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.

Prenatal vitamin D and enamel hypoplasia in human primary maxillary central incisors: a pilot study.

BACKGROUND: Enamel hypoplasia (EH) increases risk for dental caries and also is associated with vitamin D deficiencies. This pilot study evaluates the feasibility to determine the association of human maternal circulating vitamin D concentrations during pregnancy and EH in infant's teeth that develop in utero. METHODS: A pilot population of 37 children whose mothers participated in a RCT of vitamin D supplementation during pregnancy was evaluated. Major outcome was EH and major exposure was maternal monthly serum circulating 25(OH)D concentrations during pregnancy. EH was assessed using the Enamel Defect Index and digital images made by a ProScope High Resolution™ handheld digital USB microscope at 50x magnification. RESULTS: During initial 8 weeks of study, 29/37 children had evaluable data with mean age of 3.6 ± 0.9 years; 48% male; and 45% White, 31% Hispanic, and 24% Black. EH was identified in 13 (45%) of the children. Maternal mean 25(OH)D concentrations were generally lower for those children with EH. CONCLUSIONS: Preliminary results suggest follow-up of children of mothers in a vitamin D supplementation RCT during pregnancy provides an important approach to study the etiology of EH in the primary teeth. Further study is needed to discern thresholds and timing of maternal serum 25(OH)D concentrations during pregnancy associated with absence of EH in teeth that develop in utero. Potential dental public health implications for prevention of early childhood caries via sound tooth structure as related to maternal vitamin D sufficiency during pregnancy need to be determined.

The efficacy assessment of a self-administered immunotherapy protocol.

BACKGROUND: We previously reported the safety of a self-administered subcutaneous immunotherapy (SCIT) protocol. Here we report the results of the retrospective efficacy trial of the United Allergy Service (UAS) self-administered SCIT protocol. We hypothesized that by utilizing a slow SCIT buildup phase, designed to attain recommended allergen concentrations on a cumulative basis, efficacious outcomes and clinical relevance would be achieved. METHODS: We enrolled 60 SCIT patients and 56 control patients. The study contrasted baseline and treatment period combined symptom plus medication scores (CSMS) as the primary outcome measure and rhinoconjunctivitis quality of life questionnaire (RQLQ) scores as the secondary study outcome measure. Changes in pollen counts were also examined with regard to effects on these efficacy parameters. RESULTS: The treatment group showed significantly improved CSMS (standardized mean difference [SMD]: -1.57; 95% confidence interval [CI], -1.97 to -1.18; p < 0.001) and RQLQ (SMD: -0.91; 95% CI, -1.23 to -0.59; p < 0.001). These treatment group outcome measures were respectively improved by 33% and 29% compared to baseline and greater than 40% in comparison to the control group (p < 0.0001). Significant results were also shown when examining these outcome measures with regards to either monotherapy or poly-allergen SCIT. Furthermore, a comparison to recent meta-analyses of SCIT studies showed equivalent efficacy and clinical relevance. Assessment of pollen counts during the baseline and treatment periods further corroborated the efficacy of the UAS SCIT protocol. CONCLUSION: These efficacy results, and our previous safety results, show that a carefully designed and implemented self-administered SCIT protocol is efficacious and safe.

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.

Health characteristics and outcomes of two randomized vitamin D supplementation trials during pregnancy: a combined analysis.

OBJECTIVE: To assess the safety and health effects of vitamin D supplementation during pregnancy. METHODS AND DESIGN: Datasets from two randomized clinical trials were first analyzed separately then combined for this analysis using a common data dictionary. In the NICHD trial, women were randomized to 400, 2000, or 4000IU vitamin D3/day, stratified by race. In the Thrasher Research Fund trial, participants were randomized to 2000 or 4000IU vitamin D3/day. Study drugs were from the same manufacturing lot for both trials. Identical questionnaires were given for comparable sociodemographics & clinical characteristics. Outcome measures were: [1] maternal and neonatal 25(OH)D achieved, and [2] maternal comorbidities of pregnancy (COP). SAS 9.3 was used for all analyses. RESULTS: In the combined cohort, there were 110 controls, 201 in the 2000IU group, and 193 in the 4000IU group. No differences between groups in baseline 25(OH)D were found; however, delivery and cord blood values were greater in the 4000IU group (p<0.0001), an effect that persisted even after controlling for race and study. A greater percent were vitamin D replete in the 4000IU group (p<0.0001). There was a trend where the 4000IU group had decreased rates of comorbidities of pregnancy. There was a strong association between COP and final maternal 25(OH)D; an effect that persisted even after controlling for race and study (p=0.006). CONCLUSIONS: Supplementation with 4000IU/day was associated with lower risk of hypovitaminosis D than Control and 2000IU groups. While not statistically significant, there was a trend toward lower rates of COP as supplementation dose increased. Maternal delivery 25(OH)D was inversely associated with any comorbidity of pregnancy, with fewer events as 25(OH)D increased. Future studies are needed to confirm these findings and determine the mechanisms of action of such effects. This article is part of a Special Issue entitled 'Vitamin D Workshop'.

Vitamin D supplementation during pregnancy: double-blind, randomized clinical trial of safety and effectiveness.

The need, safety, and effectiveness of vitamin D supplementation during pregnancy remain controversial. In this randomized, controlled trial, women with a singleton pregnancy at 12 to 16 weeks' gestation received 400, 2000, or 4000 IU of vitamin D(3) per day until delivery. The primary outcome was maternal/neonatal circulating 25-hydroxyvitamin D [25(OH)D] concentration at delivery, with secondary outcomes of a 25(OH)D concentration of 80 nmol/L or greater achieved and the 25(OH)D concentration required to achieve maximal 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] production. Of the 494 women enrolled, 350 women continued until delivery: Mean 25(OH)D concentrations by group at delivery and 1 month before delivery were significantly different (p < 0.0001), and the percent who achieved sufficiency was significantly different by group, greatest in 4000-IU group (p < 0.0001). The relative risk (RR) for achieving a concentration of 80 nmol/L or greater within 1 month of delivery was significantly different between the 2000- and the 400-IU groups (RR = 1.52, 95% CI 1.24-1.86), the 4000- and the 400-IU groups (RR = 1.60, 95% CI 1.32-1.95) but not between the 4000- and. 2000-IU groups (RR = 1.06, 95% CI 0.93-1.19). Circulating 25(OH)D had a direct influence on circulating 1,25(OH)(2)D(3) concentrations throughout pregnancy (p < 0.0001), with maximal production of 1,25(OH)(2)D(3) in all strata in the 4000-IU group. There were no differences between groups on any safety measure. Not a single adverse event was attributed to vitamin D supplementation or circulating 25(OH)D levels. It is concluded that vitamin D supplementation of 4000 IU/d for pregnant women is safe and most effective in achieving sufficiency in all women and their neonates regardless of race, whereas the current estimated average requirement is comparatively ineffective at achieving adequate circulating 25(OH)D concentrations, especially in African Americans.

Analyzing adherence to prenatal supplement: does pill count measure up?

Objective. To determine if adherence as measured by pill count would show a significant association with serum-based measures of adherence. Methods. Data were obtained from a prenatal vitamin D supplementation trial where subjects were stratified by race and randomized into three dosing groups: 400 (control), 2000, or 4000 IU vitamin D(3)/day. One measurement of adherence was obtained via pill counts remaining compared to a novel definition for adherence using serum 25-hydroxy-vitamin D (25-OH-D) levels (absolute change in 25(OH)D over the study period and the subject's steady-state variation in their 25(OH)D levels). A multivariate logistic regression model examined whether mean percent adherence by pill count was significantly associated with the adherence measure by serum metabolite levels. Results. Subjects' mean percentage of adherence by pill count was not a significant predictor of adherence by serum metabolite levels. This finding was robust across a series of sensitivity analyses. Conclusions. Based on our novel definition of adherence, pill count was not a reliable predictor of adherence to protocol, and calls into question how adherence is measured in clinical research. Our findings have implications regarding the determination of efficacy of medications under study and offer an alternative approach to measuring adherence of long half-life supplements/medications.

Circulating 25-hydroxyvitamin d levels in fully breastfed infants on oral vitamin d supplementation.

Objective. To examine the effectiveness of oral vitamin D(3) (400 IU) supplementation on the nutritional vitamin D status of breastfeeding infants. Design. As part of a larger ongoing vitamin D RCT trial of lactating women, infants of mothers assigned to control received 1 drop of 400 IU vitamin D(3)/day starting at one month of age. Infant 25(OH)D levels (mean +/- S.D.) were measured by RIA at visits 1, 4, and 7. Results. The infant mean +/- S.D. 25(OH)D at baseline was 16.0 +/-9.3 ng/mL (range 1.0-40.8; n = 33); 24 (72.7%) had baseline levels <20 ng/mL (consistent with deficiency). The mean levels increased to 43.6 +/-14.1 (range 18.2-69.7) at 4 months and remained relatively unchanged at month 7: 42.5 +/-12.1 ng/mL (range 18.9-67.2). The change in values between 1 and 4 months and 1 and 7 months was statistically significant (P

Trace element concentrations in skin of free-ranging bottlenose dolphins (Tursiops truncatus) from the southeast Atlantic coast.

Concentrations of trace elements (Al, As, Ba, Be, Cd, Co, Cr, Cu, Fe, Li, Mn, Ni, Pb, Sb, Se, Sn, Tl, U, V, Zn) and total mercury (THg) were determined in skin samples collected from free-ranging bottlenose dolphin (Tursiops truncatus) populations. Dolphins were captured in the estuarine waters of Charleston (CHS), South Carolina (n=74) and the Indian River Lagoon (IRL), Florida (n=75) during 2003, 2004 and 2005. A subset of the skin tissue samples were used to determine methylmercury (MeHg) levels in CHS (n=17) and IRL (n=8) bottlenose dolphins. Distributions of trace element concentrations by age (adult vs. juvenile), gender (male vs. female) and study area (CHS vs. IRL) were examined. In general, higher elemental skin concentrations were found in CHS adult males than those of IRL adult males, except for THg and MeHg. For CHS dolphins, adult females showed significantly higher THg levels than juvenile females while higher Mn levels were found in juvenile females. For IRL dolphins, adult males showed significantly higher As concentrations than that in juvenile males and females while higher Co and V levels were found in juvenile males than adult males. Of all elements measured in this study, significantly higher levels of Fe, Se and Zn concentrations in skin tissue of both dolphin populations were similar to other studies reported previously. Percentage of MeHg/THg in skin tissue of CHS and IRL dolphin was about 72% and 73%, respectively. Dietary levels of trace elements may play an important role in contributing to concentration differences for As, Co, Mn, Sb, Se, THg and Tl between CHS and IRL dolphins. Total Hg concentrations were significantly correlated with the age of CHS dolphins, while an inverse relationship was detected for Cu, Mn, Pb, U and Zn. The only significant correlation found between trace element concentration and IRL dolphins' age was Mn. Geographic differences in several trace element concentrations (As, Co, Mn, Sb, Se, THg and Tl) in skin tissue may be potentially useful to discriminate between dolphin populations and is a possibility that warrants further investigation.

High-dose vitamin D3 supplementation in a cohort of breastfeeding mothers and their infants: a 6-month follow-up pilot study.

OBJECTIVE: To examine the effect of high-dose maternal vitamin D(3) (vitD) supplementation on the nutritional vitD status of breastfeeding (BF) women and their infants compared with maternal and infant controls receiving 400 and 300 IU vitD/day, respectively. DESIGN: Fully lactating women (n = 19) were enrolled at 1-month postpartum into a randomized- control pilot trial. Each mother received one of two treatments for a 6-month study period: 0 or 6000 IU vitD(3) plus a prenatal vitamin containing 400 IU vitD(3). The infants of mothers assigned to the control group received 300 IU vitD(3)/day; those infants of mothers in the high-dose group received 0 IU (placebo). Maternal serum and milk vitD and 25(OH)D were measured at baseline then monthly; infant serum vitD and 25(OH)D were measured at baseline, and months 4 and 7. Urinary calcium/creatinine ratios were measured monthly in both mothers and infants. Dietary and BF history and outdoor activity questionnaires were completed at each visit. Changes in skin pigmentation were measured by spectrophotometry. Data were analyzed using chi-square, t-test, and analysis of variance (ANOVA) on an intent-to-treat basis. RESULTS: High-dose (6400 IU/day) vitD(3) safely and significantly increased maternal circulating 25(OH)D and vitD from baseline compared to controls (p < 0.0028 and 0.0043, respectively). Mean milk antirachitic activity of mothers receiving 400 IU vitD/day decreased to a nadir of 45.6 at visit four and varied little during the study period (45.6-78.6 IU/L), whereas the mean activity in the 6400 IU/day group increased from 82 to 873 IU/L (p < 0.0003). There were no differences in circulating 25(OH)D levels of infants supplemented with oral vitD versus infants whose only source of vitD was breast milk. CONCLUSION: With limited sun exposure, an intake of 400 IU/day vitamin D(3) did not sustain circulating maternal 25(OH)D levels, and thus, supplied only extremely limited amounts of vitamin D to the nursing infant via breast milk. Infant levels achieved exclusively through maternal supplementation were equivalent to levels in infants who received oral vitamin D supplementation. Thus, a maternal intake of 6400 IU/day vitamin D elevated circulating 25(OH)D in both mother and nursing infant.

An evaluation of Echinacea angustifolia in experimental rhinovirus infections.

BACKGROUND: Echinacea has been widely used as an herbal remedy for the common cold, but efficacy studies have produced conflicting results, and there are a variety of echinacea products on the market with different phytochemical compositions. We evaluated the effect of chemically defined extracts from Echinacea angustifolia roots on rhinovirus infection. METHODS: Three preparations of echinacea, with distinct phytochemical profiles, were produced by extraction from E. angustifolia roots with supercritical carbon dioxide, 60 percent ethanol, or 20 percent ethanol. A total of 437 volunteers were randomly assigned to receive either prophylaxis (beginning seven days before the virus challenge) or treatment (beginning at the time of the challenge) either with one of these preparations or with placebo. The results for 399 volunteers who were challenged with rhinovirus type 39 and observed in a sequestered setting for five days were included in the data analysis. RESULTS: There were no statistically significant effects of the three echinacea extracts on rates of infection or severity of symptoms. Similarly, there were no significant effects of treatment on the volume of nasal secretions, on polymorphonuclear leukocyte or interleukin-8 concentrations in nasal-lavage specimens, or on quantitative-virus titer. CONCLUSIONS: The results of this study indicate that extracts of E. angustifolia root, either alone or in combination, do not have clinically significant effects on infection with a rhinovirus or on the clinical illness that results from it.