to be a valuable tool to better understand the pathophysiology of this disorder and to better classify its subtypes, particularly when integrated with other omic data., Competing Interests: Conflict of Interest: RTG, RSK, BC, NP, AW, SW, KJG and HM declare that they have no conflicts of interest. JALS is a consultant to Metabolon, Inc.

Introduction: Preeclampsia is a leading cause of maternal and fetal mortality worldwide, yet its exact pathogenesis remains elusive., Objectives: This study, nested within the Vitamin D Antenatal Asthma Reduction Trial (VDAART), aimed to develop integrated omics models of preeclampsia that have utility in both prediction and in the elucidation of underlying biological mechanisms., Methods: Metabolomic profiling was performed on first trimester plasma samples of 47 pregnant women from VDAART who subsequently developed preeclampsia and 62 controls with healthy pregnancies, using liquid-chromatography tandem mass-spectrometry. Metabolomic profiles were generated based on logistic regression models and assessed using Received Operator Characteristic Curve analysis. These profiles were compared to profiles from generated using third trimester samples. The first trimester metabolite profile was then integrated with a pre-existing transcriptomic profile using network methods., Results: In total, 72 (0.9%) metabolite features were associated (p<0.01) with preeclampsia after adjustment for maternal age, race, and gestational age. These features had moderate to good discriminatory ability; in ROC curve analyses a summary score based on these features displayed an area under the curve (AUC) of 0.794 (95%CI 0.700, 0.888). This profile retained the ability to distinguish preeclamptic from healthy pregnancies in the third trimester (AUC:0.762 (95% CI 0.663, 0.860)). Additionally, metabolite set enrichment analysis identified common pathways, including glycerophospholipid metabolism, at the two time-points. Integration with the transcriptomic signature refined these results suggesting a particular role for lipid imbalance, immune function and the circulatory system., Conclusions: These findings suggest it is possible to develop a predictive metabolomic profile of preeclampsia. This profile is characterized by changes in lipid and amino acid metabolism and dysregulation of immune response and can be refined through interaction with transcriptomic data. However validation in larger and more diverse populations is required., Competing Interests: Conflict of Interest: All authors declare that they have no conflicts of interest.

Background: Low vitamin D status in pregnancy was proposed as a risk factor of preeclampsia., Methods: We assessed the effect of vitamin D supplementation (4,400 vs. 400 IU/day), initiated early in pregnancy (10-18 weeks), on the development of preeclampsia. The effects of serum vitamin D (25-hydroxyvitamin D [25OHD]) levels on preeclampsia incidence at trial entry and in the third trimester (32-38 weeks) were studied. We also conducted a nested case-control study of 157 women to investigate peripheral blood vitamin D-associated gene expression profiles at 10 to 18 weeks in 47 participants who developed preeclampsia., Results: Of 881 women randomized, outcome data were available for 816, with 67 (8.2%) developing preeclampsia. There was no significant difference between treatment (N = 408) or control (N = 408) groups in the incidence of preeclampsia (8.08% vs. 8.33%, respectively; relative risk: 0.97; 95% CI, 0.61-1.53). However, in a cohort analysis and after adjustment for confounders, a significant effect of sufficient vitamin D status (25OHD ≥30 ng/ml) was observed in both early and late pregnancy compared with insufficient levels (25OHD <30 ng/ml) (adjusted odds ratio, 0.28; 95% CI, 0.10-0.96). Differential expression of 348 vitamin D-associated genes (158 upregulated) was found in peripheral blood of women who developed preeclampsia (FDR <0.05 in the Vitamin D Antenatal Asthma Reduction Trial [VDAART]; P < 0.05 in a replication cohort). Functional enrichment and network analyses of this vitamin D-associated gene set suggests several highly functional modules related to systematic inflammatory and immune responses, including some nodes with a high degree of connectivity., Conclusions: Vitamin D supplementation initiated in weeks 10-18 of pregnancy did not reduce preeclampsia incidence in the intention-to-treat paradigm. However, vitamin D levels of 30 ng/ml or higher at trial entry and in late pregnancy were associated with a lower risk of preeclampsia. Differentially expressed vitamin D-associated transcriptomes implicated the emergence of an early pregnancy, distinctive immune response in women who went on to develop preeclampsia., Trial Registration: ClinicalTrials.gov NCT00920621., Funding: Quebec Breast Cancer Foundation and Genome Canada Innovation Network. This trial was funded by the National Heart, Lung, and Blood Institute. For details see Acknowledgments., Competing Interests: The authors have declared that no conflict of interest exists.