Trending Topics pieces (Article Analyses, Evidence Clips and Other Topics) are published in timely response to recent media and journal articles, position statements, clinical guidelines, etc. Since they are based on the most recent evidence/publications, they may not be consistent with PEN evidence in other PEN content areas. As soon as possible, when this occurs, the PEN content will be reviewed and updated as needed.
Vitamin D and COVID-19: Do Latest Studies Support Supplementation?
To date, research on vitamin D supplementation and COVID-19 outcomes has been limited, so the PEN Team reviewed two recent studies on vitamin D and COVID-19 to see what, if anything, has changed.
Conversations continue on social media about the potential role of vitamin D supplementation in the prevention and treatment of COVID-19. The PEN Team noticed that a common rationale was that patients with COVID-19 tended to have lower vitamin D status (25(OH)D levels). We decided to take a look at two recent studies that reported this connection to determine if the results support vitamin D supplementation to improve COVID-19 outcomes.
First, we looked at an observational study by De Smet et al. that noted that patients with COVID-19 had progressively lower 25(OH)D levels with more severe COVID respiratory disease (1). The study authors also observed that those with vitamin D deficiency were almost four times more likely to die (adjusted odds ratio [OR] 3.87; 95% confidence interval [CI], 1.30 to 11.55). Vitamin D deficiency was prevalent among the patients with COVID-19 infections, more so among the men (67%) than among the women (47%). These researchers adjusted for several variables that are risk factors for COVID-19 mortality (age, ethnicity, chronic lung disease, coronary artery disease/hypertension, diabetes and extent of lung damage).
From other vitamin D research, we know that the marker for vitamin D status (25(OH)D) can be lowered by infections (2). Therefore, low 25(OH)D levels may not reflect poor vitamin D status in a person with an infection. De Smet et al. were not able to determine whether what looked like a vitamin D deficiency was actually a nutritional deficiency or whether the COVID-19 infection lowered the participants 25(OH)D, making these patients appear to have a vitamin D deficiency (1). For this reason, this observational study does not provide evidence that vitamin D supplementation would be helpful for improving outcomes of a COVID-19 infection.
The second study we examined was a randomized control trial of vitamin D supplementation in people with mild symptomatic and asymptomatic COVID-19 infections. Rastogi et al. randomized 40 people with mild COVID-19 infections to 60,000 IU/day of vitamin D3 or placebo for seven days (3). The researchers observed that more participants in the intervention group became COVID-19 RNA negative before day 21 compared to participants in the control arm (62.5% versus 20.8%, P<0.018). Vitamin D supplementation lowered fibrinogen levels significantly but not the other inflammatory markers (SARS-CoV-2 RNA, D-dimer, procalcitonin CRP and ferritin). These researchers only reported differences in indirect markers (3) and did not report World Health Organization-recommended patient-important outcomes (patient survival and patient health care system use over the course of clinical illness) (4). The PEN Team thinks that this trial does not answer the question of whether vitamin D supplementation improves COVID-19 outcomes.
What This Means
After reviewing these studies, the PEN Team has two key questions:
1. What is the relationship between vitamin D deficiency and COVID-19 severity?
2. What is the impact of vitamin D supplementation on patient-important outcomes, such as disease severity, hospitalization and death?
Before dietitians can make recommendations on the use of vitamin D supplementation to improve COVID-19 outcomes, randomized control trials examining the prevention of COVID-19 (including severe COVID-19) and the treatment of COVID-19 with patient-important outcomes are needed.
- De Smet D, De Smet K, Herroelen P, Gryspeerdt S, Martens GA. Serum 25(OH)D Level on Hospital Admission Associated With COVID-19 Stage and Mortality. Am J Clin Pathol. 2020 Nov 25:aqaa252. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717135/
- Hernández-Álvarez E, Pérez-Barrios C, Blanco-Navarro I, Pérez-Sacristán B, Donoso-Navarro E, Silvestre RA, et al. Association between 25-OH-vitamin D and C-reactive protein as a marker of inflammation and cardiovascular risk in clinical practice. Ann Clin Biochem. 2019 Jul;56(4):502-7. Available from: https://pubmed.ncbi.nlm.nih.gov/31043057/
- Rastogi A, Bhansali A, Khare N, Suri V, Yaddanapudi N, Sachdeva N, et al. Short term, high-dose vitamin D supplementation for COVID-19 disease: a randomised, placebo-controlled, study (SHADE study). Postgrad Med J. 2020 Nov 12:postgradmedj-2020-139065. Abstract available from: https://pubmed.ncbi.nlm.h.gov/33184146/
- WHO Working Group on the Clinical Characterisation and Management of COVID-19 infection. A minimal common outcome measure set for COVID-19 clinical research. Lancet Infect Dis. 2020 Aug;20(8):e192-e197. Abstract available from https://pubmed.ncbi.nlm.nih.gov/32539990/
Should I Recommend Vitamin D Supplements to Protect Against COVID-19? Updated November 2020
The Bottom Line:
- No studies have examined the effect of vitamin D to prevent or treat COVID-19 infections.
- Information extrapolated from randomized trials that examined respiratory tract infection prevention have not reported consistent beneficial effects of vitamin D compared to placebo in adults or children.
- Potential risks that have been identified include a higher rate of repeat episodes of pneumonia.
- While observational studies suggest that lower serum vitamin D levels are associated with inflammatory response, lower serum vitamin D levels are associated with other factors and not only with inadequate vitamin D intake.
- Vitamin D is an essential nutrient and vitamin D supplementation is recommended in a number of countries for various ages during the life cycle for general health.
Vitamin D Update: Supplementation and Pregnancy and Perinatal Outcomes and 25-hyroxy-vitamin D as a Marker for Nutrient Deficiency and Sufficiency
Vitamin D has been a very active area of research in recent decades. Not only have there been numerous research studies published, there have also been numerous systematic reviews published summarizing these studies. Recently, researchers in Alberta, Canada undertook a systematic review of the systematic reviews that investigated the importance of vitamin D in pregnancy for important perinatal and infant outcomes (1).
This systematic review of systematic reviews found 42 systematic reviews of 204 primary studies that evaluated either vitamin D supplementation in pregnant women and/or examined the association between serum vitamin D levels for at least one predefined perinatal outcome (1). The researchers evaluated the systematic reviews for research quality using the AMSTAR tool and only analyzed data from the 13 systematic reviews with high AMSTAR scores.
The systematic reviews of randomized controlled trials (RCTs) with the highest quality of evidence showed no benefits from vitamin D supplementation regarding preterm birth, preeclampsia, gestational diabetes, stillbirth, low birth weight or caesarean section (1). A significant difference was found for small-for-gestational age; however, this evidence was low quality for two reasons: 1) the high risks of bias in the included studies without an accompanying sensitivity analysis to examine the low risk of bias studies separately, and 2) imprecision due to the small numbers of small-for-gestational age births in the included studies. Systematic reviews of observational studies showed that women with low 25-hyroxy-vitamin D levels had higher rates of preterm birth, preeclampsia, gestational diabetes and small-for-gestational age.
The findings of this systematic review (1) reinforce the findings of a 2017 systematic review (2) that found that the superior health of people with higher vitamin D serum levels suggested by the frequent associations observed in observational studies are not seen in randomized trials of vitamin D supplementation. Additionally, there is increasing evidence that serum 25-hyroxy-vitamin D, the vitamin D status marker, is a negative acute phase reactant, which decreases in response to other variables (2-9). Specifically, researchers have observed that 25-hyroxy-vitamin D decreases in response to inflammation (3), acute illness (4), ill health (2), critical illness (5), surgery (6,7) and when C-reactive protein increases (3,7-9). If a marker changes in response to other variables, then it has limited use as a nutritional adequacy marker.
- Bialy L, Fenton T, Shulhan-Kilroy J, Johnson DW, McNeil DA, Hartling L. Vitamin D supplementation to improve pregnancy and perinatal outcomes: an overview of 42 systematic reviews. BMJ Open. 2020 Jan 20;10(1):e032626. Abstract available from: https://www.ncbi.nlm.nih.gov/pubmed/31964667
- Autier P, Mullie P, Macacu A, Dragomir M, Boniol M, Coppens K, et al. Effect of vitamin D supplementation on non-skeletal disorders: a systematic review of meta-analyses and randomised trials. Lancet Diabetes Endocrinol. 2017 Dec;5(12):986-1004. Abstract available from: https://www.ncbi.nlm.nih.gov/pubmed/29102433
- McMillan DC, Maguire D, Talwar D. Relationship between nutritional status and the systemic inflammatory response: micronutrients. Proc Nutr Soc. 2019 Feb;78(1):56-67. Abstract available from: https://www.ncbi.nlm.nih.gov/pubmed/30220267
- Kostoglou-Athanassiou I, Pantazi E, Kontogiannis S, Kousouris D, Mavropoulos I, Athanassiou P. Vitamin D in acutely ill patients. J Int Med Res. 2018 Oct;46(10):4246-57. Abstract available from: https://www.ncbi.nlm.nih.gov/pubmed/30157690
- Czarnik T, Czarnik A, Gawda R, Gawor M, Piwoda M, Marszalski M, et al. Vitamin D kinetics in the acute phase of critical illness: a prospective observational study. J Crit Care. 2018 Feb;43:294-9. Abstract available from: https://www.ncbi.nlm.nih.gov/pubmed/28968524
- Binkley N, Coursin D, Krueger D, Iglar P, Heiner J, Illgen R, et al. Surgery alters parameters of vitamin D status and other laboratory results. Osteoporos Int. 2017 Mar;28(3):1013-20. Abstract available from: https://www.ncbi.nlm.nih.gov/pubmed/27826645
- Waldron JL, Ashby HL, Cornes MP, Bechervaise J, Razavi C, Thomas OL, et al. Vitamin D: a negative acute phase reactant. J Clin Pathol. 2013 Jul;66(7):620-2. Abstract available from: https://www.ncbi.nlm.nih.gov/pubmed/?term=23454726
- Kruit A, Zanen P. The association between vitamin D and C-reactive protein levels in patients with inflammatory and non-inflammatory diseases. Clin Biochem. 2016 May;49(7-8):534-7. Abstract available from: https://www.ncbi.nlm.nih.gov/pubmed/?term=26778547
- Silva MC, Furlanetto TW. Does serum 25-hydroxyvitamin D decrease during acute-phase response? A systematic review. Nutr Res. 2015 Feb;35(2):91-6. Abstract available from: https://www.ncbi.nlm.nih.gov/pubmed/?term=25631715
Trending Topic - Recent Research on Vitamin D
Folate During Pregnancy and Autism - A Recent Study
The authors of an exploratory study, observed a strong relationship between pregnant women’s very high plasma levels of folic acid (>59 nmol/L) and vitamin B12 (>600 pmol/L) and the occurrence of autism in their child (HR: 17.59; P value: <0.001). They also observed that taking prenatal vitamin supplements was associated with a lower risk of autism (HR 0.33 to 0.67 - statistically significant for 3-5 times per week consistent with other frequencies but no dose response relationship noted). They concluded that their findings, "warrant additional investigation and highlight the need to identify optimum prenatal folate and vitamin B12 levels that maximize health benefits, at the same time minimize the risk of excess and its associated adverse consequences such as Autism Spectrum Disorder (ASD).”
This work is observational, so it only notes associations, and these associations do not make sense. Due to its observational design this study did not show any cause and effect relationships. Prenatal vitamin supplements contain more folic acid than can be consumed by eating food, so how did these women with the high levels obtain these high levels when folic acid supplementation was associated with protection from autism in their child? It is possible these high levels are a marker of something going on metabolically. The study results do not suggest that the routine supplementation of folic acid to prevent neural tube defects increases the risk of developing autism rather than a nutrition effect.
There are three main areas of concern:
- It is irresponsible to promote a press release prior to following the standard process of scientific discovery which is a peer review of the study by other researchers.
- It is not clear if autism was actually diagnosed in the children or if they were labeled autistic because of parent report since the abstract states that there was a very high rate of autism in the children (7.7%). This high rate raises questions about the accuracy of this study.
- News articles such as CTV News, Excess Folic Acid During Pregnancy Linked to Autism in Children: Study lead to public concern, with many unsure what to do.
More quality research is needed before any claims or change in practice can be recommended. For more information, see an assessment by The Independent in the U.K., Scientists Urge Caution Over 'Alarmist' Claim of Link Between Pregnancy Folate and Autism.
Iodine Deficiency in the U.K.
An editorial on Iodine Deficiency in the U.K.: Grabbing the Low-hanging Fruit recently appeared in The Lancet Diabetes & Endocrinology. While WHO recommends that iodized household salt be the primary source of additional dietary iodine, the U.K. is reluctant to do this. The U.K. Scientific Advisory Committee on Nutrition (SACN) has not updated the U.K. recommendations for iodine during pregnancy considering insufficient evidence is available to justify it. Currently, U.K. educational campaigns focus on increasing awareness of the importance of iodine during pregnancy, and to promote the consumption of iodine-rich foods, such as milk and while fish and supplementation of the mineral. See BDA Food Fact Sheet: Iodine.