ALERT! New Study Warns That Vitamin B9 or Folic Acid Supplementation Can Actually Increase Risk Of SARS-CoV-2 Infection By 1.5 Times And Mortality By 2.6 Times!

A new study by researchers from University of Otago-New Zealand, University of California-Davis-USA, University of Alabama at Birmingham-USA, University of Queensland-Australia and Birmingham VA Medical Center-USA has found that that vitamin B9 or Folic Acid supplementation can actually increase risk of SARS-CoV-2 infection by 1.5 times and mortality by 2.6 times compared to those that do not take these supplements.

According to the study team, “Folate metabolism is implicated in SARS-CoV-2 infectivity. Medication affecting folate metabolism may influence the risk of COVID-19 diagnosis and outcomes.”
 
The main purpose of the study was to determine if methotrexate (an antifolate) or folic acid prescription were associated with differential risk, for COVID-19 diagnosis or mortality.
 
The study involved a case-control analysis of COVID-19 from the population-based UK Biobank (UKBB) cohort. Updated medical information was retrieved on the 13th December 2021. Data from 380,380 UKBB participants with general practice prescription data for 2019 to 2021 were used.
 
Criteria for COVID-19 diagnosis were 1) a positive SARS-CoV-2 test or 2) ICD-10 code for confirmed COVID-19 (U07.1) or probable COVID-19 (U07.2) in hospital records, or death records. By these criteria 26,003 individuals were identified with COVID-19 of whom 820 were known to have died from COVID-19. Logistic regression statistical models were adjusted for age sex, ethnicity, Townsend deprivation index, BMI, smoking status, presence of rheumatoid arthritis, sickle cell disease, use of anticonvulsants, statins and iron supplements.
 
All individuals who were prescription of folic acid and/or methotrexate were studied for outcomes. The outcomes of COVID-19 diagnosis and COVID-19 related mortality were analyzed by multivariable logistic regression. The odds ratios from different exposures were compared.
 
The study findings showed that compared with individuals prescribed neither folic acid nor methotrexate, people prescribed folic acid supplementation had increased risk of diagnosis of COVID-19 (OR 1.51 [1.42 ; 1.61]).
 
However, the prescription of methotrexate with or without folic acid was not associated with COVID-19 diagnosis (P≥0.18).
 
Alarmingly, individuals prescribed folic acid supplementation had positive association with death after a diagnosis of COVID-19 (OR 2.64 [2.15 ; 3.24]) in a fully adjusted model.
 
The prescription of methotrexate in combination with folic acid was not associated with an increased risk for COVID-19 related death (1.07 [0.57 ; 1.98]).
 
The study findings showed an increased risk for COVID-19 diagnosis and COVID-19-related death for people prescribed folic acid supplementation.
 
The study team said, “Prescription and use of supplemental folic acid may confer increased risk of infection with SARS-CoV-2 and increased risk of death resulting from COVID-19. Our results indicate that methotrexate attenuates an increased risk for COVID-19 diagnosis and death conferred by folic acid.”
 
The study findings also contradicted many previous studies that found that folic acid deficiency was responsible for COVID-19 disease severity!
 
The study findings were published on a preprint server and are currently being peer reviewed. https://www.medrxiv.org/content/10.1101/2022.02.10.22270804v1
 
The vitamin B9 also called folic acid/folate has vital functions in one-carbon units transfer in intermediary metabolism in mitochondria. Further, it is involved in various reactions such as methionine production from homocysteine and the synthesis of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA).
 
Methotrexate, a structural analogue of folate has potent antifolate activity and is in widespread use as an antineoplastic agent and as a first-line disease-modifying antirheumatic drug (DMARD) treatment for rheumatoid arthritis (RA).
 
Folic acid (at doses commonly ranging from 1-2 mg daily) or folinic acid supplementation is often included to lower the toxicity of low-dose methotrexate therapy.
 
Past evidence have indicated that folate metabolism is involved in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infectiousness. Hence, medicines affecting folate metabolism may influence the probability of SARS-CoV-2 diagnosis and outcomes, including mortality. https://www.nature.com/articles/s41467-021-21903-z
 
The study team determined whether methotrexate or folic acid prescriptions alone or combined were linked to a higher or lower probability for SARS-CoV-2 diagnosis or associated mortality, respectively, in an extensive population-based cohort from the UK.
 
The study team conducted the case-control investigation of COVID-19 using the population-based UK Biobank (UKBB) cohort. Information, including general practice prescription data for 2019 to 2021, was gathered for 380,380 UKBB participants. Further, updated medical data was retrieved on December 13, 2021.
 
In the study, COVID-19 diagnosis was made using the following criteria: 1) a SARS-CoV-2-positive polymerase chain reaction (PCR) test or 2) 10th revision of International Classification of Diseases (ICD-10) code, U07.1 indicating confirmed SARS-CoV-2, or U07.2 for possible COVID-19 in hospital or death records. Of the 26,003 subjects with COVID-19 identified using the above-mentioned criteria, 820 had COVID-19 as the known cause of death.
 
The compiled data were analyzed by logistic regression statistical models adjusted for gender, age, ethnicity, smoking status, body mass index (BMI), Townsend deprivation index, presence of sickle cell disease, rheumatoid arthritis (RA), use of statins, iron supplements, and anticonvulsants.
 
The study findings indicate that individuals prescribed with folic acid had high chances of COVID-19 diagnosis relative to those without either methotrexate or folic acid.
 
Methotrexate prescription with or without folic acid did not increase the chances of COVID-19 diagnosis since the proportion of methotrexate recipients diagnosed with SARS-CoV-2 was comparable to the individuals who were not taking either of the drugs evaluated in the study.
 
Alarmingly, the study confirmed that individuals in a fully adjusted model taking folic acid supplementation demonstrated a positive association with mortality following the COVID-19 diagnosis.
 
The study finding showed that those consuming folic acid had a 1.5- and 2.6-times risk of COVID-19 diagnosis and SARS-CoV-2-related death, respectively, compared to those who are not on this drug.
 
However, the prescription of methotrexate combined with folic acid did not elevate the risk for COVID-19-associated mortality. Moreover, combining methotrexate with folic acid might reduce the risk of SARS-CoV-2 diagnosis and COVID-19-associated death induced by folic acid since cohorts on folic acid and methotrexate combination had no increased risk of SARS-CoV-2 diagnosis or COVID-19-related death.
 
This study finding indicates that the folate supply enhanced the replication of SARS-CoV-2, and using an antifolate drug like methotrexate potentially reduced this adverse effect.
 
The study team failed to estimate the risk of COVID-19-related mortality in those administering methotrexate alone due to the small size of that cohort.
 
The findings reinforce the hypothesis that high folate levels resulting from folic acid supplementation led to increased chances of acquiring clinically detectable SARS-CoV-2 infection and mortality following COVID-19 diagnosis.
 
It should be noted however, the generalizability of the current findings is limited to individuals older than 45 years and those from White European ethnicities of the UK population.
 
The study findings however provide crucial information for future studies evaluating the impact of folic acid supplementation on COVID-19-associated morbidity and mortality, especially during gestation and individuals on anticonvulsants requiring supplemental folic acid.
 
Despite an excessive level of folic acid increases SARS-CoV-2 replication, as seen in the present study, inadequate folic acid levels might also result in impaired host resistance to SARS-CoV-2 infection as indicated by previous studies.
 
Combining both the observations, an optimal range of physiological folate status may be related to host resistance to SARS-CoV-2 and disease severity.
 
The study findings demonstrate a high risk of SARS-CoV-2 diagnosis and associated death in those taking folic acid than those without this drug and suggests that co-administration of methotrexate with folic acid might attenuate this risk. Further investigations exploring the impact of folate status and folic acid intake on susceptibility to SARS-CoV-2 infection and its fatal complications are warranted.
 
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