COVID-19 Mortality Risk Correlates Inversely with Vitamin D3 Status,and a Mortality Rate Close to Zero Could Theoretically Be Achieved at 50 ng/mL 25(OH)D3: Results of a Systematic Review and Meta-Analysis

Background: Much research shows that blood calcidiol (25(OH)D3) levels correlate strongly with SARS-CoV-2 infection severity. There is open discussion regarding whether low D3 is caused by the infection or if deficiency negatively affects immune defense. The aim of this study was to collect further evidence on this topic. Methods: Systematic literature search was performed to identify retrospective cohort as well as clinical studies on COVID-19 mortality rates versus D3 blood levels. Mortality rates from clinical studies were corrected for age, sex, and diabetes. Data were analyzed using correlation and linear regression. Results: One population study and seven clinical studies were identified, which reported D3 blood levels preinfection or on the day of hospital admission. The two independent datasets showed a negative Pearson correlation of D3 levels and mortality risk (r(17) = −0.4154, p = 0.0770/r(13) = −0.4886, p = 0.0646). For the combined data, median (IQR) D3 levels were 23.2 ng/mL (17.4–26.8), and a significant Pearson correlation was observed (r(32) = −0.3989, p = 0.0194). Regression suggested a theoretical point of zero mortality at approximately 50 ng/mL D3. Conclusions: The datasets provide strong evidence that low D3 is a predictor rather than just a side effect of the infection. Despite ongoing vaccinations, we recommend raising serum 25(OH)D levels to above 50 ng/mL to prevent or mitigate new outbreaks due to escape mutations or decreasing antibody activity.     

Effects of Vitamin D Supplementation on 24-Hour Blood Pressure in Patients with Low 25-Hydroxyvitamin D Levels: A Randomized Controlled Trial

Accumulating evidence suggests that potential cardiovascular benefits of vitamin D supplementation may be restricted to individuals with very low 25-hydroxyvitamin D (25(OH)D) concentrations; the effect of vitamin D on blood pressure (BP) remains unclear. We addressed this issue in a post hoc analysis of the double-blind, randomized, placebo-controlled Styrian Vitamin D Hypertension Trial (2011–2014) with 200 hypertensive patients with 25(OH)D levels <30 ng/mL. We evaluated whether 2800 IU of vitamin D3/day or placebo (1:1) for 8 weeks affects 24-hour systolic ambulatory BP in patients with 25(OH)D concentrations <20 ng/mL, <16 ng/mL, and <12 ng/mL and whether achieved 25(OH)D concentrations were associated with BP measures. Taking into account correction for multiple testing, p values < 0.0026 were considered significant. No significant treatment effects on 24-hour BP were observed when different baseline 25(OH)D thresholds were used (all p-values > 0.30). However, there was a marginally significant trend towards an inverse association between the achieved 25(OH)D level with 24-hour systolic BP (−0.196 per ng/mL 25(OH)D, 95% CI (−0.325 to −0.067); p = 0.003). In conclusion, we could not document the antihypertensive effects of vitamin D in vitamin D-deficient individuals, but the association between achieved 25(OH)D concentrations and BP warrants further investigations on cardiovascular benefits of vitamin D in severe vitamin D deficiency.     

Fat-Soluble Vitamin Supplementation Using Liposomes,Cyclodextrins, or Medium-Chain Triglycerides in Cystic Fibrosis: A Randomized Controlled Trial

Fat-soluble vitamin deficiency remains a challenge in cystic fibrosis (CF), chronic pancreatitis, and biliary atresia. Liposomes and cyclodextrins can enhance their bioavailability, thus this multi-center randomized placebo-controlled trial compared three-month supplementation of fat-soluble vitamins in the form of liposomes or cyclodextrins to medium-chain triglycerides (MCT) in pancreatic-insufficient CF patients. The daily doses were as follows: 2000 IU of retinyl palmitate, 4000 IU of vitamin D3, 200 IU of RRR-α-tocopherol, and 200 µg of vitamin K2 as menaquinone-7, with vitamin E given in soybean oil instead of liposomes. All participants received 4 mg of β-carotene and 1.07 mg of vitamin K1 to ensure compliance with the guidelines. The primary outcome was the change from the baseline of all-trans-retinol and 25-hydroxyvitamin D3 concentrations and the percentage of undercarboxylated osteocalcin. Out of 75 randomized patients (n = 28 liposomes, n = 22 cyclodextrins, and n = 25 MCT), 67 completed the trial (89%; n = 26 liposomes, n = 18 cyclodextrins, and n = 23 MCT) and had a median age of 22 years (IQR 19–28), body mass index of 20.6 kg/m² [18.4–22.0], and forced expiratory volume in 1 s of 65% (44–84%). The liposomal formulation of vitamin A was associated with the improved evolution of serum all-trans-retinol compared to the control (median +1.7 ng/mL (IQR −44.3–86.1) vs. −38.8 ng/mL (−71.2–6.8), p = 0.028). Cyclodextrins enhanced the bioavailability of vitamin D3 (+9.0 ng/mL (1.0–17.0) vs. +3.0 ng/mL (−4.0–7.0), p = 0.012) and vitamin E (+4.34 µg/mL (0.33–6.52) vs. −0.34 µg/mL (−1.71–2.15), p = 0.010). Liposomes may augment the bioavailability of vitamin A and cyclodextrins may strengthen the supplementation of vitamins D3 and E relative to MCT in pancreatic-insufficient CF but further studies are required to assess liposomal vitamin E (German Clinical Trial Register number DRKS00014295, funded from EU and Norsa Pharma).     

Serum 25-hydroxyvitamin D Concentration Significantly Decreases in Patients with COVID-19 Pneumonia during the First 48 Hours after Hospital Admission

It is unclear how ongoing inflammation in Coronavirus Disease 2019 (COVID-19) affects 25-hydroxyvitamin D (25[OH]D) concentration. The objective of our study was to examine serum 25(OH)D levels during COVID-19 pneumonia. Patients were admitted between 1 November and 31 December 2021. Blood samples were taken on admission (day 0) and every 24 h for the subsequent four days (day 1–4). On admission, 59% of patients were 25(OH)D sufficient (>30 ng/mL), and 41% had 25(OH)D inadequacy (<30 ng/mL). A significant fall in mean 25(OH)D concentration from admission to day 2 (first 48 h) was observed (30.7 ng/mL vs. 26.4 ng/mL; p < 0.0001). No subsequent significant change in 25(OH)D concentration was observed between day 2 and 3 (26.4 ng/mL vs. 25.9 ng/mL; p = 0.230) and day 3 and day 4 (25.8 ng/mL vs. 25.9 ng/mL; p = 0.703). The absolute 25(OH)D change between hospital admission and day 4 was 16% (4.8 ng/mL; p < 0.0001). On day 4, the number of patients with 25(OH)D inadequacy increased by 18% (p = 0.018). Therefore, serum 25(OH)D concentration after hospital admission in acutely ill COVID-19 patients should be interpreted with caution. Whether low 25(OH)D in COVID-19 reflects tissue level vitamin D deficiency or represents only a laboratory phenomenon remains to be elucidated in further prospective trials of vitamin D supplementation.     

Association between Suboptimal 25-Hydroxyvitamin D Status and Overweight/Obesity in Infants: A Prospective Cohort Study in China

This study aimed to investigate whether 25-hydroxyvitamin D (25(OH)D) concentrations are correlated to overweight/obesity in infants and to explore a threshold of 25(OH)D. A total of 1205 six-month-old infants from two community hospitals in Shanghai were randomly recruited, and 925 of them were followed up at 12 months. Concentration of 25(OH)D, weight, and length were measured at two time points. Overweight/obesity was defined as a weight-for-length Z-score >97th percentile. The prevalence of overweight/obesity at 6 and 12 months was 6.88% and 5.26%, respectively. The occurrence of vitamin D (VitD) deficiency (<20 ng/mL) at 6 and 12 months was 6.56% and 2.05%, respectively. Concentration of 25(OH)D at the corresponding age was negatively associated with weight-for-length percentile (WLP) at both 6 (adjusted β: −0.14; 95% CI: −0.27, −0.02; p = 0.02) and 12 months (adjusted β: −0.22; 95% CI: −0.41, −0.02; p = 0.03), while the relationship between 25(OH)D at 6 months and WLP at 12 months was nonlinear, where 35 ng/mL was identified as an inflection point. Those with a concentration of 25(OH)D <35 ng/mL at 6 months had a higher risk of overweight/obesity (adjusted OR: 1.42; 95% CI: 1.06, 1.91; p = 0.02) compared to the group with a concentration of 25(OH)D ≥35 ng/mL. Moreover, a concentration of 25(OH)D <35 ng/mL at two time points significantly increased the risk of overweight/obesity at 12 months compared to the group with 25(OH)D concentration ≥35 ng/mL at two time points (adjusted OR: 2.91; 95% CI: 1.13, 7.46; p = 0.03). A suboptimal 25(OH)D concentration <35 ng/mL significantly increases the risk of overweight/obesity in infants.     

Vitamin D Status and Gestational Diabetes in Russian Pregnant Women in the Period between 2012 and 2021: A Nested Case–Control Study

Several meta-analyses found an association between low maternal serum 25-hydroxyvitamin D (25(OH)D) level and gestational diabetes mellitus (GDM). However, some of them reported significant heterogeneity. We examined the association of serum 25(OH)D concentration measured in the first and in the second halves of pregnancy with the development of GDM in Russian women surveyed in the periods of 2012–2014 and 2018–2021. We conducted a case–control study (including 318 pregnant women) nested on two previous studies. In 2012–2014, a total of 214 women (83 GDM and 131 controls) were enrolled before 15 weeks of gestation and maternal serum 25(OH)D concentrations were measured twice: at 8th–14th week of gestation and simultaneously with two-hour 75 g oral glucose tolerance test (OGTT) at 24th–32nd week of gestation. In the period of 2018–2021, 104 women (56 GDM and 48 controls) were included after OGTT and 25(OH)D concentrations were measured at 24th–32nd week of gestation. Median 25(OH)D levels were 20.0 [15.1–25.7] vs. 20.5 [14.5–27.5] ng/mL (p = 0.565) in GDM and control group in the first half of pregnancy and 25.3 [19.8–33.0] vs. 26.7 [20.8–36.8] ng/mL (p = 0.471) in the second half of pregnancy, respectively. The prevalence rates for vitamin D deficiency (25(OH)D levels < 20 ng/mL) were 49.4% and 45.8% (p = 0.608) in the first half of pregnancy and 26.2% vs. 22.1% (p = 0.516) in the second half of pregnancy in women who developed GDM and in women without GDM, respectively. The frequency of vitamin D supplements intake during pregnancy increased in 2018–2021 compared to 2012–2014 (p = 0.001). However, the third trimester 25(OH)D levels and prevalence of vitamin D deficiency (25.5 vs. 23.1, p = 0.744) did not differ in women examined in the periods of 2012–2014 and 2018–2021. To conclude, there was no association between gestational diabetes risk and maternal 25(OH)D measured both in the first and in the second halves of pregnancy. The increased prevalence of vitamin D supplements intake during pregnancy by 2018–2021 did not lead to higher levels of 25(OH)D.     

Vitamin D Serum Levels in Subjects Tested for SARS-CoV-2: What Are the Differences among Acute,Healed, and Negative COVID-19 Patients? A Multicenter Real-Practice Study

Vitamin D might play a role in counteracting COVID-19, albeit strong evidence is still lacking in the literature. The present multicenter real-practice study aimed to evaluate the differences of 25(OH)D₃ serum levels in adults tested for SARS-CoV-2 (acute COVID-19 patients, subjects healed from COVID-19, and non-infected ones) recruited over a 6-month period (March–September 2021). In a sample of 117 subjects, a statistically significant difference was found, with acute COVID-19 patients demonstrating the lowest levels of serum 25(OH)D₃ (9.63 ± 8.70 ng/mL), significantly lower than values reported by no-COVID-19 patients (15.96 ± 5.99 ng/mL, p = 0.0091) and healed COVID-19 patients (11.52 ± 4.90 ng/mL, p > 0.05). Male gender across the three groups displayed unfluctuating 25(OH)D₃ levels, hinting at an inability to ensure adequate levels of the active vitamin D3 form (1α,25(OH)2D3). As a secondary endpoint, we assessed the correlation between serum 25(OH)D₃ levels and pro-inflammatory cytokine interleukin-6 (IL-6) in patients with extremely low serum 25(OH)D₃ levels (<1 ng/mL) and in a subset supplemented with 1α,25(OH)₂D₃. Although patients with severe hypovitaminosis-D showed no significant increase in IL-6 levels, acute COVID-19 patients manifested high circulating IL-6 at admission (females = 127.64 ± 22.24 pg/mL, males = 139.28 ± 48.95 ng/mL) which dropped drastically after the administration of 1α,25(OH)₂D₃ (1.84 ± 0.77 pg/mL and 2.65 ± 0.92 ng/mL, respectively). Taken together, these findings suggest that an administration of 1α,25(OH)₂D₃ might be helpful for treating male patients with an acute COVID-19 infection. Further studies on rapid correction of vitamin D deficiency with fast acting metabolites are warranted in COVID-19 patients.     

Applying Machine Learning to Determine 25(OH)D Threshold Levels Using Data from the AMATERASU Vitamin D Supplementation Trial in Patients with Digestive Tract Cancer

Some controversy remains on thresholds for deficiency or sufficiency of serum 25-hydroxyvitamin D (25(OH)D) levels. Moreover, 25(OH)D levels sufficient for bone health might differ from those required for cancer survival. This study aimed to explore these 25(OH)D threshold levels by applying the machine learning method of multivariable adaptive regression splines (MARS) in post hoc analyses using data from the AMATERASU trial, which randomly assigned Japanese patients with digestive tract cancer to receive vitamin D or placebo supplementation. Using MARS, threshold 25(OH)D levels were estimated as 17 ng/mL for calcium and 29 ng/mL for parathyroid hormone (PTH). Vitamin D supplementation increased calcium levels in patients with baseline 25(OH)D levels ≤17 ng/mL, suggesting deficiency for bone health, but not in those >17 ng/mL. Vitamin D supplementation improved 5-year relapse-free survival (RFS) compared with placebo in patients with intermediate 25(OH)D levels (18–28 ng/mL): vitamin D, 84% vs. placebo, 71%; hazard ratio, 0.49; 95% confidence interval, 0.25–0.96; p = 0.04. In contrast, vitamin D supplementation did not improve 5-year RFS among patients with low (≤17 ng/mL) or with high (≥29 ng/mL) 25(OH)D levels. MARS might be a reliable method with the potential to eliminate guesswork in the estimation of threshold values of biomarkers.     

Temporal Association of Reduced Serum Vitamin D with COVID-19 Infection: Two Single-Institution Case–Control Studies

(1) Background: Vitamin D supplementation has been proposed for the prevention and treatment of COVID-19, but it is not clear if reduced serum vitamin D predisposes individuals to COVID-19 and/or is a secondary consequence of infection. This study assessed the temporal association between serum vitamin D and COVID-19 with two single-institution case–control studies through the University of California San Diego (UCSD) Health System. (2) Methods: This study included patients who tested positive for COVID-19 from 1 January to 30 September 2020 with serum 25-hydroxy-vitamin D (25(OH)D) measured within 180 days of diagnosis. Patients were separated based on whether 25(OH)D was measured before (n = 107 cases, 214 controls) or after (n = 203 cases, 406 controls) COVID-19 diagnosis. COVID-19 infection status was the outcome variable in the pre-diagnosis study, whereas serum 25(OH)D level was the outcome variable in the post-diagnosis study. (3) Results: Serum 25(OH)D levels were not associated with the odds of subsequent COVID-19 infection (OR 1.0, 95% CI: 1.0 to 1.0, p = 0.98). However, COVID-19-positive individuals had serum 25(OH)D measurements that were 2.7 ng/mL lower than the controls (95% CI: −5.2 to −0.2, p = 0.03). (4) Conclusions: In our study population, serum 25(OH)D levels were not associated with the risk of acquiring COVID-19 infection but were reduced in subjects after COVID-19 infection. These results support the possibility that reduced serum 25(OH)D is a consequence and not a cause of COVID-19 infection.     

Association between Maternal Serum 25-Hydroxyvitamin D Concentrations and the Risk of Preterm Birth in Central Sudan: A Case–Control Study

There are few published studies on the association between vitamin D concentrations and preterm birth (PB) in sub-Saharan Africa. The current study aimed to assess the association between 25-hydroxyvitamin D (25[OH)] D) levels and PB. A matched case–control study (60 women in each arm) was conducted in Medani maternity hospital in central Sudan. The cases were women with spontaneous PB, and healthy women with term deliveries were the controls. The clinical/medical and obstetric history was gathered using a questionnaire. The enzyme-linked immunosorbent assay was used to measure the serum 25(OH)D levels. Women with PB had significantly lower median (interquartile range) 25(OH)D concentrations compared with the controls (18.4 (7.3) ng/mL vs. 20.2 (16.5) ng/mL, p = 0.001). Forty-two (70.0%) women with PB and 29 (48.3%) women in the control group had vitamin D deficiency (25(OH)D level ≤ 20 ng/mL). The results of the multivariable logistic regression showed that the 25(OH)D concentrations were negatively associated with PB (adjusted odds ratio (aOR) = 0.92, 95% confidence interval (CI) = 0.87–0.97). Vitamin D-deficient pregnant women were at a higher risk of PB (aOR = 2.69, 95% CI = 1.17–6.23). Low 25(OH)D concentrations were found at the time the variable was determined in women with spontaneous PB and were an independent risk factor for PB.     

Correlation between Serum 25-Hydroxyvitamin D Level and Depression among Korean Women with Secondary Amenorrhea: A Cross-Sectional Observational Study

Vitamin D deficiency is considered a major public health problem worldwide and has been reported as having an association with depression. However, studies on the association between vitamin D deficiency and depressive symptoms in secondary amenorrhea (SA) patients are still scarce. This study examined the relationship between serum 25-hydroxyvitamin D (25(OH)D) levels and depressive symptoms among Korean women with SA. In this cross-sectional observational study, 78 patients with SA were initially recruited. Clinical and biochemical parameters, including serum 25(OH)D level, were measured. Data from 63 SA patients who met the study inclusion criteria and completed psychiatric assessments were finally analyzed. We analyzed their association with depression using a hierarchical regression model. The average serum 25(OH)D level was 34.40 ± 24.02 ng/mL, and 41.3% of the women with SA were vitamin D-deficient (<20 ng/mL). The total score of the Korean version of the Hamilton Depression Rating Scale (K-HDRS) was negatively related to serum 25(OH)D levels, free testosterone, and serum anti-Müllerian hormone (AMH) after adjusting for age and BMI (r = −0.450, p < 0.001; r = −0.258, p = 0.045; and r = −0.339, p = 0.006, respectively). Serum 25(OH)D levels and AMH levels were the most powerful predictors of depressive severity when using the K-HDRS in SA patients (β = −0.39, p < 0.005; β = −0.42, p < 0.005, respectively). This study showed that low serum 25(OH)D levels were associated with the severity of depressive symptoms in SA patients. This observation suggests that the evaluation of vitamin D deficiency for the risk of depression may be necessary in patients with SA.     

Vitamin D Supplementation Does Not Influence SARS-CoV-2 Vaccine Efficacy or Immunogenicity: Sub-Studies Nested within the CORONAVIT Randomised Controlled Trial

Vitamin D deficiency has been reported to associate with the impaired development of antigen-specific responses following vaccination. We aimed to determine whether vitamin D supplements might boost the immunogenicity and efficacy of SARS-CoV-2 vaccination by conducting three sub-studies nested within the CORONAVIT randomised controlled trial, which investigated the effects of offering vitamin D supplements at a dose of 800 IU/day or 3200 IU/day vs. no offer on risk of acute respiratory infections in UK adults with circulating 25-hydroxyvitamin D concentrations <75 nmol/L. Sub-study 1 (n = 2808) investigated the effects of vitamin D supplementation on the risk of breakthrough SARS-CoV-2 infection following two doses of SARS-CoV-2 vaccine. Sub-study 2 (n = 1853) investigated the effects of vitamin D supplementation on titres of combined IgG, IgA and IgM (IgGAM) anti-Spike antibodies in eluates of dried blood spots collected after SARS-CoV-2 vaccination. Sub-study 3 (n = 100) investigated the effects of vitamin D supplementation on neutralising antibody and cellular responses in venous blood samples collected after SARS-CoV-2 vaccination. In total, 1945/2808 (69.3%) sub-study 1 participants received two doses of ChAdOx1 nCoV-19 (Oxford–AstraZeneca); the remainder received two doses of BNT162b2 (Pfizer). Mean follow-up 25(OH)D concentrations were significantly elevated in the 800 IU/day vs. no-offer group (82.5 vs. 53.6 nmol/L; mean difference 28.8 nmol/L, 95% CI 22.8–34.8) and in the 3200 IU/day vs. no offer group (105.4 vs. 53.6 nmol/L; mean difference 51.7 nmol/L, 45.1–58.4). Vitamin D supplementation did not influence the risk of breakthrough SARS-CoV-2 infection in vaccinated participants (800 IU/day vs. no offer: adjusted hazard ratio 1.28, 95% CI 0.89 to 1.84; 3200 IU/day vs. no offer: 1.17, 0.81 to 1.70). Neither did it influence IgGAM anti-Spike titres, neutralising antibody titres or IFN-γ concentrations in the supernatants of S peptide-stimulated whole blood. In conclusion, vitamin D replacement at a dose of 800 or 3200 IU/day effectively elevated 25(OH)D concentrations, but it did not influence the protective efficacy or immunogenicity of SARS-CoV-2 vaccination when given to adults who had a sub-optimal vitamin D status at baseline.     

Low 25(OH)D Level Is Associated with Severe Course and Poor Prognosis in COVID-19

We evaluated associations between serum 25-hydroxyvitamin D [25(OH)D] level and severity of new coronavirus infection (COVID-19) in hospitalized patients. We assessed serum 25(OH)D level in 133 patients aged 21–93 years. Twenty-five (19%) patients had severe disease, 108 patients (81%) had moderate disease, and 18 (14%) patients died. 25(OH)D level ranged from 3.0 to 97.0 ng/mL (median, 13.5 [25%; 75%, 9.6; 23.3] ng/mL). Vitamin D deficiency was diagnosed in 90 patients, including 37 with severe deficiency. In patients with severe course of disease, 25(OH)D level was lower (median, 9.7 [25%; 75%, 6.0; 14.9] ng/mL), and vitamin D deficiency was more common than in patients with moderate course (median, 14.6 [25%; 75%, 10.6; 24.4] ng/mL, p = 0.003). In patients who died, 25(OH)D was 9.6 [25%; 75%, 6.0; 11.5] ng/mL, compared with 14.8 [25%; 75%, 10.1; 24.3] ng/mL in discharged patients (p = 0.001). Severe vitamin D deficiency was associated with increased risk of COVID-19 severity and fatal outcome. The threshold for 25(OH)D level associated with increased risk of severe course was 11.7 ng/mL. Approximately the same 25(OH)D level, 10.9 ng/mL, was associated with increased risk of mortality. Thus, most COVID-19 patients have vitamin D deficiency; severe vitamin D deficiency is associated with increased risk of COVID-19 severity and fatal outcome.     

Vitamin D Nutritional Status of Chinese Pregnant Women,Comparing the Chinese National Nutrition Surveillance (CNHS) 2015–2017 with CNHS 2010–2012

Optimal vitamin D (vitD) status is beneficial for both pregnant women and their newborns. The aim of this study was to evaluate the vitamin D status of Chinese pregnant women in the latest China Nutrition and Health Surveillance (CNHS) 2015–2017, analyze the risk factors of vitamin D deficiency (VDD), and compare them with those in CNHS 2010–2012. Serum 25 hydroxyvitamin D (25(OH)D) was measured by ELISA method. City type, district, latitude, location, age, vitamin D supplements intake, education, marital status, annual family income, etc., were recorded. The median 25(OH)D concentration was 13.02 (10.17–17.01) ng/mL in 2015–2017, and 15.48 (11.89–20.09) ng/mL in 2010–2012. The vitamin D sufficient rate was only 12.57% in 2015–2017, comparing to 25.17% in 2010–2012. The risk factors of vitamin D inadequacy (25(OH)D < 20 ng/mL) in 2015–2017 were not exactly consistent with that in 2010–2012. The risk factors included season of spring (p < 0.0001) and winter (p < 0.001), subtropical (p < 0.001), median (p < 0.0001) and warm temperate zones (p < 0.0001), the western (p = 0.027) and the central areas (p = 0.041), while vitD supplements intake (p = 0.021) was a protective factor in pregnant women. In conclusion, vitD inadequacy is very common among Chinese pregnant women. We encourage pregnant women to take more effective sunlight and proper vitD supplements, especially for those from the subtropical, warm and medium temperate zones, the western and the central, and in the seasons of spring and winter.     

Vitamin D Status in Pediatric and Young Adult Cystic Fibrosis Patients. Are the New Recommendations Effective?

Introduction: In recent years, guidelines for vitamin D supplementation have been updated and prophylactic recommended doses have been increased in patients with cystic fibrosis (CF). Objective: To evaluate safety and efficacy of these new recommendations. Results: Two cohorts of pancreatic insufficient CF patients were compared before (cohort 1: 179 patients) and after (cohort 2: 71 patients) American CF Foundation and European CF Society recommendations were published. Cohort 2 patients received higher Vitamin D doses: 1509 (1306–1711 95% CI) vs 1084 (983–1184 95% CI) IU/Day (p < 0.001), had higher 25 OH vitamin D levels: 30.6 (27.9–33.26 95% CI) vs. 27.4 (25.9–28.8 95% CI) ng/mL (p = 0.028), and had a lower prevalence of insufficient vitamin D levels (<30 ng/mL): 48% vs 65% (p = 0.011). Adjusted by confounding factors, patients in cohort 1 had a higher risk of vitamin D insufficiency: OR 2.23 (1.09–4.57 95% CI) (p = 0.028). Conclusion: After the implementation of new guidelines, CF patients received higher doses of vitamin D and a risk of vitamin D insufficiency decreased. Despite this, almost a third of CF patients still do not reach sufficient serum calcidiol levels.     

Pharmacokinetics of High-Dose Weekly Oral Vitamin D3 Supplementation during the Third Trimester of Pregnancy in Dhaka,Bangladesh

A pharmacokinetic study was conducted to assess the biochemical dose-response and tolerability of high-dose prenatal vitamin D3 supplementation in Dhaka, Bangladesh (23°N). Pregnant women at 27–30 weeks gestation (n = 28) were randomized to 70,000 IU once + 35,000 IU/week vitamin D3 (group PH: pregnant, higher dose) or 14,000 IU/week vitamin D3 (PL: pregnant, lower dose) until delivery. A group of non-pregnant women (n = 16) was similarly administered 70,000 IU once + 35,000 IU/week for 10 weeks (NH: non-pregnant, higher-dose). Rise (∆) in serum 25-hydroxyvitamin D concentration ([25(OH)D]) above baseline was the primary pharmacokinetic outcome. Baseline mean [25(OH)D] were similar in PH and PL (35 nmol/L vs. 31 nmol/L, p = 0.34). A dose-response effect was observed: ∆[25(OH)D] at modeled steady-state was 19 nmol/L (95% CI, 1 to 37) higher in PH vs. PL (p = 0.044). ∆[25(OH)D] at modeled steady-state was lower in PH versus NH but the difference was not significant (−15 nmol/L, 95% CI −34 to 5; p = 0.13). In PH, 100% attained [25(OH)D] ≥ 50 nmol/L and 90% attained [25(OH)D] ≥ 80 nmol/L; in PL, 89% attained [25(OH)D] ≥ 50 nmol/L but 56% attained [25(OH)D] ≥ 80 nmol/L. Cord [25(OH)D] (n = 23) was slightly higher in PH versus PL (117 nmol/L vs. 98 nmol/L; p = 0.07). Vitamin D3 was well tolerated; there were no supplement-related serious adverse clinical events or hypercalcemia. In summary, a regimen of an initial dose of 70,000 IU and 35,000 IU/week vitamin D3 in the third trimester of pregnancy was non-hypercalcemic and attained [25(OH)D] ≥ 80 nmol/L in virtually all mothers and newborns. Further research is required to establish the safety of high-dose vitamin D3 in pregnancy and to determine if supplement-induced [25(OH)D] elevations lead to maternal-infant health benefits.     

Vitamin D Deficiency Is Significantly Associated with Retinopathy in Type 2 Diabetes Mellitus: A Case-Control Study

Aim: Results from meta-analyses point to an association between vitamin D deficiency and the onset of diabetic retinopathy (DR). The objectives of the present study were to evaluate the association of vitamin D for the development of DR and to determine the levels of vitamin D associated with a greater risk of DR. Methods: Between November 2013 and February 2015, we performed a case-control study based on a sample of patients with diabetes in Spain. The study population comprised all patients who had at least one evaluable electroretinogram and recorded levels of 25(OH)D. We collected a series of analytical data: 25(OH)D, 1,25(OH)2D, iPTH, calcium, albumin, and HbA1c. Glycemic control was evaluated on the basis of the mean HbA1c values for the period 2009–2014. A logistic regression analysis was performed to identify the variables associated with DR. Results: The final study sample comprised 385 patients, of which 30 (7.8%) had DR. Significant differences were found between patients with and without DR for age (69.54 vs. 73.43), HbA1c (6.68% vs. 7.29%), years since diagnosis of diabetes (10.9 vs. 14.17), level of 25(OH)D (20.80 vs. 15.50 ng/mL), level of 1,25(OH)2D (35.0 vs. 24.5 pg/mL), treatment with insulin (14.9% vs. 56.7%), hypertension (77.7% vs. 100%), cardiovascular events (33.2% vs. 53.3%), and kidney failure (22.0% vs. 43.3%). In the multivariate analysis, the factors identified as independent risk factors for DR were treatment of diabetes (p = 0.001) and 25(OH)D (p = 0.025). The high risk of DR in patients receiving insulin (OR 17.01) was also noteworthy. Conclusions: Levels of 25(OH)D and treatment of diabetes were significantly associated with DR after adjusting for other risk factors. Combined levels of 25(OH)D < 16 ng/mL and levels of 1,25(OH)2D < 29 pg/mL are the variables that best predict the risk of having DR with respect to vitamin D deficiency. The risk factor with the strongest association was the treatment of type 2 diabetes mellitus. This was particularly true for patients receiving insulin, who had a greater risk of DR than those receiving insulin analogues. However, further studies are necessary before a causal relationship can be established.     

The Association between 25-Hydroxyvitamin D Concentration and Telomere Length in the Very-Old: The Newcastle 85+ Study

(1) Introduction: vitamin D may maintain the telomere length, either directly or via the inflammation effect and/or modulating the rate of cell proliferation. Whilst results from cross-sectional studies investigating the association between 25(OH)D concentration and telomere length have been mixed, there is a dearth of data from prospective studies which have assessed these associations. This study aimed to examine the association between 25(OH)D concentration in plasma and telomere length in blood cells in very-old adults (≥85 years old) at baseline, 18 months and 36 months by controlling for related lifestyle factors. (2) Methodology: our prospective cohort study comprised 775 participants from the Newcastle 85+ Study who had 25(OH)D measurements at baseline. Plasma 25(OH)D was stratified as <25 nmol/L (low), 25–50 nmol/L (moderate) and >50 nmol/L (high). Peripheral blood mononuclear cell telomere length was measured by quantitative real-time polymerase chain reaction at baseline, 18 and 36 months from baseline. (3) Results: a positive significant association was found between 25(OH)D concentration and telomere length amongst very-old participants at baseline (95% CI = 12.0–110.3, B = 61.2 ± 5.0, p = 0.015). This association was negative at 18 months (95% CI = −59.9–−7.5, B = −33.7 ± 13.3, p = 0.012) but was non-significant at 36 months. (4) Conclusion: Circulating 25(OH)D concentration shows inconsistent relationships with telomere length over time in very-old (85+ year old) adults.     

25-Hydroxyvitamin D and Its Relationship with Autonomic Dysfunction Using Time- and Frequency-Domain Parameters of Heart Rate Variability in Korean Populations: A Cross-Sectional Study

Previous studies have demonstrated that reduced heart rate variability (HRV) and hypovitaminosis D are associated with cardiovascular disease (CVD). However, few reports have investigated the effects of vitamin D on HRV. This cross-sectional study analyzed serum 25-hydroxyvitamin D (25(OH)D) and HRV indices using 5-min R-R interval recordings with an automatic three-channel electrocardiography in healthy subjects (103 males and 73 females). Standard deviation of N-N interval (SDNN), square root of mean squared differences of successive N-N intervals (RMSSD), total power (TP), very low frequency (VLF), low frequency (LF), and high frequency (HF) were reported. The mean age of subjects was 55.3 ± 11.3 years and the mean 25(OH)D level was 21.2 ± 9.9 ng/mL. In a multiple linear regression model, 25(OH)D was positively correlated with SDNN (β = 0.240, p < 0.002), and LF (β = 0.144, p = 0.044). Vitamin D deficiency (25(OH)D < 15 ng/mL) was associated with decreased SDNN (<30 m/s) (OR, 3.07; 95% confidence interval (CI), 1.32–7.14; p = 0.014) after adjusting for covariates. We found that lower 25(OH)D levels were associated with lower HRV, suggesting a possible explanation for the higher risk of CVD in populations with hypovitaminosis D.     

The Association between Vitamin D Status and Autism Spectrum Disorder (ASD): A Systematic Review and Meta-Analysis

The association between vitamin D status and autism spectrum disorder (ASD) is well-investigated but remains to be elucidated. We quantitatively combined relevant studies to estimate whether vitamin D status was related to ASD in this work. PubMed, EMBASE, Web of Science, and the Cochrane Library were searched to include eligible studies. A random-effects model was applied to pool overall estimates of vitamin D concentration or odds ratio (OR) for ASD. In total, 34 publications involving 20,580 participants were identified in this present study. Meta-analysis of 24 case–control studies demonstrated that children and adolescents with ASD had significantly lower vitamin D concentration than that of the control group (mean difference (MD): −7.46 ng/mL, 95% confidence interval (CI): −10.26; −4.66 ng/mL, p < 0.0001, I² = 98%). Quantitative integration of 10 case–control studies reporting OR revealed that lower vitamin D was associated with higher risk of ASD (OR: 5.23, 95% CI: 3.13; 8.73, p < 0.0001, I² = 78.2%). Analysis of 15 case–control studies barring data from previous meta-analysis reached a similar result with that of the meta-analysis of 24 case–control studies (MD: −6.2, 95% CI: −9.62; −2.78, p = 0.0004, I² = 96.8%), which confirmed the association. Furthermore, meta-analysis of maternal and neonatal vitamin D showed a trend of decreased early-life vitamin D concentration in the ASD group (MD: −3.15, 95% CI: −6.57; 0.26, p = 0.07, I² = 99%). Meta-analysis of prospective studies suggested that children with reduced maternal or neonatal vitamin D had 54% higher likelihood of developing ASD (OR: 1.54, 95% CI: 1.12; 2.10, p = 0.0071, I² = 81.2%). These analyses indicated that vitamin D status was related to the risk of ASD. The detection and appropriate intervention of vitamin D deficiency in ASD patients and pregnant and lactating women have clinical and public significance.