Maternal Plasma 25-hydroxyvitamin Research Articles

Maternal Plasma 25-Hydroxyvitamin D during Gestation Is Positively Associated with Neurocognitive Development in Offspring at Age 4–6 Years

BackgroundVitamin D is critical to embryonic neuronal differentiation and other developmental processes that may affect future neurocognitive function. However, observational studies have found inconsistent associations between gestational vitamin D and neurocognitive outcomes. ObjectivesWe examined the association of gestational 25-hydroxyvitamin D [25(OH)D] with children's IQ at 4–6 y, and explored whether associations differed by race. MethodsThis study used data from the CANDLE (Conditions Affecting Neurocognitive Development and Learning in Early Childhood) cohort. Between 2006 and 2011, CANDLE recruited 1503 women in their second trimester of healthy singleton pregnancies. Inclusion criteria for this analysis were gestation of ≥34 wk and availability of 25(OH)D and IQ data. Associations between second-trimester 25(OH)D plasma concentration and Stanford-Binet IQ scores in offspring at 4–6 y were examined using multivariable linear regression; interaction terms were used to explore possible effect modification by race. ResultsMean ± SD 25(OH)D concentration among 1019 eligible dyads was 21.6 ± 8.4 ng/mL, measured at a mean ± SD gestational age of 23.0 ± 3.0 wk. Vitamin D deficiency [25(OH)D < 20 ng/mL] was observed in 45.6%. Maternal 25(OH)D differed by race with a mean ± SD of 19.8 ± 7.2 ng/mL in Blacks sand 25.9 ± 9.3 ng/mL in Whites ( P < 0.001). In adjusted models a 10-ng/mL increase in 25(OH)D was associated with a 1.17-point higher Full Scale IQ (95% CI: 0.27, 2.06 points), a 1.17-point higher Verbal IQ (95% CI: 0.19, 2.15 points), and a 1.03-point higher Nonverbal IQ (95% CI: 0.10, 1.95 points). We observed no evidence of effect modification by race. ConclusionsSecond-trimester maternal 25(OH)D was positively associated with IQ at 4–6 y, suggesting that gestational vitamin D status may be an important predictor of neurocognitive development. These findings may help inform prenatal nutrition recommendations and may be especially relevant for Black and other dark-skinned women at high risk of vitamin D deficiency.

Maternal Vitamin D Sufficiency Is Associated with Lower Circulating TNF-α in Breastfeeding Infants

Abstract Objectives Exclusively breastfeeding (BrF) infants are at risk for vitD deficiency if they or their mothers are not supplemented. However, it is unknown if maternal or direct infant vitD supplementation could have differential effects on the BrF child. We hypothesized that maternal vitD status may affect concentrations of pro-inflammatory cytokines in infants. Methods Exclusively BrF infants and mothers were enrolled in a clinical study in which infant vitD sufficiency was achieved by either direct supplementation with 400 IU/d vitD3 or mothers were supplemented with 6400 IU/d. Infant and maternal plasma 25-hydroxyvitamin D (25-D) values were determined by radioimmunoassay at enrollment (1-mo infant) and completion (5-mo). Concentrations of 10 pro-inflammatory cytokines in infant plasma were determined by electrochemiluminescence. ANOVA, t-tests and linear correlations were used to calculate relationships between vitD and circulating cytokines in 49 infant-mother pairs at study enrollment and 39 pairs at completion. Results Plasma concentrations of 10 pro-inflammatory cytokines measured were very low (pg/ml range). Neither infant nor maternal vitD status (sufficiency defined as plasma 25-D &amp;gt; 30 ng/ml) were associated with 9 measured cytokines in infant blood (IFN-γ, IL-1b, –2, –4, –6, –8, –10, –12, –13). In contrast, concentrations of tumor necrosis factor (TNF)-α in infant plasma were inversely correlated to maternal vitD status (r = −0.37; P = 0.02 at study completion). At study enrollment, BrF infants of vitD-sufficient mothers had mean 20% lower plasma TNF-α concentration than infants of vitD-insufficient mothers (P = 0.02), regardless of the infant's own vitD status. VitD sufficiency in infants per se was associated with mean 5% lower plasma TNF-α concentration, non-significantly different to that of vitD-deficient infants. Conclusions These results indicate that vitD-mediated changes in breastmilk composition can affect the immune system of BrF infants. Circulating concentrations of the major pro-inflammatory cytokine TNF-α were significantly lower in infants with vitD-sufficient mothers regardless of the infant's own vitD status. Studies are currently investigating vitD-associated effects on responses of BrF infants’ immune cells to antigenic challenge. Funding Sources NIH/NCATS, SC Translational Research Institute, MUSC Pediatrics.

Comparison of maternal plasma 25-Hydroxyvitamin D concentrations between pregnant women with GDM and without GDM at 24-28 weeks of gestation who referred to Azad University Hospitals in Tehran between 2016 and 2017

Comparison of maternal plasma 25-Hydroxyvitamin D concentrations between pregnant women with GDM and without GDM at 24-28 weeks of gestation who referred to Azad University Hospitals in Tehran between 2016 and 2017

Influence of vitamin D on key bacterial taxa in infant microbiota in the KOALA Birth Cohort Study

Vitamin D has immunomodulatory properties giving it the potential to affect microbial colonization of the intestinal tract. We investigated whether maternal vitamin D supplemention, maternal plasma 25-hydroxyvitamin D concentration, or direct supplementation of the infant influences key bacterial taxa within microbiota of one month old infants. Infant and maternal vitamin D supplement use was ascertained via questionnaires. Maternal plasma 25-hydroxyvitamin D was determined at approximately the 36th week of pregnancy. In 913 one month old infants in the prospective KOALA Birth Cohort Study, fecal Bifidobacterium spp., Escherichia coli, Clostridium difficile, Bacteroides fragilis group, Lactobacillus spp. and total bacteria were quantified with real-time polymerase chain reaction assays targeting 16S rRNA gene sequences. The association between vitamin D exposure and prevalence or abundance of a specific bacterial group or species was analyzed using logistic or linear regression, respectively. There was a statistically significant negative linear trend between counts of Bifidobacterium spp. and levels of maternal vitamin D supplementation and maternal 25-hydroxyvitamin D quintiles, respectively. In addition, a positive linear trend between quintile groups and B. fragilis group counts was observed. Lower counts of C. difficile were associated with vitamin D supplementation of breast fed infants whose mothers were more likely to adhere to an alternative lifestyle in terms of, e.g., dietary habits. These data suggest that vitamin D influences the abundance of several key bacterial taxa within the infant microbiota. Given that intestinal microbiotic homeostasis may be an important factor in the prevention of immune mediated diseases and that vitamin D status is a modifiable factor, further investigation of the impact of postnatal vitamin D supplementation should be conducted in older infants.

Maternal vitamin D, DNA methylation at imprint regulatory regions and offspring weight at birth, 1 year and 3 years.

Background/ObjectiveVitamin D deficiency during pregnancy is associated with poor birth outcomes in some studies, but few have examined weight beyond birth. Additionally, little is known about how vitamin D influences DNA methylation of regulatory regions known to be involved in growth, as possible mediators to weight status in offspring.Subjects/MethodsWe conducted linear regressions to assess maternal plasma 25-hydroxyvitamin D (25(OH)D) by quartile and birth weight for gestational age z-score, 1-year weight-for-length z-score, and 3-year body mass index (BMI) z-score among 476 mother/infant dyads from a prospective cohort. We assessed maternal 25(OH)D and infant DNA methylation at 9 differentially methylated regions (DMRs) of genomically imprinted genes with known functions in fetal growth, including H19, IGF2, MEG3, MEG3-IG, MEST, NNAT, PEG3, PLAGL1, and SGCE/PEG10.ResultsMean (standard deviation, SD) maternal 25(OH)D was 41.1 (14.2) nmol/L at a mean (SD) of 13.2 (5.5) weeks gestation. After adjustment for potential confounders, the first (Q1) and second (Q2) quartiles of 25(OH)D, compared to the fourth (Q4), were associated with lower birth weight for gestational age z-scores (−0.43 units; CI −0.79, −0.07; p=0.02 for Q1 and −0.56 units; CI −0.89, −0.23; p=0.001 for Q2). Q1 compared to Q4 was associated with higher 1-year weight-for-length z-scores (0.78 units; 0.08, 1.54; p=0.04) and higher 3-year BMI z-scores (0.83 units; 0.11, 0.93; p=0.02). We did not observe associations between maternal 25(OH)D and methylation for any of the 9 DMRs after correcting for multiple testing.ConclusionsReduced maternal 25(OH)D was associated with lower birth weight for gestational age z-scores but higher 1-year weight-for-length and 3-year BMI z-scores in offspring. However, 25(OH)D does not appear to be operating through the regulatory sequences of the genomically imprinted genes we examined.

Maternal Vitamin D Status and Adverse Birth Outcomes in Children from Rural Western Kenya.

Maternal plasma 25-hydroxyvitamin D (25(OH)D) status and its association with pregnancy outcomes in malaria holoendemic regions of sub-Saharan Africa is poorly defined. We examined this association and any potential interaction with malaria and helminth infections in an ongoing pregnancy cohort study in Kenya. The association of maternal plasma 25(OH)D status with pregnancy outcomes and infant anthropometric measurements at birth was determined in a subset of women (n = 63). Binomial and linear regression analyses were used to examine associations between maternal plasma 25(OH)D and adverse pregnancy outcomes. Fifty-one percent of the women had insufficient (<75 nmol/L) and 21% had deficient (<50 nmol/L) plasma 25(OH)D concentration at enrollment. At birth, 74.4% of the infants had insufficient and 30% had deficient plasma 25(OH)D concentrations, measured in cord blood. Multivariate analysis controlling for maternal age and body mass index (BMI) at enrollment and gestational age at delivery found that deficient plasma 25(OH)D levels were associated with a four-fold higher risk of stunting in neonates (p = 0.04). These findings add to the existing literature about vitamin D and its association with linear growth in resource-limited settings, though randomized clinical trials are needed to establish causation.

25-Hydroxyvitamin D in pregnancy and genome wide cord blood DNA methylation in two pregnancy cohorts (MoBa and ALSPAC)

The aim of the study was to investigate whether maternal mid-pregnancy 25-hydroxyvitamin D concentrations are associated with cord blood DNA methylation.DNA methylation was assessed using the Illumina HumanMethylation450 BeadChip, and maternal plasma 25-hydroxyvitamin D was measured in 819 mothers/newborn pairs participating in the Norwegian Mother and Child Cohort (MoBa) and 597 mothers/newborn pairs participating in the Avon Longitudinal Study of Parents and Children (ALSPAC).Across 473,731CpG DNA methylation sites in cord blood DNA, none were strongly associated with maternal 25-hydroxyvitamin D after adjusting for multiple tests (false discovery rate (FDR)>0.5; 473,731 tests). A meta-analysis of the results from both cohorts, using the Fisher method for combining p-values, also did not strengthen findings (FDR>0.2). Further exploration of a set of CpG sites in the proximity of four a priori defined candidate genes (CYP24A1, CYP27B1, CYP27A1 and CYP2R1) did not result in any associations with FDR<0.05 (56 tests). In this large genome wide assessment of the potential influence of maternal vitamin D status on DNA methylation, we did not find any convincing associations in 1416 newborns. If true associations do exist, their identification might require much larger consortium studies, expanded genomic coverage, investigation of alternative cell types or measurements of 25-hydroxyvitamin D at different gestational time points.

High Vitamin D Status before Conception, but Not during Pregnancy, Is Inversely Associated with Maternal Gestational Diabetes Mellitus in Guinea Pigs

Background: Whether there is a dose-dependent effect of maternal dietary cholecalciferol during pregnancy on maternal glucose tolerance is unknown. In addition, circulating osteocalcin is increased by 1,25-dihydroxyvitamin D [1,25(OH)2D] and may improve glucose homeostasis.Objective: This study was designed to test whether dietary cholecalciferol during pregnancy dose-dependently affects maternal glucose tolerance and maternal and neonatal glucose concentrations in relation to plasma osteocalcin and body composition.Methods: Female guinea pigs (n = 45; 4 mo old) were randomly assigned to 5 doses of cholecalciferol (0, 0.25, 0.5, 1, or 2 IU/g diet) fed from mating to delivery. Plasma vitamin D metabolites, minerals, and osteocalcin, and blood glucose were measured before mating, at midgestation (day 42), and at day 2 postpartum in sows and in 2-d-old pups. At day 50 of pregnancy (early third trimester), a 3-h oral-glucose-tolerance test (OGTT) (2 g/kg) was conducted. Body composition was measured before mating and at day 2 postpartum in sows and in pups.Results: A positive dose-response to dietary cholecalciferol was observed for change in maternal plasma 25-hydroxyvitamin D [25(OH)D] through pregnancy (P < 0.0001), with 1,25(OH)2D increasing by 198% in the 1-IU/g group by midgestation vs. a reduction of 43.6% in the 0-IU/g group (P = 0.05). Twenty-four (54.5%) sows had gestational diabetes mellitus (GDM) on the basis of nonfed glucose and 39 (88.6%) had GDM on the basis of 2-h OGTT glucose concentrations. There were no group differences in maternal OGTT or changes in glucose, minerals, osteocalcin concentrations, and body composition. Pre-mating 25(OH)D was inversely related to 3-h area under the curve for blood glucose from the OGTT (r = −0.31, P = 0.05). In guinea pig pups, although both 25(OH)D (P < 0.0001) and 1,25(OH)2D (P < 0.0001) followed a dose-response to maternal diet, glucose, osteocalcin, minerals, and body composition were not altered.Conclusions: Dietary vitamin D intake during pregnancy in guinea pigs does not affect the already high rate of GDM, whereas higher prepregnancy vitamin D status appears to be protective.

Childhood bone mineral content is associated with methylation status of the RXRA promoter at birth.

Maternal vitamin D deficiency has been associated with reduced offspring bone mineral accrual. Retinoid-X receptor-alpha (RXRA) is an essential cofactor in the action of 1,25-dihydroxyvitamin D (1,25[OH]2 -vitamin D), and RXRA methylation in umbilical cord DNA has been associated with later offspring adiposity. We tested the hypothesis that RXRA methylation in umbilical cord DNA collected at birth is associated with offspring skeletal development, assessed by dual-energy X-ray absorptiometry, in a population-based mother-offspring cohort (Southampton Women's Survey). Relationships between maternal plasma 25-hydroxyvitamin D (25[OH]-vitamin D) concentrations and cord RXRA methylation were also investigated. In 230 children aged 4 years, a higher percent methylation at four of six RXRA CpG sites measured was correlated with lower offspring bone mineral content (BMC) corrected for body size (β = -2.1 to -3.4 g/SD, p = 0.002 to 0.047). In a second independent cohort (n = 64), similar negative associations at two of these CpG sites, but positive associations at the two remaining sites, were observed; however, none of the relationships in this replication cohort achieved statistical significance. The maternal free 25(OH)-vitamin D index was negatively associated with methylation at one of these RXRA CpG sites (β = -3.3 SD/unit, p = 0.03). Thus, perinatal epigenetic marking at the RXRA promoter region in umbilical cord was inversely associated with offspring size-corrected BMC in childhood. The potential mechanistic and functional significance of this finding remains a subject for further investigation.

Maternal plasma 25-hydroxyvitamin D levels, angiogenic factors, and preeclampsia

The objective of the study was to examine the associations of maternal plasma levels of 25-hydroxyvitamin D [25(OH)D] with angiogenesis and endothelial dysfunction indicators: soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF), intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), and risk of preeclampsia. In this prospective cohort study (n = 697), maternal plasma 25(OH)D levels were measured at 12-18 and 24-26 weeks; sFlt-1, PlGF, ICAM-1, and VCAM-1 levels were measured at 24-26 weeks. Maternal PlGF levels were significantly lower in women with 25(OH)D less than 50 nmol/L at 12-18 weeks (median, 449.5 vs 507.9 pg/mL, P = 0.04) and 24-26 weeks (median, 450.4 vs 522.5 pg/mL, P = 0.007). Both maternal 25(OH)D and PlGF levels were inversely associated with the risk of preeclampsia (both P < .05). However, based on a test of interaction, there was no evidence that the association between vitamin D and preeclampsia depended on the level of PlGF. Maternal vitamin D deficiency is associated with low PlGF levels and increased preeclampsia risk. However, our data do not support the hypothesis that the association between vitamin D deficiency and preeclampsia is mediated by impaired angiogenesis.

Vitamin D deficiency in pregnancy and gestational diabetes mellitus

We examined the association of second-trimester maternal plasma 25-hydroxyvitamin D (25[OH]D) during pregnancy with gestational diabetes mellitus (GDM). Among 1314 pregnant women who participated in Project Viva, a birth cohort study, we measured 25(OH)D levels at 26-28 weeks gestation during GDM screening using a 1-hour 50-g glucose challenge test. We found 25(OH)D levels of <25 nmol/L in 44 of 1087 women (4.0%) with normal glucose tolerance, 9 of 159 women (5.7%) with impaired glucose tolerance, and 9 of 68 women (13.2%) with GDM. Analyses that were adjusted for sociodemographics, season, maternal body mass index, gestational weight gain, and dietary factors suggested that women with 25(OH)D levels of <25 vs ≥25 nmol/L may have higher odds of experiencing GDM (odds ratio, 2.2; 95% confidence interval, 0.8-5.5). Glucose levels after the glucose challenge test were associated inversely with 25(OH)D levels (P < .01). Second-trimester 25(OH)D levels were associated inversely with glucose levels after 1-hour 50-g glucose challenge test; low 25(OH)D levels may be associated with increased risk of GDM.

Longitudinal vitamin D status in pregnancy and the risk of pre‐eclampsia

Whether vitamin D deficiency in pregnancy is a cause of pre-eclampsia remains controversial. Most previous studies to date have assessed exposure at only one time-point in pregnancy. We assessed longitudinal vitamin D status during pregnancy and the risk of pre-eclampsia. Prospective cohort study. Seventeen urban obstetric hospitals, Canada. Pregnant women who were participants in a trial of vitamin C and E supplementation for the prevention of pre-eclampsia. Canadian participants who consented to participate in a biobank with plasma specimens available at the baseline visit were included (n = 697). Maternal plasma 25-hydroxyvitamin D (25(OH)D) concentrations were measured at 12-18 and 24-26 weeks of gestation using chemiluminescence immunoassay. Pre-eclampsia. Of the women, 39% were vitamin D deficient (25(OH)D <50 nmol/l). A strong positive correlation was observed in maternal 25(OH)D concentrations between the two gestational age windows (r = 0.69, P < 0.0001). Mean maternal 25(OH)D concentrations at 24-26 weeks of gestation were significantly lower in women who subsequently developed pre-eclampsia compared with those who did not (mean ± SD: 48.9 ± 16.8 versus 57.0 ± 19.1 nmol/l, P = 0.03). Women with 25(OH)D < 50 nmol/l at 24-26 weeks gestation experienced an increased risk of pre-eclampsia (adjusted odds ratio 3.24, 95% confidence interval 1.37-7.69), whereas the association was not statistically significant for maternal 25(OH)D level at 12-18 weeks of gestation. Lower maternal 25(OH)D levels at late mid-trimester were associated with an increased risk of pre-eclampsia.