Predicting comorbidities of pregnancy: A comparison between total and free 25(OH)D and their associations with parathyroid hormone.

Pregnancy is a unique time when amplified sex steroid concentrations promote an escalation in vitamin D binding protein (DBP) synthesis, associated with increased total vitamin D and metabolites, including 25-hydroxyvitamin D (25(OH)D). Free 25(OH)D concentration increases disproportionately to total 25(OH)D during pregnancy, likely an adaptation to supply the woman and fetus with readily available 25(OH)D. Highlighting the importance of the calcium metabolic stress during pregnancy, the interactional relationship between serum 25(OH)D and PTH has been evaluated. Maternal total 25(OH)D and total 25(OH)D/iPTH are measures of vitamin D status and biomarkers for potential pregnancy complications. It has been proposed that free 25(OH)D and free 25(OH)D/iPTH could be better indicators of vitamin D status and predictors of pregnancy complications such as gestational diabetes (GDM), hypertensive disorders of pregnancy, and preterm delivery. This study aims to determine if free 25(OH)D and its association with PTH are more accurate predictors of comorbidities of pregnancy than total 25(OH)D and its association with PTH. In this post hoc analysis of the Kellogg Pregnancy Study, a double-blind randomized placebo-controlled trial, participants included 297 women with singleton pregnancies: 191 participants were randomized into a group receiving a daily prenatal (400 IU vitamin D3) while 196 received a prenatal plus extra supplementation (4400 IU vitamin D3). Blood and urine samples were collected monthly. 297 participants' serum total 25(OH)D concentrations were measured using radioimmunoassay at baseline (visit 1) and 5-7 months' gestation (visit 6-7). 93 participants' serum free 25(OH)D and PTH concentrations were measured using ELISA and immunoradiometric assay, respectively, at visit 1 and 6-7; 66 participants had paired samples and were included in this analysis. Data were analyzed using SAS 9.4, Cary, N.C. or SPSS v28, IBM Corporation, Armonk, N.Y. Results were considered significant with a p < 0.05. A significant relationship exists between the ratio of total 25(OH)D/iPTH and free 25(OH)D/iPTH grouped by total 25(OH)D ≥ 30 ng/mL and < 30 ng/mL as an indicator of maternal vitamin D status. There was a statistically significant relationship between lower mean free 25(OH)D/iPTH and the development of GDM at visit 1 (p = 0.0003) and at visit 6-7 (p = 0.001) while total 25(OH)D/iPTH and GDM were significantly related only at visit 1 (p = 0.029). In this exploratory cohort, neither free 25(OH)D/iPTH nor total 25(OH)D/iPTH were significantly associated with increased incidence of preterm delivery, hypertensive disorders, or combined comorbidities of pregnancy. An univariate logistic regression evaluating the outcome of gestational diabetes while independently controlling for independent factors showed the ratio of free 25(OH)D/iPTH was more closely associated with gestational diabetes than the ratio of total 25(OH)D/iPTH, although neither were significant. This proof-of-concept analysis suggests that the ratio of free 25(OH)D/iPTH is associated with the development of gestational diabetes throughout pregnancy while total 25(OH)D/iPTH is only associated with the outcome early in pregnancy. Further investigation is warranted to explore this relationship between calcium metabolic stress during pregnancy with a larger cohort to improve validity,reproducibility, and relevance to other pregnancy comorbidities.

Vitamin D and Child Neurodevelopment-A Post Hoc Analysis.

INTRODUCTION: Vitamin D (VitD) has been shown to impact neurodevelopment. Studies have shown that higher 25-hydroxy-vitamin D (25(OH)D) concentrations (the indicator of vitD status) may be associated with better neurodevelopmental outcomes, although current data are conflicting. This study examined the relationship between total circulating 25(OH)D concentrations and neurodevelopmental outcomes in 3-5-year-old (3-5 yo) children. METHODS: In this study, pregnant women were randomized to receive 400 (standard dose), 2000, or 4000 IU vitD3/day. Offspring then underwent the Brigance Screen at 3-5 yo. The 25(OH)D concentration was measured at birth and 3-5 yo. Relationships between Brigance scores and 25(OH)D and Brigance scores and vitamin D binding protein (VDBP) genotype were examined. RESULTS: Higher 25(OH)D at the time of testing was associated with better overall performance on neurodevelopmental testing as measured by the Brigance quotient (B = 0.208, p = 0.049). Scores were then broken down into sub-scores. Children born to mothers in the 2000 IU/day group scored higher on the Brigance language component of the assessment versus the standard dose group (B = 4.667, p = 0.044). The group of children who had the Gc1f-1s or Gc1f-2 genotypes scored higher on the Brigance academic component (B = 9.993, p < 0.001) and lower on the Brigance language component versus the 1f1f genotype (B = -9.313, p < 0.001). Children with the Gc1s-1s, Gc1s-2, or Gc2-2 genotypes also scored lower than the Gc1f-1f genotype (B = -6.757, p = 0.003). CONCLUSION: These results suggest that higher 25(OH)D concentrations early in life and higher doses of maternal vitamin D supplementation during pregnancy may have a positive association with neurodevelopmental outcomes. This study also suggests that the VDBP genotype is associated with neurodevelopment and differentially affects various fields of neurodevelopment.

Oral Contraceptive Pills Increase Circulating 25-Hydroxy-Vitamin D Concentrations in Women Who Are Lactating.

OBJECTIVE: This article aims to determine the association between maternal 25-hydroxy-vitamin D [25(OH)D] status and intake of hormonal oral contraceptive pills (OCPs) in women who are lactating. STUDY DESIGN: Women who were exclusively breastfeeding participated in a randomized controlled trial assessing vitamin D supplementation at 400, 2,400, or 6,400 international unit (IU)/d from 1 month through 7 months postpartum. This observational, secondary analysis assessed whether OCPs were associated with maternal 25(OH)D concentrations in women who are lactating. Multivariate regression models were used to predict 25(OH)D concentrations and create parameter estimates for each variable. RESULTS: In a bivariate analysis, the use of OCPs at 4 months was associated with increased serum 25(OH)D (p = 0.02). OCPs' use at 7 months was associated with a higher trend in 25(OH)D, but this finding was not statistically significant (p = 0.1). In a multivariate regression model at 4 months, independent positive predictors of 25(OH)D concentrations were the use of OCPs (p = 0.03) and treatment with vitamin D at 6,400 IU/d (p ≤ 0.0001). Negative predictors were Black (p = 0.001) and Hispanic (p = 0.0001) race and ethnicity, and body mass index (BMI) greater than 30 (p = 0.0002). The same pattern occurred at 7 months, with more southern latitude as a positive independent predictor (p = 0.04) of 25(OH)D concentration. CONCLUSION: The use of OCPs was associated with greater 25(OH)D in women who are lactating. Additionally, treatment with vitamin D at 6,400 IU/d and southern latitude was associated with greater 25(OH)D in women who are lactating. Black and Hispanic race and ethnicity, and BMI greater than 30, were independently associated with lower 25(OH)D in women who are lactating. KEY POINTS: · The association of OCP with serum 25(OH)D concentrations during postpartum lactation is unknown.. · OCPs' use was associated with higher 25(OH)D concentrations in postpartum women who are lactating.. · Treatment with vitamin D and southern latitude was associated with greater 25(OH)D in women who are lactating.. · Black and Hispanic, and BMI > 30 were associated with lower 25(OH)D in women who are lactating.. · Practitioners can counsel women who are lactating on OCPs' use and the positive effects on their 25(OH)D status..

Does maternal vitamin D status influence placental weight or vascular and inflammatory pathology? Secondary analysis from the Kellogg Pregnancy Study.

INTRODUCTION: Positive effects of vitamin D (vitD) supplementation on comorbidities of pregnancy (COP) have been explored; however, few studies have elucidated the pathophysiology behind the development of these COP and the potential relationship with derangements in placental development and morphology. Additionally, it is known that placentas weighing 10th-90th % for gestational age are associated with better outcomes. Therefore, the objective of this study was to assess the impact of resulting circulating serum 25(OH)D concentrations associated with intake of high or low doses of supplementary vitD on placental development and morphology in women who participated in a randomized double blind, placebo-controlled trial of vitD supplementation. We hypothesized that if maternal serum 25(OH)D concentration (vitD status marker) is insufficient/deficient, then placental weight and % for gestational age (GA) will be smaller and will correlate with increased vascular and inflammatory placental pathologic findings. METHODS: The findings of the present study are a secondary analysis of data generated from a previously reported randomized controlled trial (RCT), the Kellogg Vitamin D Pregnancy Study. Pregnant women (n = 297) in this RCT (January 2013 - April 2018) were randomly assigned to 400 IU vs. 4400 IU vitD/day (10-14 weeks' gestational age) and followed to delivery. 132 placentas were analyzed by pathologists blinded to treatment, and the 2016 Amsterdam Consensus Criteria were used to categorize grouping/grading of placental pathology and weight. Total [25(OH)D] was measured using radioimmunoassay (ng/mL). Chi-square and Student's t-test were used to show the difference in maternal characteristics by treatment group and by placental weight. Chi-square analysis was used to determine differences between the percent pathology findings by treatment group. Students t-test was used to determine the differences in vitD status and the frequency of placental lesions. Association between [25(OH)D] area under the curve (AUC) and placental morphology were determined in a regression model that included maternal BMI ≥ 30 kg/m2, race/ethnicity, and vitD treatment group allocation. Data were analyzed using SAS v9.4 (Cary, NC) and statistical significance was indicated by p < 0.05. RESULTS: The percent pathology findings by treatment group were not significantly different for each of the placental pathology categories as defined by the 2016 Amsterdam Consensus Criteria including placental weight. However, when using 25(OH)D as a biomarker for vitD status, linear regression model showed maternal serum [25(OH)D] AUC was significantly associated with greater placental weight (p = 0.023). Logistic regression models showed mothers with BMI ≥ 30 kg/m2 had larger placental weight (p = 0.046), and Hispanic and white/Caucasian mothers had greater placental weights than Black American mothers (p = 0.025). When placentas ≥ 90th % for GA, n = 7, were removed from the placental pool, Pearson correlation still showed a positive association between maternal serum 25(OH)D AUC and placental weight (p = 0.011). In a second linear regression model of placentas ≥ 90th % for GA (n = 7) vs. placentas < 90th % (n = 108), maternal serum 25(OH)D AUC was significantly greater in those placentas ≥ 90th % (p = 0.03); however, this was not associated with increased perinatal mortality. CONCLUSION FINDINGS: suggest increasing maternal serum [25(OH)D] via vitamin D supplementation during pregnancy did not adversely affect placental morphology; trends showed those in the treatment group had fewer placental lesions. Placental weight was found to be significantly associated with [25(OH)D] AUC, which represents maternal vitamin D status over the course of pregnancy; 7 placentas ≥ 90th % for GA were not associated with perinatal mortality.

Post Hoc Analysis of National Institute of Child Health and Human Development Vitamin-D Pregnancy Cohort and The Role of Functional Vitamin-D Deficiency in Pregnancy.

OBJECTIVE: Our objective was to conduct a secondary, post hoc analysis of the National Institute of Child Health and Human Development (NICHD) vitamin D (vitD) pregnancy study by Hollis et al, which reported on the effect of vitD supplementation in pregnant women and determine the potential interaction between intact parathyroid hormone (iPTH) concentrations, vitD status, and various comorbidities associated with pregnancy. Women with low 25-hydroxy vitamin D (25(OH)D) concentrations and high iPTH concentrations during pregnancy, known as functional vitamin-D deficiency (FVDD), were more likely to acquire complications also affecting their neonates. STUDY DESIGN: This post hoc analysis of data collected from a diverse group of pregnant women participating in the NICHD vitD pregnancy study was applied to investigate the applicability of the concept of FVDD in pregnancy (Hemmingway, 2018) in identifying potential risks for certain comorbidities of pregnancy. This analysis defines FVDD as maternal serum 25(OH)D concentrations below 20 ng/mL and iPTH concentrations above 65 pg/mL creating a definitive ratio number, 0.308, to classify mothers as having FVDD prior to delivery (PTD). Statistical analyses were performed using SAS 9.4 (Cary, NC). RESULTS: In total, 281 women (85 African American, 115 Hispanic, and 81 Caucasian) with 25(OH)D and iPTH concentrations measured at monthly visits were included in this analysis. No statistically significant association was found between mothers classified as having FVDD at baseline or 1-month PTD and hypertensive disorders of pregnancy, infection, or admittance to the neonatal intensive care unit. When combining all comorbidities of pregnancy in this cohort, results showed those with FVDD at baseline, 24 weeks' gestation, and 1-month PTD were more likely to experience a comorbidity (p = 0.001; p = 0.001; p = 0.004, respectively). Those with FVDD 1-month PTD were 7.1 times (confidence interval [CI]: 1.71-29.81) more likely to have preterm birth (<37 weeks) than women without FVDD. CONCLUSION: Participants were more likely to have experienced preterm birth if they met the criteria for FVDD. This study supports the importance of FVDD during pregnancy. KEY POINTS: · Functional vitamin D deficiency (FVDD) is defined as the ratio of 25(OH)D divided by iPTH concentration ≤0.308.. · At a minimum, it is recommended that vitamin D status be kept in the healthy range based on current recommendations for pregnant individuals.. · FVDD is a more sensitive predictor of pregnancy risk than 25(OH)D alone.. · FVDD identified those with greater risk of preterm birth in this cohort..

Maternal Vitamin D Status Correlates to Leukocyte Antigenic Responses in Breastfeeding Infants.

It is unknown if vitamin D (vitD) sufficiency in breastfeeding mothers can lead to physiological outcomes for their children that are discernible from infant vitD sufficiency per se. In a 3-month, randomized vitD supplementation study of mothers and their exclusively breastfeeding infants, the effects of maternal vitD sufficiency were determined on infant plasma concentrations of 25-hydroxyvitamin D (i.e., vitD status) and 11 cytokines. An inverse correlation was seen between maternal vitD status and infant plasma TNF concentration (r = −0.27; p < 0.05). Infant whole blood was also subjected to in vitro antigenic stimulation. TNF, IFNγ, IL-4, IL-13, and TGFß1 responses by infant leukocytes were significantly higher if mothers were vitD sufficient but were not as closely correlated to infants' own vitD status. Conversely, IL-10 and IL-12 responses after antigenic challenge were more correlated to infant vitD status. These data are consistent with vitD-mediated changes in breast milk composition providing immunological signaling to breastfeeding infants and indicate differential physiological effects of direct-infant versus maternal vitD supplementation. Thus, consistent with many previous studies that focused on the importance of vitD sufficiency during pregnancy, maintenance of maternal sufficiency likely continues to affect the health of breastfed infants.

Comparison of Infant Bone Mineral Content and Density After Infant Daily Oral Vit D 400 IU Supplementation Versus Nursing Mother Oral 6,400 IU Supplementation: A Randomized Controlled Lactation Study.

Background: Vitamin D (vitD) plays a major role in maintenance of bone mineral homeostasis. It is unknown if bone mineral content (BMC) and bone mineral density (BMD) differ between infants who receive direct vitD supplementation and those who receive vitD indirectly via their mother's breast milk, while she received a high dose of vitD. It is hypothesized that there would be no differences in BMC or BMD by treatment group. Design/Methods: Randomized, double-blind trial to compare BMD and BMC of infants who received direct vitD (400 IU vitD3/day) in addition to their mother receiving standard dosage (400 IU vitD3/day) versus infants whose mothers were their only source of vitD and were given high-dose supplementation (6,400 IU vitD3/day). Participants were exclusively breastfeeding mothers and their infant consuming only human milk. Infant BMC and BMD were measured by dual-energy X-ray absorptiometry (DXA) scans of the infant's total body using Hologic Discovery A Densitometer and analyzed using Hologic Infant software at 1, 4, and 7 months of age. Results: Infant BMC and BMD did not differ significantly at 1, 4, or 7 months of age between direct and indirect supplementation arms. The mean difference in BMC from 1 to 7 months was 1.624 and 1.464 g for the 400 and 6,400 IU groups, respectively, (p = 0.5); the mean difference in BMD over this same period was 0.042 and 0.032 g/cm2 for the 400 and 6,400 IU groups, respectively (p = 0.2). Although some differences among races were observed, this did not reflect changes in bone growth between the treatment arms. Conclusion: High-dose vitD supplementation of mothers during lactation provided an efficacious alternative to direct supplementation of infants, as evidenced by noninferior infant BMD and BMC. Clinical Trial Registration number: NCT00412074.

Evaluating Vitamin D Status in Infants Less than Seven Months; What Are the Preferred Biochemical Measurements?

Background: To ensure the safety of higher dose vitamin D supplementation in pregnant and lactating mothers, and urinary calcium/creatinine (UCa/Cr) ratios, serum calcium, and serum 25(OH)D concentrations are closely monitored. To achieve optimal maternal and infant vitamin D status, while avoiding hypercalcemia, safety measures assessing vitD supplementation must be reliable. Whether or not this holds true for infants before 7 months of age, remains unknown. Objective: Analyze the association among UCa/Cr ratio, serum calcium, intact serum parathyroid hormone (iPTH), 25(OH)D, and 25(OH)D/iPTH ratio in infants to determine whether evidence supports the use of these parameters as valuable measures of hypervitaminosis D or toxicity in infants. Methods: A series of analyses were performed on the cohort of infants who participated in the National Institute of Child Health and Human Development lactation vitD supplementation trial to determine the association among UCa/Cr ratio, serum calcium, iPTH, 25(OH)D, and 25(OH)D/iPTH ratio. Results: Upon multivariate analysis, serum calcium was significantly associated with 25(OH)D (p = 0.0441), iPTH (p = 0.0017), and 25(OH)D/iPTH ratio (p = 0.0001). Infant UCa/Cr did not associate with 25(OH)D but did associate with iPTH (p = 0.0008) and 25(OH)D/iPTH ratio (p = 0.0001). The correlation between UCa/Cr and 25(OH)D/iPTH ratios was significantly stronger than the association between UCa/Cr ratio and iPTH. Serum calcium more strongly correlated with 25(OH)D/iPTH ratio versus 25(OH)D and iPTH. Conclusion: In this healthy cohort of infants 1 to 7 months old, UCa/Cr and serum calcium are more valid indicators of 25(OH)D/iPTH ratio than either 25(OH)D or iPTH alone. Moreover, serum calcium (and not UCa/Cr) is a valid indicator of infant total circulating 25(OH)D and should be measured if vitamin D toxicity is a concern. Clinical Trial Registration number: FDA IND Number: 66,346; ClinicalTrials.gov Number: NCT00412074.

Sociodemographic factors affecting perceived stress during pregnancy and the association with immune-mediator concentrations.

OBJECTIVES: Determine which sociodemographic factors are most associated with increased maternal perceived stress during pregnancy. Evaluate the association between maternal stress and plasma immune-mediator concentrations (IMCs). METHODS: As part of a prospective, randomized clinical trial, 247 participants completed a Perceived Stress Scale survey (PSS-10) during each trimester of pregnancy. Blood samples were collected from participants and were analyzed for 25-hydroxyvitamin D (25(OH)D) concentration and for several IMCs: interferon-gamma, interleukins (IL-) IL-2, IL-4, IL-5, IL-10, vascular endothelial growth factor, c-reactive protein, and tumor necrosis factor alpha (TNF-α) (R&D Elisa). The potential associations between PSS-10 scores, sociodemographic factors, and IMCs were assessed. RESULTS: In bivariate analysis, participants who were not married and/or had high risk pregnancies were more likely to have increased PSS-10 scores (p<0.05). Increased PSS-10 scores were associated with higher serum concentrations of IL-2 and TNF-α, and decreased concentrations of IL-10 and 25(OH)D. In linear regression analysis, single marital status, high-risk pregnancy, IL-2, and TNF-α were independent predictors of PSS-10 scores. CONCLUSIONS: This study identifies specific sociodemographic factors that are associated with increased perceived stress during pregnancy. This study also provides evidence that increased perceived stress is associated with physiological changes as measured by changes in circulating IL-2, TNF-α, IL-10, and 25(OH)D concentrations.

Effects of vitamin D supplementation on circulating concentrations of growth factors and immune-mediators in healthy women during pregnancy.

BACKGROUND: For the second aim of the Kellogg Foundation grant, this double-blind RCT investigated the impact of plasma vitamin D metabolite 25-hydroxyvitamin D (25(OH)D) on plasma immune-mediators during pregnancy. We hypothesized that higher 25(OH)D concentrations would associate with reduced pro-inflammatory and increased tolerogenic immune-mediator concentrations. METHODS: Pregnant women enrolled at 10-14 weeks gestation were randomized to 400 or 4400 IU vitamin D3/day. Data on health, safety, circulating 25(OH)D, and 9 immune-mediators were collected at each trimester. Associations between immune-mediators and 25(OH)D at baseline and at second and third trimesters were examined. RESULTS: Baseline TGF-ß and second and third trimesters IFN-γ and IL-2 were associated with baseline 25(OH)D. Baseline immune-mediators were associated with immune-mediators at second and third trimesters for all immune-mediators except IL-5 and IL-10. Race was associated with baseline TGF-ß, VEGF and IL-10 and with IL-10 at second and third trimesters. CONCLUSIONS: Both treatment groups had increased 25(OH)D at second and third trimesters, greatest in the 4400 IU group. Though associations between baseline 25(OH)D and baseline TGF-ß and second and third trimester IFN-γ and IL-2 were noted, vitamin D supplementation throughout pregnancy did not impact immune-mediators at later trimesters. Supplementing with vitamin D before conception conceivably influences immune-mediator responses during pregnancy. IMPACT: In this vitamin D supplementation clinical trial, baseline (first trimester) but not increasing plasma 25(OH)D concentration impacted select plasma immune-mediator profiles in pregnant women. Baseline 25(OH)D was associated with baseline TGF-ß and with IFN-γ and IL-2 at second and third trimesters. Baseline IFN-γ, CRP, TGF-ß, TNF-α, VEGF, IL-2, and IL-4 were associated with concentrations at second and third trimesters for respective immune-mediators; however, 25(OH)D concentration at second and third trimesters were not. Some racial differences existed in immune-mediator concentrations at baseline and at second and third trimesters. This study assesses the impact of vitamin D supplementation on multiple immune-mediators in pregnant women of different racial/ethnic groups using longitudinal data from a relatively large randomized controlled trial. This study found that race was associated with baseline TGF-ß, VEGF, and IL-10 and with IL-10 at second and third trimesters, a novel finding that sheds light where relationships were less well defined. The results of this study suggest that vitamin D supplementation before conception or early in pregnancy, rather than during pregnancy, may be necessary to significantly impact immune-mediator response. This study sets premise for future clinical trials to evaluate the effect of vitamin D supplementation before conception or prior to pregnancy.

Safety Aspects of a Randomized Clinical Trial of Maternal and Infant Vitamin D Supplementation by Feeding Type Through 7 Months Postpartum.

Background: The safety of higher dose vitamin D (vitD) supplementation in women who change from exclusive or full breastfeeding to combination feeding or who continue supplementation after cessation of breastfeeding is unknown. Objective: Compare vitD supplementation safety of 6,400 to 400 IU/day and 2,400 IU/day using specific laboratory parameters in postpartum women and their infants through 7 months postpartum by feeding type. Design: In this randomized controlled trial, mothers (exclusively breastfeeding or formula-feeding) were randomized at 4-6 weeks' postpartum to 400, 2,400, or 6,400 IU vitD3 (cholecalciferol)/day for 6 months. Breastfeeding infants in 400 IU group received oral 400 IU vitD3/day; infants in 2,400 and 6,400 IU groups received placebo. Maternal safety parameters (serum vitD, 25-hydroxy-vitamin D [25(OH)D; calcidiol], calcium, phosphorus, intact PTH; urinary calcium/creatinine ratios; and feeding type/changes) were measured monthly; infant parameters were measured at months 1, 4, and 7. Sufficiency was defined as 25(OH)D >50 nmol/L. Feeding type was defined as exclusive/full, combination, or formula-feeding. Data were analyzed using SAS 9.4. Results: Four hundred nineteen mother-infant pairs were randomized into the three treatment groups and followed: 346 breastfeeding and 73 formula-feeding pairs. A dose of 6400 IU/day safely and significantly increased maternal vitD and 25(OH)D from baseline in all mothers regardless of feeding type (p < 0.0001) and was superior to the 400 and 2,400 IU groups in achieving vitD sufficiency with no other differences in safety parameters by treatment or feeding type. Infants in the 2,400 IU group were more likely vitD-deficient than the other groups; otherwise, there were no infant safety parameter differences. Conclusions: While 6,400 IU/day was more effective than 400 or 2,400 IU/day in achieving maternal vitD sufficiency in all feeding groups, the groups did not differ on other safety parameters. Similarly, infant safety parameters did not differ by treatment group or feeding status. Clinical Trial Registration: FDA IND Number: 66,346; ClinicalTrials.gov Number: NCT00412074.

Association of Bacterial Vaginosis with Vitamin D in Pregnancy: Secondary Analysis from the Kellogg Pregnancy Study.

Objective Bacterial vaginosis (BV) is associated with vitamin D deficiency and poor pregnancy outcomes. We studied a nested cohort from a randomized controlled trial to investigate the association between BV and vitamin D concentration in pregnancy. Study Design Subjects with randomly assigned 400 versus 4,400 IU of daily cholecalciferol (vitamin D 3 ) had vaginal swabs collected for Gram staining and Nugent score calculation, as well as plasma 25-hydroxyvitamin D (25(OH)D) measurement at three pregnancy time points. Results Fifty-two (21.2%) of the 245 women included in the analysis were diagnosed with BV at study entry. Women with BV were also more likely to be African American ( p < 0.0001) and have lower 25(OH)D concentrations at 22 to 24 weeks' gestation ( p = 0.03). There were no differences in pregnancy outcomes of interest within this group compared with the remaining study subjects. In mixed regression modeling, while race ( p = 0.001) and age ( p = 0.03) were significant predictors of BV prevalence independently, 25(OH)D concentration ( p = 0.81), gestational age ( p = 0.06), and body mass index ( p = 0.87) were not. Conclusion Neither vitamin D deficiency in early pregnancy nor supplementation decreased BV incidence during pregnancy. Pregnancy outcomes (preterm birth and hypertensive disorders of pregnancy) were similar among women with and without BV.

Bioequivalence Studies of Vitamin D Gummies and Tablets in Healthy Adults: Results of a Cross-Over Study.

The objective of this investigation was to compare bioavailability between single oral dose Vitamin D3 (vitD3) gummies vs. tablets in healthy adults. An initial crossover, randomized clinical trial involving healthy adults (n = 9) was conducted followed by a larger, confirmatory study (n = 31). Healthy participants aged 18-45 years with body mass index (BMI) 18-30 without anemia or vitD deficiency were randomized to receive 20,000 international units (IU) vitD3 as single dose gummies or tablets with serial samples obtained to measure plasma vitD3 at baseline, 3, 6, 10, 24, and 48 h followed by a 2-week washout period. The same participants then crossed over to receive 20,000 IU vitD3 in the form not previously given, with sampling at the same time points. Deidentified blood samples were analyzed for vitD3 concentration by liquid chromatography (LC)-mass spectroscopy. In Study 1, results suggested bioavailability was greater with gummies compared with tablets, (effect size 1.08 at 24 h). In Study 2, the area under the concentration curve (AUC) was higher with gummies than tablets (gummy mean (95% CI): 1474 ng·/mL (1393-1555); tablet mean (95% CI): 774 ng·h/mL (693-855), p < 0.0001). Average peak blood concentration (Cmax) values were significantly higher with gummies (gummy: 47.3 ng/mL; tablet: 23.4 ng/mL; p < 0.0001). VitD3 gummies had greater bioavailability than tablets with higher vitD concentrations over time, which may have implications for achieving vitD sufficiency.

Vitamin D binding protein polymorphisms significantly impact vitamin D status in children.

BACKGROUND: Polymorphic alleles of the vitamin D (vitD)-binding protein (VDBP) gene are associated with discriminatory differences in circulating concentrations of 25-hydroxyvitamin D (25-D), the indicator of vitD status (sufficiency defined by the Endocrine Society as ≥75 nmol/L). Within a diverse group of children, we hypothesized that reaching recommended daily allowance (RDA) of vitD intake would have differential impact on vitD status depending on VDBP variability. METHODS: VDBP alleles (Gc1S, Gc1F, Gc2) in 123 children (1-4 annual visits/child; ages 1-8 years) were compared for relationships with serum 25-D concentrations and daily vitD intake. RESULTS: In African-American children, reaching the vitD RDA was associated with significantly higher mean serum 25-D concentrations for the 20% carrying the VDBP 1S allele than for the large majority without this allele (77 vs. 61 nmol/L 25-D; p = 0.038). Children with the Gc1S/1S homozygous genotype (30% Caucasians, 24% Hispanics, 2% African-Americans) who met RDA had 51% (39 nmol/L) greater mean serum 25-D than those below RDA (p < 0.0001). CONCLUSIONS: VDBP genetic variability was a significant factor affecting childhood vitD status when following RDA guidelines. This study may inform public health policy of uniformity in recommended childhood vitD dosage, especially regarding racially/ethnically associated disparities.

The relationship between physical activity and vitamin D status in postpartum lactating and formula-feeding women.

Existing research shows an association between physical activity levels and vitamin D status in the elderly, men, women, children, and adolescent populations. This association has not yet been investigated in postpartum women. We hypothesized that based on the relationship between vitamin D and physical activity found in other populations, greater physical activity levels in postpartum women will be associated with higher serum 25(OH)D levels. A post hoc analysis of 286 postpartum women with self reported physical activity data from the America on the Move survey, and measured circulating serum 25(OH)D (measured by RIA) as an indicator of vitamin D status, was gathered at baseline (4-6 weeks postpartum), 4 months, and 7 months postpartum. The data were analyzed using SAS 9.4 (Cary, NC). 39.9% of women at visit 1 (baseline), 52.8% of women at visit 4 (month 4), and 55.9% of women at visit 7 (month 7) were meeting the NIH recommendation of 150min of moderate intensity (3-6 METs) physical activity per week. Significant differences were seen in physical activity by race (p=0.007). Caucasians were more likely to meet the standard recommendation than African Americans or Hispanics. Using multiple regression models to examine associations between duration of physical activity and 25(OH)D concentration, controlling for race, BMI, feeding type, and METs, it was found that at visit 1, an increase in physical activity was associated with an increase in 25(OH)D of 1.3nmol/L (p=0.03) and achieving at least 2.5h/wk of physical activity had a trending association with an increase in 25(OH)D of 7.23nmol/L (p=.05). At visit 4 (also controlling for treatment group and sun exposure) achieving at least 1.5h/wk of physical activity was associated with an increase in 25(OH)D of 11.73nmol/L (p=.04). By visit 7, no association between physical activity and maternal 25(OH)D was observed. In a repeated measures, mixed model analysis predicting maternal 25(OH)D during the study, achieving at least the recommended 150min per week of physical activity (>2.5h) was not significantly associated with vitamin D status (pNS). While no definitive conclusions can be drawn regarding precise levels of physical activity influencing 25(OH)D levels in postpartum women, the data suggest that increased activity during the first 4 months after birth is associated with improved vitamin D status. Additional research is needed because of the inconsistency seen at visit 7.

Maternal Versus Infant Vitamin D Supplementation During Lactation: A Randomized Controlled Trial.

OBJECTIVE: Compare effectiveness of maternal vitamin D3 supplementation with 6400 IU per day alone to maternal and infant supplementation with 400 IU per day. METHODS: Exclusively lactating women living in Charleston, SC, or Rochester, NY, at 4 to 6 weeks postpartum were randomized to either 400, 2400, or 6400 IU vitamin D3/day for 6 months. Breastfeeding infants in 400 IU group received oral 400 IU vitamin D3/day; infants in 2400 and 6400 IU groups received 0 IU/day (placebo). Vitamin D deficiency was defined as 25-hydroxy-vitamin D (25(OH)D) <50 nmol/L. 2400 IU group ended in 2009 as greater infant deficiency occurred. Maternal serum vitamin D, 25(OH)D, calcium, and phosphorus concentrations and urinary calcium/creatinine ratios were measured at baseline then monthly, and infant blood parameters were measured at baseline and months 4 and 7. RESULTS: Of the 334 mother-infant pairs in 400 IU and 6400 IU groups at enrollment, 216 (64.7%) were still breastfeeding at visit 1; 148 (44.3%) continued full breastfeeding to 4 months and 95 (28.4%) to 7 months. Vitamin D deficiency in breastfeeding infants was greatly affected by race. Compared with 400 IU vitamin D3 per day, 6400 IU/day safely and significantly increased maternal vitamin D and 25(OH)D from baseline (P < .0001). Compared with breastfeeding infant 25(OH)D in the 400 IU group receiving supplement, infants in the 6400 IU group whose mothers only received supplement did not differ. CONCLUSIONS: Maternal vitamin D supplementation with 6400 IU/day safely supplies breast milk with adequate vitamin D to satisfy her nursing infant's requirement and offers an alternate strategy to direct infant supplementation.

A randomized trial of vitamin D supplementation in 2 community health center networks in South Carolina.

OBJECTIVE: We sought to determine whether 4000 IU/d (vs 2000 IU/d) of vitamin D during pregnancy is safe and improves maternal/neonatal 25-hydroxyvitamin D [25(OH)D] in a dose-dependent manner. STUDY DESIGN: A total of 257 pregnant women 12-16 weeks' gestation were enrolled. Randomization to 2000 vs 4000 IU/d followed 1-month run-in at 2000 IU/d. Participants were monitored for hypercalciuria, hypercalcemia, and 25(OH)D status. RESULTS: Maternal 25(OH)D (n = 161) increased from 22.7 ng/mL (SD 9.7) at baseline to 36.2 ng/mL (SD 15) and 37.9 ng/mL (SD 13.5) in the 2000 and 4000 IU groups, respectively. While maternal 25(OH)D change from baseline did not differ between groups, 25(OH)D monthly increase differed between groups (P < .01). No supplementation-related adverse events occurred. Mean cord blood 25(OH)D was 22.1 ± 10.3 ng/mL in 2000 IU and 27.0 ± 13.3 ng/mL in 4000 IU groups (P = .024). After controlling for race and study site, preterm birth and labor were inversely associated with predelivery and mean 25(OH)D, but not baseline 25(OH)D. CONCLUSION: Maternal supplementation with vitamin D 2000 and 4000 IU/d during pregnancy improved maternal/neonatal vitamin D status. Evidence of risk reduction in infection, preterm labor, and preterm birth was suggestive, requiring additional studies powered for these endpoints.