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Circulating levels of maternal vitamin D and risk of ADHD in offspring: results from the Vitamin D Antenatal Asthma Reduction Trial.
Chu, SH, Huang, M, Kelly, RS, Kachroo, P, Litonjua, AA, Weiss, ST, Lasky-Su, J
International journal of epidemiology. 2022;51(3):910-918
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Acting as both a nutrient and a hormone, vitamin D has been found to play a critical role in neurodevelopment across sensitive periods in utero, infancy and early childhood. Among neurodevelopmental and behavioural disorders in early life, attention-deficit/hyperactivity disorder (ADHD) is the most common among children worldwide. Low levels of circulating 25-hydroxy-vitamin D [25(OH)D] have been shown to associate with prevalent ADHD. The aims of this study were to (i) determine the association between maternal vitamin D levels in the first and third trimesters of pregnancy and the risk of offspring ADHD by age 6 years or later; and (ii) to identify potential sensitive periods in utero during which vitamin D levels might be most important for reducing risk of ADHD. This is an ancillary study of the Vitamin D Antenatal Asthma Reduction Trial (VDAART). The VDAART was a randomised, double-blinded, multicentre, clinical trial in which 876 participating mothers were recruited between 10–18 weeks of gestation and assigned to receive either 4400 or 400 IU/day of vitamin D throughout pregnancy. Results show protective associations between maternal 25(OH)D sufficiency in the third trimester and child ADHD, but not at baseline. Furthermore, both at baseline and in the third trimester, there were higher odds of ADHD in male offspring as compared with female offspring with 25(OH)D insufficient mothers (analyses limited by small sample sizes) Authors conclude that higher levels of maternal vitamin D during pregnancy may play a protective role against risk of ADHD in offspring, but further studies are needed to confirm this association and any therapeutic potential therein.
Expert Review
Conflicts of interest:
None
Take Home Message:
Ensure that women in pregnancy, and possibly also those seeking to conceive, have adequate vitamin D status in order to reduce the risk of ADHD in offspring.
Evidence Category:
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A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
Background
This paper describes a secondary data analysis from an RCT that looked at the effect of prenatal vitamin D supplementation on risk of childhood asthma in offspring. Enrolled women aged 18–39 years with a history of asthma, eczema or allergic rhinitis, or whose partner (biological father of child) had a history of the aforementioned condition, received either 400 IU or 4400 IU vitamin D daily for the duration of their pregnancy. Offspring follow-up is still ongoing.
Aims
The current study aims were twofold: (i) to determine the association between maternal vitamin D levels in trimesters 1 and 3 and the risk of attention deficit/hyperactivity disorder (ADHD) in offspring diagnosed by age 6 years or later; and (ii) to identify potentially sensitive periods during gestation in which vitamin D levels may be especially important for reducing risk of ADHD.
Methods
The analytical sample included 679 mother-child pairs, from the original sample of 876 participating mothers. No sample size calculation was reported, though the sample was considered representative of the overall RCT study population.
Maternal vitamin D (serum 25(OH)D) was classified as follows
- Highly deficient <12 ng/mL
- Deficient 12 ng/mL to 19.9 ng/mL
- Insufficient 20 ng/mL to 29.9 ng/mL
- Sufficient ≥30 ng/mL
ADHD status was assessed through parental reporting between ages 6 and 9 years.
Results
No baseline associations between a vitamin D sufficient status and offspring ADHD in maternal samples collected during trimester 1 were observed (OR 1.06, 95% CI 0.51–2.19; P.0.871), though this association became statistically significant at trimester 3 (OR 0.47, 95% CI 0.26–0.84; P.0.011). This translated to a 53% less chance of having a child with ADHD at age 6 or later among mothers with vitamin D sufficiency compared with children of mothers with vitamin D deficiency. There was also a linear trend in the protective association of vitamin D sufficiency (≥30 ng/mL) on reduced risk of offspring ADHD at age 6 years or later in data from trimester 3. Stratified analyses revealed a protective association for sufficient maternal vitamin D status and offspring ADHD among males (OR 0.47, 95% CI 0.23–0.94).
Conclusions
The authors concluded that vitamin D sufficiency (≥30 ng/mL) in the 3rd trimester of gestation may decrease the risk of ADHD development in offspring.
Notes: The authors reported no relevant conflicts of interest.
Clinical practice applications:
Ensuring a sufficient vitamin D status by the 3rd trimester of pregnancy may help to lessen the risk of ADHD in offspring. Nutritional therapists and other clinicians working with pregnant women or women looking to conceive should consider checking vitamin D status and providing corrective supplementation and lifestyle advice to augment vitamin D levels where indicated.
Considerations for future research:
The authors of this study postulated that the statistically significant protective association between vitamin D at trimester 3 and ADHD in offspring was not significant in trimester 1 due to a low observed variability in vitamin D status (>75% of women were vitamin D insufficient), and thus the statistical test being underpowered to see difference between groups with sufficient or insufficient status.
Further research could expand upon this hypothesis to test whether vitamin D status in trimester 1, or preconceptually, may offer a protective association for ADHD and other related neurological conditions that may manifest in early life.
Abstract
BACKGROUND Low levels of circulating 25-hydroxy-vitamin D [25(OH)D] have been shown to associate with prevalent attention-deficit/hyperactivity disorder (ADHD), but few studies have examined the association between 25(OH)D during fetal development and risk of childhood ADHD. METHODS Maternal plasma 25(OH)D was measured at 10-18 and 32-38 weeks of gestation, with sufficiency defined as 25(OH)D ≥ 30 ng/ml. Offspring ADHD status between ages 6-9 years was measured by parent report of clinical ADHD diagnosis among 680 mother-child pairs from the Vitamin D Antenatal Asthma Reduction Trial. Association between maternal 25(OH)D and child ADHD was assessed using logistic regression, adjusting for maternal age, race and ethnicity. Effect modification by offspring sex was also assessed. RESULTS No associations between maternal 25(OH)D at 10-18 weeks of gestation and offspring ADHD were observed. In the third trimester, we observed associations between maternal vitamin D sufficiency and offspring ADHD [odds ratio (OR) 0.47, 95% confidence interval (CI) 0.26-0.84], in addition to maternal 25(OH)D sufficiency category, comparing the deficient (OR 0.34, 95% CI 0.12-0.94), insufficient (OR 0.41, 95% CI 0.15-1.10) and sufficient (OR 0.20, 95% CI 0.08-0.54) categories against highly deficient 25(OH)D, respectively. Stratified analyses revealed a protective association for sufficient maternal 25(OH)D and child ADHD among males (OR 0.47, 95% CI 0.23-0.94); the synergy index for additive effect modification of risk was 1.78 (95% CI 0.62-5.08). CONCLUSIONS Higher levels of maternal vitamin D in the third trimester are associated with lower risk of ADHD in offspring, with modest evidence for a stronger effect among male offspring. However, larger studies will be necessary to confirm these findings.
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Can Vitamin D and L-Cysteine Co-Supplementation Reduce 25(OH)-Vitamin D Deficiency and the Mortality Associated with COVID-19 in African Americans?
Jain, SK, Parsanathan, R
Journal of the American College of Nutrition. 2020;39(8):694-699
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African Americans are more susceptible to vitamin D deficiency. In addition they have lower amounts of cellular glutathione (GSH), which is an antioxidant produced in the body from L-cysteine, capable of affecting genes involved in vitamin D production. Clinical trials have indicated a relationship between vitamin D deficiency and poorer outcomes in patients with COVID-19. This review paper looked at data in humans, animal models and at the cellular level and proposed that African Americans are susceptible to vitamin D deficiency due to increased skin pigmentation affecting its production. Reduced GSH was attributed to decreased dietary intake of L-cysteine, and lower levels of biological compounds, which are involved in the production of GSH. Research surrounding vitamin D’s role in immunity and lowering viral infection risk was reviewed and several routes were proposed, such as increasing anti-microbial action, decreasing inflammation, increasing anti-oxidants and blocking viruses entering cells. It was concluded that randomised control trials on vitamin D supplementation have been underwhelming. This disconnect with trials showing a relationship between low vitamin D levels and poor clinical outcomes is due to the fact that vitamin D was tested in isolation. More randomised control trials are needed to investigate co-supplementation with L-cysteine on outcomes of COVID-19 infection in African Americans. Clinicians could use this review to understand the relationship between vitamin D and L-cysteine and, in lieu of any randomised control trials, as a potential justification for co- supplementation of Vitamin D and L-cysteine in patients with vitamin D deficiency and COVID-19.
Abstract
Early reports indicate an association between the severity of the COVID-19 infection and the widespread 25-hydroxy vitamin D deficiency known to exist in populations around the world. Vitamin D deficiency is extremely common among African American (AA) communities, where the COVID-19 infection rate is three-fold higher, and the mortality rate nearly six-fold higher, compared with rates in predominantly white communities. COVID-19 infection primarily affects the lungs and airways. Previous reports have linked 25-hydroxy vitamin D deficiency with subclinical interstitial lung disease. AA are at risk for lower cellular glutathione (GSH) levels, and GSH deficiency epigenetically impairs VD biosynthesis pathway genes. Compared with vitamin D alone, co-supplementation of vitamin D and L-cysteine (a GSH precursor) showed a better efficacy in improving levels of GSH and VD-regulatory genes at the cellular/tissue level, increasing 25(OH) vitamin D levels, and reducing inflammation biomarkers in the blood in mice studies. We propose that randomized clinical trials are needed to examine the potential of co-supplementation with anti-inflammatory antioxidants, vitamin D and L-cysteine in correcting the 25(OH)VD deficiency and preventing the 'cytokine storm,' one of the most severe consequences of infection with COVID-19, thereby preventing the adverse clinical effects of COVID-19 infection in the vulnerable AA population.
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Effects of Roux-en-Y Gastric Bypass on Osteoclast Activity and Bone Density in Morbidly Obese Patients with Type 2 Diabetes.
Tangalakis, LL, Tabone, L, Spagnoli, A, Muehlbauer, M, Omotosho, P, Torquati, A
Obesity surgery. 2020;30(1):290-295
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Gastric surgery and the resultant weight loss can improve an individual’s outcomes in a number of diseases, such as heart disease and type 2 diabetes, however an unfortunate side effect is bone loss. Roux-en-Y gastric bypass is a process whereby the size of your stomach is significantly reduced, and it is unclear as to the effect this type of surgery has on bone density. This cohort study of sixty-one individuals who underwent Roux-en-Y gastric bypass aimed to determine the effect on bone density one year post surgery. The results showed that following surgery, bone resorption was increased compared to control and although bone density was similar between the two groups, bone mineral content and bone surface area were decreased. Women who were post-menopausal demonstrated diminished bone health, although this was not significant. It was concluded that Roux-en-Y gastric bypass surgery results in a negative impact on bone health. This study could be used by healthcare professionals to understand the importance of considering bone health when recommending surgery, especially in those at high-risk of bone loss such as post-menopausal women.
Abstract
INTRODUCTION Roux-en-Y gastric bypass (RYGB) is a well-established treatment for morbid obesity and type 2 diabetes. The effects of RYGB on bone metabolism and bone health are largely unknown. OBJECTIVE Determine the changes in osteoclast function and bone density 1 year after RYGB as compared with a control group undergoing a diabetes support and education program (DSE). DESIGN A prospective cohort study with patients matched for weight and age assigned to RYGB or DSE. SETTING Large academic institution. PATIENTS OR OTHER PARTICIPANTS Patients with type 2 diabetes mellitus and morbid obesity (body mass index greater than 35 kg/m2). INTERVENTION Subjects either received laparoscopic RYBG or DSE, which consisted of nutritional, exercise, and dietary counseling performed by a certified diabetic educator and a nutritionist three times over a year. MAIN OUTCOME MEASURE Osteoclast activity, bone mineral density. RESULTS One year after, intervention subjects undergoing RYGB have a 280% increase in osteoclast activity as compared with a 7.6% increase in the DSE control group (P < 0.001). Furthermore, there was a statistically significant increase in sclerostin levels in subjects undergoing RYGB compared with an increase in the control group. The total bone mineral density was statistically unchanged within 1 year of intervention in both groups. A statistically significant decrease in bone mineral density in the left ribs (decrease of 6.8%, P < 0.05) and lumbar spine (decrease of 4.0%, P < 0.05) was seen 1 year after RYGB. CONCLUSIONS There is a significant increase in osteoclast activity observed 1 year after RYGB; the long-term clinical implications of this increased bone metabolism are unknown.
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Relationship between vitamin D status and the vaginal microbiome during pregnancy.
Jefferson, KK, Parikh, HI, Garcia, EM, Edwards, DJ, Serrano, MG, Hewison, M, Shary, JR, Powell, AM, Hollis, BW, Fettweis, JM, et al
Journal of perinatology : official journal of the California Perinatal Association. 2019;39(6):824-836
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The composition of the vaginal microflora can significantly impact both reproductive and neonatal health. Numerous studies support the important role for sufficient serum or plasma concentrations of 25-hydroxy vitamin D (25(OH)D) during pregnancy in preventing negative outcomes. The study’s hypothesis was that vitamin D status is associated with the vaginal microbiome. This study is an analysis of a sub-cohort from a randomised, placebo-controlled clinical trial of vitamin D supplementation of pregnant women who were enrolled during the first trimester of pregnancy and followed until delivery. Participants (n=387) were randomised and received supplement: 191 received 400 IU (control group) and 196 received 4400 IU (treatment group). Results show that women in both the control and treatment groups displayed higher circulating 25(OH)D concentrations with increasing gestational age. Furthermore, among women of African ancestry, there was a negative correlation between 25(OH)D and abundance of Megasphaera [type of anaerobic microflora]. Authors conclude that certain vaginal bacteria are associated with plasma 25(OH)D concentration.
Abstract
OBJECTIVE Evidence supports an inverse association between vitamin D and bacterial vaginosis (BV) during pregnancy. Furthermore, both the vaginal microbiome and vitamin D status correlate with pregnancy outcome. Women of African ancestry are more likely to experience BV, to be vitamin D deficient, and to have certain pregnancy complications. We investigated the association between vitamin D status and the vaginal microbiome. STUDY DESIGN Subjects were assigned to a treatment (4400 IU) or a control group (400 IU vitamin D daily), sampled three times during pregnancy, and vaginal 16S rRNA gene taxonomic profiles and plasma 25-hydroxyvitamin D [25(OH)D] concentrations were examined. RESULT Gestational age and ethnicity were significantly associated with the microbiome. Megasphaera correlated negatively (p = 0.0187) with 25(OH)D among women of African ancestry. Among controls, women of European ancestry exhibited a positive correlation between plasma 25(OH)D and L. crispatus abundance. CONCLUSION Certain vaginal bacteria are associated with plasma 25(OH)D concentration.
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High-Dose Vitamin D3 Administration Is Associated With Increases in Hemoglobin Concentrations in Mechanically Ventilated Critically Ill Adults: A Pilot Double-Blind, Randomized, Placebo-Controlled Trial.
Smith, EM, Jones, JL, Han, JE, Alvarez, JA, Sloan, JH, Konrad, RJ, Zughaier, SM, Martin, GS, Ziegler, TR, Tangpricha, V
JPEN. Journal of parenteral and enteral nutrition. 2018;42(1):87-94
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Anaemia is common in critically ill patients and is associated with increased mortality and potentially an extended need for a ventilator. Treatment for anaemia can be invasive and carries a level of risk; therefore further studies on complementary therapies are warranted. Vitamin D has the potential to decrease anaemia through decreasing the production of the iron-regulatory hormone hepcidin. The study aimed to test whether high dose vitamin D would affect haemoglobin concentrations in critically ill patients. In this pilot double-blind randomised control trial, 30 critically ill patients were assigned 250,000 IU vitamin D, 500,000 IU vitamin D or placebo split over 5 doses in 5 days. Blood was taken weekly for up to four weeks and analysed for vitamin D and hepcidin concentrations. Vitamin D concentrations increased significantly in both groups that received vitamin D, compared to no change in the placebo group. Compared to placebo, haemaglobin concentrations significantly increased by 8% in the group receiving 500,000 IU vitamin D but not in the lower dose group. After one week, hepcidin concentrations were significantly decreased in the 500,000 IU vitamin D group, however this was not sustained and no differences between either group and placebo were observed at the end of the study. This did not translate into a reduction in anaemia in either group at any point throughout the study. Extremely high dose vitamin D supplementation was shown to significantly increase circulating vitamin D concentrations and acutely reduce hepcidin. Although anaemia was not affected, clinicians could use this study as an example of safe usage of high dose vitamin D in critically ill patients to improve haemaglobin concentrations, which could reduce the need for invasive treatments, reduce hospital stay duration and treatment costs.
Abstract
BACKGROUND Anemia and vitamin D deficiency are highly prevalent in critical illness, and vitamin D status has been associated with hemoglobin concentrations in epidemiologic studies. We examined the effect of high-dose vitamin D therapy on hemoglobin and hepcidin concentrations in critically ill adults. MATERIALS AND METHODS Mechanically ventilated critically ill adults (N = 30) enrolled in a pilot double-blind, randomized, placebo-controlled trial of high-dose vitamin D3 (D3 ) were included in this analysis. Participants were randomized to receive placebo, 50,000 IU D3 , or 100,000 IU D3 daily for 5 days (totaling 250,000 IU D3 and 500,000 IU D3 , respectively). Blood was drawn weekly throughout hospitalization for up to 4 weeks. Linear mixed-effects models were used to assess change in hemoglobin and hepcidin concentrations by treatment group over time. RESULTS At enrollment, >75% of participants in all groups had plasma 25-hydroxyvitamin D (25(OH)D) concentrations <30 ng/mL, and >85% of participants across groups were anemic. In the 500,000-IU D3 group, hemoglobin concentrations increased significantly over time (Pgroup × time = .01) compared with placebo but did not change in the 250,000-IU D3 group (Pgroup × time = 0.59). Hepcidin concentrations decreased acutely in the 500,000-IU D3 group relative to placebo after 1 week (P = .007). Hepcidin did not change significantly in the 250,000-IU D3 group. CONCLUSION In these critically ill adults, treatment with 500,000 IU D3 was associated with increased hemoglobin concentrations over time and acutely reduced serum hepcidin concentrations. These findings suggest that high-dose vitamin D may improve iron metabolism in critical illness and should be confirmed in larger studies.
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Dietary and Policy Priorities for Cardiovascular Disease, Diabetes, and Obesity: A Comprehensive Review.
Mozaffarian, D
Circulation. 2016;133(2):187-225
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Diet-related cardiometabolic conditions, such as heart disease and diabetes, pose a significant health and economic burden across the world. In recent years, scientific advances and research have generated enormous insights, yet there remain many controversies and unanswered questions. This extensive review summarizes recent evidence of key-dietary components and their impact on cardiometabolic health. Amongst the topics covered are dietary patterns, food quality and processing, genetics, personalized nutrition, supplements, functional foods and the existing knowledge on selected food groups such as carbohydrates, meat and fats alongside relevant vitamins, minerals and plant compounds. The author highlights how an oversimplified concept of nutrition from previous decades, has led to an array of conflicting advice and undermined the nuanced and complex impact that diet and nutrition can have on the body. Thus in light of the evidence, food-based interventions and dietary patterns are suggested as favourable, with less focus on dietary components in isolation. Throughout the paper, the need for adjunct support to facilitate sustainable health-promoting behaviour changes is recognized. Calling for additional measures to address behaviour change, health systems reforms, targeting socioeconomic inequalities, employing novel technologies, and adequate policymaking. This overview of recent evidence yields a comprehensive source of information, worthwhile reviewing when designing personalised diet plans in support of cardiometabolic health.
Abstract
Suboptimal nutrition is a leading cause of poor health. Nutrition and policy science have advanced rapidly, creating confusion yet also providing powerful opportunities to reduce the adverse health and economic impacts of poor diets. This review considers the history, new evidence, controversies, and corresponding lessons for modern dietary and policy priorities for cardiovascular diseases, obesity, and diabetes mellitus. Major identified themes include the importance of evaluating the full diversity of diet-related risk pathways, not only blood lipids or obesity; focusing on foods and overall diet patterns, rather than single isolated nutrients; recognizing the complex influences of different foods on long-term weight regulation, rather than simply counting calories; and characterizing and implementing evidence-based strategies, including policy approaches, for lifestyle change. Evidence-informed dietary priorities include increased fruits, nonstarchy vegetables, nuts, legumes, fish, vegetable oils, yogurt, and minimally processed whole grains; and fewer red meats, processed (eg, sodium-preserved) meats, and foods rich in refined grains, starch, added sugars, salt, and trans fat. More investigation is needed on the cardiometabolic effects of phenolics, dairy fat, probiotics, fermentation, coffee, tea, cocoa, eggs, specific vegetable and tropical oils, vitamin D, individual fatty acids, and diet-microbiome interactions. Little evidence to date supports the cardiometabolic relevance of other popular priorities: eg, local, organic, grass-fed, farmed/wild, or non-genetically modified. Evidence-based personalized nutrition appears to depend more on nongenetic characteristics (eg, physical activity, abdominal adiposity, gender, socioeconomic status, culture) than genetic factors. Food choices must be strongly supported by clinical behavior change efforts, health systems reforms, novel technologies, and robust policy strategies targeting economic incentives, schools and workplaces, neighborhood environments, and the food system. Scientific advances provide crucial new insights on optimal targets and best practices to reduce the burdens of diet-related cardiometabolic diseases.