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Safety of Vitamin D Food Fortification and Supplementation: Evidence from Randomized Controlled Trials and Observational Studies.

ABSTRACT: The safety considerations of food-based solutions for vitamin D deficiency prevention, such as fortification and supplementation, are critical. On the basis of collective data from 20 randomized controlled trials (RCTs) and 20 national healthy surveys, as well as prospective cohort studies (PCSs) across the ODIN project ("Food-based solutions for optimal vitamin D nutrition and health through the life cycle", FP7-613977), we analyzed the potential safety issues arising from vitamin D intakes and/or supplementation. These adverse consequences included high serum 25-hydroxyvitamin D (S-25(OH)D) concentrations (>125 nmol/L), high serum calcium concentrations, and vitamin D intakes in excess of the tolerable upper intake levels (ULs). In the RCTs (n = 3353, with vitamin D doses from 5-175 µg/day), there were no reported adverse effects. The prevalence of high S-25(OH)D was <10% when vitamin D supplements were administered, and <0.1% for fortified foods. Elevated serum calcium was observed among <0.5% in both administration types. No ODIN RCT participants exceeded the age-specific ULs. In observational studies (n = 61,082), the prevalence of high 25(OH)D among children/adolescents, adults, and older adults was <0.3%, with no evidence of adverse effects. In conclusion, high S-25(OH)D concentrations >125 nmol/L were rare in the RCTs and PCSs, and no associated adverse effects were observed.

SUBMITTER: Adebayo FA

PROVIDER: S-EPMC8701201 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Safety of Vitamin D Food Fortification and Supplementation: Evidence from Randomized Controlled Trials and Observational Studies.

Adebayo Folasade A FA Itkonen Suvi T ST Öhman Taina T Kiely Mairead M Cashman Kevin D KD Lamberg-Allardt Christel C On Behalf Of The Odin Consortium

Foods (Basel, Switzerland) 20211209 12

The safety considerations of food-based solutions for vitamin D deficiency prevention, such as fortification and supplementation, are critical. On the basis of collective data from 20 randomized controlled trials (RCTs) and 20 national healthy surveys, as well as prospective cohort studies (PCSs) across the <i>ODIN</i> project ("Food-based solutions for optimal vitamin D nutrition and health through the life cycle", FP7-613977), we analyzed the potential safety issues arising from vitamin D inta ...[more]

PMID: 34945616

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Project description:Observational studies, randomized controlled trials (RCTs), and Mendelian randomization (MR) studies have yielded inconsistent results on the associations of vitamin D concentrations with multiple health outcomes. In the present umbrella review we aimed to evaluate the effects of low vitamin D concentrations and vitamin D supplementation on multiple health outcomes. We summarized current evidence obtained from meta-analyses of observational studies that examined associations between vitamin D concentrations and multiple health outcomes, meta-analyses of RCTs that investigated the effect of vitamin D supplementation on multiple health outcomes, and MR studies that explored the causal associations of vitamin D concentrations with various diseases (international prospective register of systematic reviews PROSPERO registration number CRD42018091434). A total of 296 meta-analyses of observational studies comprising 111 unique outcomes, 139 meta-analyses of RCTs comprising 46 unique outcomes, and 73 MR studies comprising 43 unique outcomes were included in the present umbrella review. Twenty-eight disease outcomes were identified by both meta-analyses of observational studies and MR studies. Seventeen of these reported disease outcomes had consistent results, demonstrating that lower concentrations of vitamin D were associated with a higher risk for all-cause mortality, Alzheimer's disease, hypertension, schizophrenia, and type 2 diabetes. The combinations of consistent evidence obtained by meta-analyses of observational studies and MR studies together with meta-analyses of RCTs showed that vitamin D supplementation was associated with a decreased risk for all-cause mortality but not associated with the risk for Alzheimer's disease, hypertension, schizophrenia, or type 2 diabetes. The results indicated that vitamin D supplementation is a promising strategy with long-term preventive effects on multiple chronic diseases and thus has the potential to decrease all-cause mortality. However, the current vitamin D supplementation strategy might not be an efficient intervention approach for these diseases, suggesting that new strategies are highly needed to improve the intervention outcomes.

Project description:BackgroundThere have been ongoing efforts to understand when and how data from observational studies can be applied to clinical and regulatory decision making. The objective of this review was to assess the comparability of relative treatment effects of pharmaceuticals from observational studies and randomized controlled trials (RCTs).MethodsWe searched PubMed and Embase for systematic literature reviews published between January 1, 1990, and January 31, 2020, that reported relative treatment effects of pharmaceuticals from both observational studies and RCTs. We extracted pooled relative effect estimates from observational studies and RCTs for each outcome, intervention-comparator, or indication assessed in the reviews. We calculated the ratio of the relative effect estimate from observational studies over that from RCTs, along with the corresponding 95% confidence interval (CI) for each pair of pooled RCT and observational study estimates, and we evaluated the consistency in relative treatment effects.ResultsThirty systematic reviews across 7 therapeutic areas were identified from the literature. We analyzed 74 pairs of pooled relative effect estimates from RCTs and observational studies from 29 reviews. There was no statistically significant difference (based on the 95% CI) in relative effect estimates between RCTs and observational studies in 79.7% of pairs. There was an extreme difference (ratio < 0.7 or > 1.43) in 43.2% of pairs, and, in 17.6% of pairs, there was a significant difference and the estimates pointed in opposite directions.ConclusionsOverall, our review shows that while there is no significant difference in the relative risk ratios between the majority of RCTs and observational studies compared, there is significant variation in about 20% of comparisons. The source of this variation should be the subject of further inquiry to elucidate how much of the variation is due to differences in patient populations versus biased estimates arising from issues with study design or analytical/statistical methods.

Project description:BackgroundCurrent thinking, which is based mainly on rodent studies, is that physiologic doses of folic acid (pterylmonoglutamic acid), such as dietary vitamin folates, are biotransformed in the intestinal mucosa and transferred to the portal vein as the natural circulating plasma folate, 5-methyltetrahydrofolic acid (5-MTHF) before entering the liver and the wider systemic blood supply.ObjectiveWe tested the assumption that, in humans, folic acid is biotransformed (reduced and methylated) to 5-MTHF in the intestinal mucosa.DesignWe conducted a crossover study in which we sampled portal and peripheral veins for labeled folate concentrations after oral ingestion with physiologic doses of stable-isotope-labeled folic acid or the reduced folate 5-formyltetrahydrofolic acid (5-FormylTHF) in 6 subjects with a transjugular intrahepatic porto systemic shunt (TIPSS) in situ. The TIPSS allowed blood samples to be taken from the portal vein.ResultsFifteen minutes after a dose of folic acid, 80 ± 12% of labeled folate in the hepatic portal vein was unmodified folic acid. In contrast, after a dose of labeled 5-FormylTHF, only 4 ± 18% of labeled folate in the portal vein was unmodified 5-FormylTHF, and the rest had been converted to 5-MTHF after 15 min (postdose).ConclusionsThe human gut appears to have a very efficient capacity to convert reduced dietary folates to 5-MTHF but limited ability to reduce folic acid. Therefore, large amounts of unmodified folic acid in the portal vein are probably attributable to an extremely limited mucosal cell dihydrofolate reductase (DHFR) capacity that is necessary to produce tetrahydrofolic acid before sequential methylation to 5-MTHF. This process would suggest that humans are reliant on the liver for folic acid reduction even though it has a low and highly variable DHFR activity. Therefore, chronic liver exposure to folic acid in humans may induce saturation, which would possibly explain reports of systemic circulation of unmetabolized folic acid.

Project description:Objective To map the diverse health outcomes associated with serum uric acid (SUA) levels.Design Umbrella review.Data sources Medline, Embase, Cochrane Database of Systematic Reviews, and screening of citations and references.Eligibility criteria Systematic reviews and meta-analyses of observational studies that examined associations between SUA level and health outcomes, meta-analyses of randomised controlled trials that investigated health outcomes related to SUA lowering treatment, and Mendelian randomisation studies that explored the causal associations of SUA level with health outcomes.Results 57 articles reporting 15 systematic reviews and144 meta-analyses of observational studies (76 unique outcomes), 8 articles reporting 31 meta-analyses of randomised controlled trials (20 unique outcomes), and 36 articles reporting 107 Mendelian randomisation studies (56 unique outcomes) met the eligibility criteria. Across all three study types, 136 unique health outcomes were reported. 16 unique outcomes in meta-analyses of observational studies had P<10-6, 8 unique outcomes in meta-analyses of randomised controlled trials had P<0.001, and 4 unique outcomes in Mendelian randomisation studies had P<0.01. Large between study heterogeneity was common (80% and 45% in meta-analyses of observational studies and of randomised controlled trials, respectively). 42 (55%) meta-analyses of observational studies and 7 (35%) meta-analyses of randomised controlled trials showed evidence of small study effects or excess significance bias. No associations from meta-analyses of observational studies were classified as convincing; five associations were classified as highly suggestive (increased risk of heart failure, hypertension, impaired fasting glucose or diabetes, chronic kidney disease, coronary heart disease mortality with high SUA levels). Only one outcome from randomised controlled trials (decreased risk of nephrolithiasis recurrence with SUA lowering treatment) had P<0.001, a 95% prediction interval excluding the null, and no large heterogeneity or bias. Only one outcome from Mendelian randomisation studies (increased risk of gout with high SUA levels) presented convincing evidence. Hypertension and chronic kidney disease showed concordant evidence in meta-analyses of observational studies, and in some (but not all) meta-analyses of randomised controlled trials with respective intermediate or surrogate outcomes, but they were not statistically significant in Mendelian randomisation studies.Conclusion Despite a few hundred systematic reviews, meta-analyses, and Mendelian randomisation studies exploring 136 unique health outcomes, convincing evidence of a clear role of SUA level only exists for gout and nephrolithiasis.

Project description:BackgroundWorldwide, pertussis remains a major health problem among children. During the recent outbreaks of pertussis, maternal antenatal immunisation was introduced in several industrial countries. This systematic review aimed to synthesize evidence for the efficacy and safety of the pertussis vaccination that was given to pregnant women to protect infants from pertussis infection.MethodsWe searched literature in the Cochrane Central Register of Controlled Trials, Medline, Embase, and OpenGrey between inception of the various databases and 16 May 2016. The search terms included 'pertussis', 'whooping cough', 'pertussis vaccine,' 'tetanus, diphtheria and pertussis vaccines' and 'pregnancy' and 'perinatal'.ResultsWe included 15 articles in this review, which represented 12 study populations, involving a total of 203,835 mother-infant pairs from the US, the UK, Belgium, Israel, and Vietnam. Of the included studies, there were two randomised controlled trials (RCTs) and the rest were observational studies. Existing evidence suggests that vaccinations administered during 19-37 weeks of gestation are associated with significantly increased antibody levels in the blood of both mothers and their newborns at birth compared to placebo or no vaccination. However, there is a lack of robust evidence to suggest whether these increased antibodies can also reduce the incidence of pertussis (one RCT, n = 48, no incidence in either group) and pertussis-related severe complications (one observational study) or mortality (no study) in infants. Meanwhile, there is no evidence of increased risk of serious complications such as stillbirth (e.g. one RCT, n = 103, RR = 0, meaning no case in the vaccine group), or preterm birth (two RCTs, n = 151, RR = 0.86, 95%CI: 0.14-5.21) related to administration of the vaccine during pregnancy.ConclusionGiven that pertussis infection is increasing in many countries and that newborn babies are at greatest risk of developing severe complications from pertussis, maternal vaccination in the later stages of pregnancy should continue to be supported while further research should fill knowledge gaps and strengthen evidence of its efficacy and safety.

Project description:Background: The use of direct oral anticoagulants (DOACs) is recommended as the preferred treatment drug in patients with nonvalvular atrial fibrillation (AF). However, the effectiveness and safety of DOACs compared with vitamin K antagonists (VKAs) in patients with cancer and AF are still controversial. Therefore, we performed a meta-analysis regarding the effectiveness and safety of DOACs vs. VKAs in AF patients with cancer. Methods: A search of the Pubmed and EMBASE databases until August 2021 was performed. Adjusted risk ratios (RRs) and 95% confidence intervals (CIs) were pooled using a random-effects model with an inverse variance method. Results: Thirteen studies were deemed to meet the criteria. For the effectiveness outcomes, the use of DOACs compared with VKAs use was significantly associated with decreased risks of stroke or systemic embolism (RR = 0.66, 95% CI: 0.54-0.80) and venous thromboembolism (RR = 0.40, 95% CI: 0.26-0.61), but not ischemic stroke (RR = 0.79, 95% CI: 0.56-1.11), myocardial infarction (RR = 0.78, 95% CI: 0.56-1.11), cardiovascular death (RR = 0.76, 95% CI: 0.53-1.09), and all-cause death (RR = 0.82, 95% CI: 0.43-1.56). For the safety outcomes, compared with VKAs use, the use of DOACs was associated with reduced risks of intracranial bleeding (RR = 0.60, 95% CI: 0.50-0.71) and gastrointestinal bleeding (RR = 0.87, 95% CI: 0.80-0.95). There were no significant differences in major bleeding (RR = 0.87, 95% CI: 0.74-1.04), major or nonmajor clinically relevant bleeding (RR = 0.87, 95% CI: 0.74-1.01), and any bleeding (RR = 0.88, 95% CI: 0.76-1.03). Conclusion: Compared with VKAs, DOACs appeared to have significant reductions in stroke or systemic embolism, venous thromboembolism, intracranial bleeding, and gastrointestinal bleeding, but comparable risks of ischemic stroke, myocardial infarction, cardiovascular death, all-cause death, major bleeding, major or nonmajor clinically relevant bleeding, and any bleeding in patients with AF and cancer.

Dataset Information

Safety of Vitamin D Food Fortification and Supplementation: Evidence from Randomized Controlled Trials and Observational Studies.

Publications

Safety of Vitamin D Food Fortification and Supplementation: Evidence from Randomized Controlled Trials and Observational Studies.

Similar Datasets

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