Maternal gestational vitamin D supplementation and offspring bone health (MAVIDOS): a multicentre, double-blind, randomised placebo-controlled trial.
ABSTRACT: BACKGROUND:Maternal vitamin D status has been associated with bone mass of offspring in many, but not all, observational studies. However, maternal vitamin D repletion during pregnancy has not yet been proven to improve offspring bone mass in a randomised controlled trial. We aimed to assess whether neonates born to mothers supplemented with vitamin D during pregnancy have greater whole-body bone mineral content (BMC) at birth than those of mothers who had not received supplementation. METHODS:The Maternal Vitamin D Osteoporosis Study (MAVIDOS) was a multicentre, double-blind, randomised, placebo-controlled trial that recruited pregnant women from three study sites in the UK (Southampton, Oxford, and Sheffield). Eligible participants were older than 18 years, with a singleton pregnancy, gestation of less than 17 weeks, and a serum 25-hydroxyvitamin D (25[OH]D) concentration of 25-100 nmol/L at 10-17 weeks' gestation. P'articipants were randomly assigned (1:1), in randomly permuted blocks of ten, to either cholecalciferol 1000 IU/day or matched placebo, taken orally, from 14 weeks' gestation (or as soon as possible before 17 weeks' gestation if recruited later) until delivery. Participants and the research team were masked to treatment allocation. The primary outcome was neonatal whole-body BMC, assessed within 2 weeks of birth by dual-energy x-ray absorptiometry (DXA), analysed in all randomly assigned neonates who had a usable DXA scan. Safety outcomes were assessed in all randomly assigned participants. This trial is registered with the International Standard Randomised Controlled Trial registry, ISRCTN 82927713, and the European Clinical Trials Database, EudraCT 2007-001716-23. FINDINGS:Between Oct 10, 2008, and Feb 11, 2014, we randomly assigned 569 pregnant women to placebo and 565 to cholecalciferol 1000 IU/day. 370 (65%) neonates in the placebo group and 367 (65%) neonates in the cholecalciferol group had a usable DXA scan and were analysed for the primary endpoint. Neonatal whole-body BMC of infants born to mothers assigned to cholecalciferol 1000 IU/day did not significantly differ from that of infants born to mothers assigned to placebo (61·6 g [95% CI 60·3-62·8] vs 60·5 g [59·3-61·7], respectively; p=0·21). We noted no significant differences in safety outcomes, apart from a greater proportion of women in the placebo group with severe post-partum haemorrhage than those in the cholecalciferol group (96 [17%] of 569 mothers in the placebo group vs 65 [12%] of 565 mothers in the cholecalciferol group; p=0·01). No adverse events were deemed to be treatment related. INTERPRETATION:Supplementation of women with cholecalciferol 1000 IU/day during pregnancy did not lead to increased offspring whole-body BMC compared with placebo, but did show that 1000 IU of cholecalciferol daily is sufficient to ensure that most pregnant women are vitamin D replete, and it is safe. These findings support current approaches to vitamin D supplementation in pregnancy. Results of the ongoing MAVIDOS childhood follow-up study are awaited. FUNDING:Arthritis Research UK, Medical Research Council, Bupa Foundation, and National Institute for Health Research.
Project description:CONTEXT:Current approaches to antenatal vitamin D supplementation do not account for interindividual differences in 25-hydroxyvitamin D (25(OH)D) response. OBJECTIVE:We assessed which maternal and environmental characteristics were associated with 25(OH)D after supplementation with cholecalciferol. DESIGN:Within-randomization-group analysis of participants in the Maternal Vitamin D Osteoporosis Study trial of vitamin D supplementation in pregnancy. SETTING:Hospital antenatal clinics. PARTICIPANTS:A total of 829 pregnant women (422 placebo, 407 cholecalciferol). At 14 and 34 weeks of gestation, maternal anthropometry, health, and lifestyle were assessed and 25(OH)D measured. Compliance was determined using pill counts at 19 and 34 weeks. INTERVENTIONS:1000 IU/d of cholecalciferol or matched placebo from 14 weeks of gestation until delivery. MAIN OUTCOME MEASURE:25(OH)D at 34 weeks, measured in a single batch (Diasorin Liaison). RESULTS:25(OH)D at 34 weeks of gestation was higher in the women randomized to vitamin D (mean [SD], 67.7 [21.3] nmol/L) compared with placebo (43.1 [22.5] nmol/L; P < .001). In women randomized to cholecalciferol, higher pregnancy weight gain from 14 to 34 weeks of gestation (kg) (? = -0.81 [95% confidence interval -1.39, -0.22]), lower compliance with study medication (%) (? = -0.28 [-0.072, -0.48]), lower early pregnancy 25(OH)D (nmol/L) (? = 0.28 [0.16, 0.40]), and delivery in the winter vs the summer (? = -10.5 [-6.4, -14.6]) were independently associated with lower 25(OH)D at 34 weeks of gestation. CONCLUSIONS:Women who gained more weight during pregnancy had lower 25(OH)D in early pregnancy and delivered in winter achieved a lower 25(OH)D in late pregnancy when supplemented with 1000 IU/d cholecalciferol. Future studies should aim to determine appropriate doses to enable consistent repletion of 25(OH)D during pregnancy.
Project description:BACKGROUND:Antenatal vitamin D status may be associated with the risk of adverse pregnancy and neonatal outcomes; however, the benefits of vitamin D supplementation during pregnancy remain unknown. METHODS:We conducted a double-blind placebo-controlled randomized trial to evaluate the effect of high-dose prenatal 3rd trimester vitamin D3 supplementation on maternal and neonatal (cord blood) serum 25-hydroxyvitamin D (25(OH)D) concentration (primary biochemical efficacy outcome) and maternal serum calcium concentration (primary safety measure). Eligibility criteria were pregnant women aged 18 to <35 years, at 26 to 29 weeks gestation, and residing in Dhaka, Bangladesh. 160 women were randomized by 1:1 allocation to one of two parallel intervention groups; placebo (n = 80) or 35,000 IU/week of vitamin D3 (n = 80) until delivery. All participants, study personnel and study investigators were blind to treatment allocation. RESULTS:Mean maternal 25(OH)D concentration was similar in the vitamin D and placebo groups at baseline (45 vs. 44 nmol/L; p = 0.66), but was significantly higher in the vitamin D group vs. placebo group among mothers at delivery (134 vs. 38 nmol/L; p < 0.001) and newborns (cord blood: 103 vs. 39; p < 0.001). In the vitamin D group, 95% of neonates and 100% of mothers attained 25(OH)D >50 nmol/L, versus 21% mothers and 19% of neonates in the placebo group. No participants met criteria for hypercalcemia, there were no known supplement-related adverse events, and major pregnancy outcomes were similar between groups. CONCLUSIONS:Antenatal 3rd-trimester vitamin D3 supplementation (35,000 IU/week) significantly raised maternal and cord serum 25(OH)D concentrations above 50 nmol/L in almost all participants without inducing hypercalcemia or other observed safety concerns. Doses up to 35,000 IU/week may be cautiously used in further research aimed at establishing the clinical effects and safety of vitamin D3 supplementation in pregnancy. TRIAL REGISTRATION:This trial was registered at ClinicalTrials.gov (NCT01126528).
Project description:BACKGROUND:Many factors have been associated with serum 25-hydroxyvitamin D [25(OH)D] concentrations in observational studies, with variable consistency. However, less information is available on factors affecting the magnitude of changes in serum 25(OH)D resulting from vitamin D supplementation. OBJECTIVE:This study aimed to identify factors associated with the serum 25(OH)D response to supplementation with 1000 IU cholecalciferol/d during the first year of a large, multicenter, randomized, placebo-controlled colorectal adenoma chemoprevention trial. METHODS:Eligible older adults who were not vitamin D-deficient [serum 25(OH)D ?12 ng/mL] were randomly assigned in a modified 2 × 2 factorial design to 1 of 4 groups: daily 1000 IU cholecalciferol, 1200 mg Ca as carbonate, both, or placebo. Women could elect 2-group (calcium ± cholecalciferol) random assignment. In secondary analyses, we used multivariable models to assess factors associated with serum 25(OH)D concentrations in all enrollees (n = 2753) and with relative changes in serum 25(OH)D after 1 y cholecalciferol supplementation among those randomly assigned (n = 2187). RESULTS:In multivariable models, 8 factors accounted for 50% of the variability of proportional change in serum 25(OH)D after cholecalciferol supplementation. Larger increases were associated with being female (34.5% compared with 20.5%; P < 0.001) and with lower baseline serum 25(OH)D (P < 0.0001), optimal adherence to study pill intake (P = 0.0002), wearing long pants and sleeves during sun exposure (P = 0.0002), moderate activity level (P = 0.01), use of extra vitamin D-containing supplements during the trial (P = 0.03), and seasons of blood draw (P ? 0.002). Several genetic polymorphisms were associated with baseline serum 25(OH)D and/or serum response, but these did not substantially increase the models' R2 values. Other factors, including body mass index, were associated with serum 25(OH)D at baseline but not with its response to supplemental cholecalciferol. CONCLUSIONS:The factors that most affected changes in serum 25(OH)D concentrations in response to cholecalciferol supplementation included sex, baseline serum 25(OH)D, supplement intake adherence, skin-covering clothes, physical activity, and season. Genetic factors did not play a major role. This trial was registered at www.clinicaltrials.gov as NCT00153816.
Project description:BACKGROUND:African-Americans have higher rates of obesity-associated chronic diseases. Serum 25-hydroxyvitamin D (25(OH)D) shows an inverse association with obesity status. We investigated whether vitamin D supplementation changes body mass index (BMI). SUBJECTS:In total, 328 overweight African-Americans were enrolled over three consecutive winter periods (2007-2010) into a randomized, double-blind, placebo-controlled trial to receive cholecalciferol supplementation (0, 1000 international units (IU), 2000 IU or 4000 IU per day) for 3 months. Plasma concentrations of 25(OH)D and anthropometric measurements were done at baseline, 3 and 6 months. RESULTS:At 3 months, vitamin D supplementation in three dose groups (1000 IU, 2000 IU or 4000 IU per day) did not cause any significant changes in BMI as compared with placebo group 3-month change in BMI per 1000 IU per day estimate (SE): 0.01 (0.039); P=0.78. CONCLUSIONS:In overweight African-Americans, short-term high-dose vitamin D supplementation did not alter BMI.
Project description:The Maternal Vitamin D Osteoporosis (MAVIDOS) trial reported higher total body bone mineral content in winter-born infants of mothers receiving vitamin D supplementation [1000 IU/day cholecalciferol] compared with placebo from 14 weeks gestation until delivery. This sub-study aimed to determine whether antenatal vitamin D supplementation altered postnatal bone formation in response to mechanical stimulation. Thirty-one children born to MAVIDOS participants randomised to either placebo (n=19) or cholecalciferol (n=12) were recruited at age 4-5 years. Children received whole body vibration (WBV) for 10 minutes on 5 consecutive days. Fasting blood samples for bone homeostasis, 25 hydroxyvitamin D (25OHD), parathyroid hormone (PTH), and bone turnover markers (Pro-collagen Type 1 N-terminal propeptide, P1NP; Cross-linked C-telopeptide of Type I Collagen, CTX) were collected pre-WBV and on day 8 (D8). Mean changes (D) in P1NP (ng/ml) between baseline and D8 in the vitamin-D intervention and placebo groups were 40.6 and -92.6 respectively and mean changes (?) in CTX (ng/ml) were 0.034 (intervention) and -0.084 (placebo) respectively. Between-group DP1NP difference was 133.2ng/ml [95% CI 0.4, 266.0; p=0.049] and ?CTX 0.05ng/ml (95% CI -0.159, 0.26ng/mL; p=0.62). Antenatal vitamin-D supplementation resulted in increased P1NP in response to WBV, suggesting early life vitamin D supplementation increases the anabolic response of bone to mechanical loading in children.
Project description:In this multicentre double-blind randomized clinical trial, we investigated the effects of oral cholecalciferol supplementation on serum hepcidin and parameters related to anaemia and CKD-MBD among haemodialysis patients. Participants were assigned in a 2:2:1:1 ratio to either (1) thrice-weekly 3,000-IU cholecalciferol, (2) once-monthly cholecalciferol (equivalent to 9,000 IU/week), (3) thrice-weekly placebo, or (4) once-monthly placebo. We also examined the effect modifications by selected single nucleotide polymorphisms in vitamin D-related genes. Out of 96 participants, 94 were available at Month 3, and 88 completed the 6-month study. After adjustment for baseline values, serum hepcidin levels were higher at Day 3 in the combined cholecalciferol (vs. placebo) group, but were lower at Month 6 with increased erythropoietin resistance. Cholecalciferol increased serum 1,25(OH)2D levels, resulting in a greater proportion of patients who reduced the dose of active vitamin D at Month 6 (31% vs. 10% in the placebo group). Cholecalciferol also suppressed intact PTH only among patients with severe vitamin D deficiency. In conclusion, cholecalciferol supplementation increases serum hepcidin-25 levels in the short term and may increase erythropoietin resistance in the long term among haemodialysis patients. Both thrice-weekly and once-monthly supplementation effectively increases serum 1,25(OH)2D levels, and hence, reduces active vitamin D drugs.Clinical Trial Registry: This study was registered at ClinicalTrials.gov and University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) as NCT02214563 (registration date: 12/08/2014) and UMIN000011786 (registration date: 15/08/2014), respectively (please refer to the links below). ClinicalTrials.gov: https://clinicaltrials.gov/ct2/show/record/NCT02214563 . UMIN-CTR: https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000017152&language=E .
Project description:To determine whether a single monthly supplement is as effective as a daily maternal supplement in increasing breast milk vitamin D to achieve vitamin D sufficiency in their infants.Forty mothers with exclusively breast-fed infants were randomized to receive oral cholecalciferol (vitamin D3) 5000 IU/d for 28 days or 150,000 IU once. Maternal serum, breast milk, and urine were collected on days 0, 1, 3, 7, 14, and 28; infant serum was obtained on days 0 and 28. Enrollment occurred between January 7, 2011, and July 29, 2011.In mothers given daily cholecalciferol, concentrations of serum and breast milk cholecalciferol attained steady levels of 18 and 8 ng/mL, respectively, from day 3 through 28. In mothers given the single dose, serum and breast milk cholecalciferol peaked at 160 and 40 ng/mL, respectively, at day 1 before rapidly declining. Maternal milk and serum cholecalciferol concentrations were related (r=0.87). Infant mean serum 25-hydroxyvitamin D concentration increased from 17±13 to 39±6 ng/mL in the single-dose group and from 16±12 to 39±12 ng/mL in the daily-dose group (P=.88). All infants achieved serum 25-hydroxyvitamin D concentrations of more than 20 ng/mL.Either single-dose or daily-dose cholecalciferol supplementation of mothers provided breast milk concentrations that result in vitamin D sufficiency in breast-fed infants.clinicaltrials.gov NCT01240265.
Project description:BACKGROUND:Vitamin D deficiency during pregnancy is common and is likely to be associated with metabolic complications in the mother. The aim of this study was to assess the efficacy of two doses of vitamin D supplementation during pregnancy on maternal and cord blood vitamin D status and metabolic and oxidative stress biomarkers. METHODS:The eligible pregnant women (n?=?84) invited to participate in the study and randomly allocated to one of the two supplementation groups (1000?IU/d vitamin D and 2000?IU/d). Biochemical assessments of mothers including serum concentrations of 25(OH)D, calcium, phosphate, iPTH, fasting serum sugar (FBS), insulin, triglyceride, total cholesterol, LDL-C, HDL-C, malondialdehyde (MDA) and total antioxidant capacity (TAC) were done at the beginning and 34?weeks of gestation. Cord blood serum concentrations of 25(OH)D, iPTH, MDA and TAC were assessed at delivery as well. To determine the effects of vitamin D supplementation on metabolic markers 1-factor repeated-measures analysis of variance (ANOVA) was used. Between groups comparisons was done by using Independent-samples Student's t-test or Mann-Whitney test. P?<?0.05 was considered as significant. RESULTS:Supplementation with 1000?IU/d and 2000?IU/d vitamin D resulted in significant changes in vitamin D status over pregnancy (24.01?±?21.7, P?<?0.001 in 1000?IU/d group and 46.7?±?30.6?nmol/L, P?<?0.001 in 2000?IU/d group). Daily intake of 2000 compared with 1000?IU/d tended to increase the serum concentration of HDL-C (10?±?8.37, P?<?0.001 in 1000?IU/d group and 9.52?±?11.39?mg/dL, P?<?0.001 in 2000?IU/d group). A significant decrement in serum concentration of iPTH observed in both groups (-?4.18?±?7.5, P?=?0.002 in 1000?IU/d group and?-?8.36?±?14.17, P?=?0.002 in 2000?IU/d group). CONCLUSIONS:Supplementation with 2000?IU/d vitamin D as compared with 1000?IU/d, is more effective in promoting vitamin D status and HDL-C serum concentration and in decreasing iPTH over pregnancy. TRIAL REGISTRATION:This trial is registered at clinicaltrials.gov ( NCT03308487 ). Registered 12 October 2017 'retrospectively registered'.
Project description:Objectives:Obese, African-American (AA) adolescents are at increased risk for vitamin D deficiency. The primary objective of this pilot study was to examine the effect of vitamin D supplementation upon 25-hydroxy vitamin D (25OHD) levels in obese, AA adolescents. Methods:A randomized, double-blinded, controlled pilot study included 26 obese (BMI???95%ile), vitamin D deficient (25OHD?<?20?ng/mL), pubertal AA adolescents (ages 12-17). Subjects received cholecalciferol 1000?IU or 5000?IU daily for 3?months. Serum 25OHD, vitamin D binding protein, parathyroid hormone, and cardiometabolic risk markers were obtained at baseline and post-treatment. Results:Of 39 subjects enrolled, 26 (67%) were vitamin D deficient (mean 25OHD 12.0?±?3.8?ng/mL) at baseline and were randomized, with 22 completing the study. Sex, age, season, pubertal stage, BMI, insulin resistance (HOMA-IR) and 25OHD were similar at baseline between the 1000?IU and 5000?IU groups. Post-treatment, 25OHD increased less in the 1000?IU group (5.6?ng/mL, p?=?0.03) vs. the 5000?IU group (15.6?ng/mL, p?=?0.002). 83% of the 5000?IU group and 30% of the 1000?IU group reached post-treatment 25OHD???20?ng/mL (p?=?0.01); 50% of the 5000?IU group, but no subject from the 1000?IU group, achieved 25OHD???30?ng/mL (p?=?0.009). We detected no group differences in mineral metabolites or cardiometabolic risk markers following supplementation. Conclusions:Cholecalciferol dosing in excess of the current Institute of Medicine dietary reference intakes was required to achieve 25OHD levels ?20?ng/mL in obese, AA adolescents. Supplementation of 5000?IU may be required to achieve the desired goal.