Vitamin B9 for COVID-19: real-time meta analysis of 18 studies (12 treatment studies and 6 sufficiency studies)
Control
Abstract
Meta analysis using the most serious outcome reported shows
8% [-18‑41%] higher risk, without reaching statistical significance.
6 sufficiency studies analyze outcomes based on serum levels,
showing 22% [7‑34%] lower risk for patients with higher vitamin B9 levels.
Results to date are contradictory. Several studies show higher mortality, however counfounding by indication may be significant — patients prescribed folic acid may have significantly higher risk on average. Studies independent of prescriptions based on patient condition show positive results1,2, as do sufficiency studies. Folic acid may not be the most effective or safest form for supplementation3. Studies show that a significant fraction of people have genetic variations limiting the ability to convert folic acid to the active form.
All data and sources to reproduce this analysis are in the appendix.
Vitamin B9 for COVID-19 — Highlights
Meta analysis of studies to date shows no significant improvements with vitamin B9.
Results are contradictory. Several studies show higher mortality, however counfounding by indication may be significant — patients prescribed folic acid may have higher risk on average. Folic acid may not be the best form for treatment.
Real-time updates and corrections with a consistent protocol for 161 treatments. Outcome specific analysis and combined evidence from all studies including treatment delay, a primary confounding factor.
Figure 1.
A. Random effects
meta-analysis. This plot shows pooled effects,
see the specific outcome analyses for individual outcomes.
Analysis validating pooled outcomes for
COVID-19 can be found below.
Effect extraction is pre-specified, using the most serious outcome reported.
For details see the appendix.
B. Timeline of results in vitamin B9 studies.
SARS-CoV-2 infection primarily begins in the upper respiratory
tract and may progress to the lower respiratory tract, other tissues, and the
nervous and cardiovascular systems, which may lead to cytokine storm,
pneumonia, ARDS, neurological injury4-16 and
cognitive deficits7,12, cardiovascular
complications17-21, organ failure, and death.
Minimizing replication as early as possible is recommended.
SARS-CoV-2 infection and replication involves the complex interplay of 100+
host and viral proteins and other factorsA,22-29, providing many
therapeutic targets for which many existing compounds have known activity.
Scientists have predicted that over 9,000 compounds may
reduce COVID-19 risk30, either by
directly minimizing infection or replication, by supporting immune system
function, or by minimizing secondary complications.
Vitamin B9 has been identified by the European Food Safety Authority (EFSA) as having sufficient evidence for a causal relationship between intake and optimal immune system function31-33.
Vitamin B9 inhibits SARS-CoV-2 In Silico34-42, reduces spike protein binding ability34, binds with the spike protein receptor binding domain for alpha and omicron variants43, inhibits the SARS-CoV-2 nucleocapsid protein41, inhibits 3CLpro and PLpro in enzymatic assays43, significantly reduces infection for alpha and omicron SARS-CoV-2 pseudoviruses43, and inhibits ACE2 expression and SARS-CoV-2 infection in a mouse model34.
We analyze all significant
controlled studies of
vitamin B9
for COVID-19.
Search methods, inclusion criteria, effect extraction criteria (more serious
outcomes have priority), all individual study data, PRISMA answers, and
statistical methods are detailed in Appendix 1. We present random
effects meta-analysis results for all studies, individual outcomes, and Randomized Controlled Trials (RCTs).
Figure 2 shows stages of possible treatment for
COVID-19. Prophylaxis refers to regularly taking medication before
becoming sick, in order to prevent or minimize infection. Early
Treatment refers to treatment immediately or soon after symptoms appear,
while Late Treatment refers to more delayed treatment.
Figure 2. Treatment stages.
Vitamin B9 inhibits SARS-CoV-2 In Silico34-42, reduces spike protein binding ability34, binds with the spike protein receptor binding domain for alpha and omicron variants43, inhibits the SARS-CoV-2 nucleocapsid protein41, inhibits 3CLpro and PLpro in enzymatic assays43, significantly reduces infection for alpha and omicron SARS-CoV-2 pseudoviruses43, and inhibits ACE2 expression and SARS-CoV-2 infection in a mouse model34.
An In Vivo animal study supports the efficacy of vitamin B934.
Preclinical research is an important part of the development of
treatments, however results may be very different in clinical trials.
Preclinical results are not used in this paper.
Table 1 summarizes the results for all studies, for Randomized Controlled Trials, and for specific outcomes.
Figure 3, 4, 5, 6, 7, 8, and 9
show forest plots for random effects meta-analysis of
all studies with pooled effects, mortality results, ventilation, ICU admission, hospitalization, cases, and sufficiency studies.
| Improvement | Studies | Patients | Authors | |
|---|---|---|---|---|
| All studies | -8% [-41‑18%] | 12 | 54,954 | 190 |
| Randomized Controlled TrialsRCTs | 88% [64‑96%] *** | 1 | 363 | 9 |
| Mortality | -53% [-140‑2%] | 6 | 34,077 | 61 |
| Cases | 7% [-24‑31%] | 6 | 18,729 | 131 |
Figure 3. Random effects meta-analysis for all studies.
This plot shows pooled effects,
see the specific outcome analyses for individual outcomes.
Analysis validating pooled outcomes for
COVID-19 can be found below.
Effect extraction is pre-specified, using the most serious outcome reported.
For details see the appendix.
Figure 4. Random effects meta-analysis for mortality results.
Figure 5. Random effects meta-analysis for ventilation.
Figure 6. Random effects meta-analysis for ICU admission.
Figure 7. Random effects meta-analysis for hospitalization.
Figure 8. Random effects meta-analysis for cases.
Figure 10 shows a forest plot for random
effects meta-analysis of all Randomized Controlled Trials.
RCT results are included in Table 1.
Currently there is only one RCT.
Figure 10. Random effects meta-analysis for all Randomized Controlled Trials.
This plot shows pooled effects,
see the specific outcome analyses for individual outcomes.
Analysis validating pooled outcomes for
COVID-19 can be found below.
Effect extraction is pre-specified, using the most serious outcome reported.
For details see the appendix.
RCTs help to make study groups more similar and can provide a higher level of
evidence, however they are subject to many biases45, and
analysis of double-blind RCTs has identified extreme levels of bias46.
For COVID-19, the overhead may delay treatment, dramatically compromising
efficacy; they may encourage monotherapy for simplicity at the cost of
efficacy which may rely on combined or synergistic effects; the participants
that sign up may not reflect real world usage or the population that benefits
most in terms of age, comorbidities, severity of illness, or other factors;
standard of care may be compromised and unable to evolve quickly based on
emerging research for new diseases; errors may be made in randomization and
medication delivery; and investigators may have hidden agendas or vested
interests influencing design, operation, analysis, reporting, and the
potential for fraud. All of these biases have been observed with COVID-19
RCTs. There is no guarantee that a specific RCT provides a higher level of
evidence.
RCTs are expensive and many RCTs are funded
by pharmaceutical companies or interests closely aligned with pharmaceutical
companies. For COVID-19, this creates an incentive to show efficacy for
patented commercial products, and an incentive to show a lack of efficacy for
inexpensive treatments. The bias is expected to be significant, for example
Als-Nielsen et al. analyzed 370 RCTs from Cochrane reviews, showing that
trials funded by for-profit organizations were 5 times more likely to
recommend the experimental drug compared with those funded by nonprofit
organizations. For COVID-19, some major philanthropic organizations are
largely funded by investments with extreme conflicts of interest for and
against specific COVID-19 interventions.
High quality RCTs for novel acute diseases are more challenging, with
increased ethical issues due to the urgency of treatment, increased risk due
to enrollment delays, and more difficult design with a rapidly evolving
evidence base. For COVID-19, the most common site of initial infection is the
upper respiratory tract. Immediate treatment is likely to be most successful
and may prevent or slow progression to other parts of the body. For a
non-prophylaxis RCT, it makes sense to provide treatment in advance and
instruct patients to use it immediately on symptoms, just as some governments
have done by providing medication kits in advance. Unfortunately, no RCTs have
been done in this way. Every treatment RCT to date involves delayed treatment.
Among the 161 treatments we have analyzed,
66% of RCTs involve very late treatment 5+ days after
onset. No non-prophylaxis COVID-19 RCTs match the potential real-world use of
early treatments. They may more accurately represent results for treatments
that require visiting a medical facility, e.g., those requiring intravenous
administration.
Currently, 53 of the treatments we analyze show statistically significant efficacy or harm, defined as ≥10% decreased risk or >0% increased risk from ≥3 studies. Of these, 58% have been confirmed in RCTs, with a mean delay of 7.8 months (66% with 8.9 months delay for low-cost treatments). The remaining treatments either have no RCTs, or the point estimate is consistent.
We need to evaluate each trial on its own merits. RCTs for a
given medication and disease may be more reliable, however they may also be
less reliable. For off-patent medications, very high conflict of interest
trials may be more likely to be RCTs, and more likely to be large trials that
dominate meta analyses.
Heterogeneity in COVID-19 studies arises from many factors including:
The time between infection or the onset of symptoms and
treatment may critically affect how well a treatment works. For example an
antiviral may be very effective when used early but may not be effective in
late stage disease, and may even be harmful. Oseltamivir, for example, is
generally only considered effective for influenza when used within 0-36 or
0-48 hours48,49. Baloxavir marboxil studies for influenza
also show that treatment delay is critical — Ikematsu et al. report
an 86% reduction in cases for post-exposure prophylaxis, Hayden et al.
show a 33 hour reduction in the time to alleviation of symptoms for treatment
within 24 hours and a reduction of 13 hours for treatment within 24-48 hours,
and Kumar (B) et al. report only 2.5 hours improvement for inpatient
treatment.
| Treatment delay | Result |
| Post-exposure prophylaxis | 86% fewer cases50 |
| <24 hours | -33 hours symptoms51 |
| 24-48 hours | -13 hours symptoms51 |
| Inpatients | -2.5 hours to improvement52 |
Figure 11 shows a mixed-effects meta-regression for efficacy
as a function of treatment delay in COVID-19 studies from 161 treatments, showing
that efficacy declines rapidly with treatment delay. Early treatment is
critical for COVID-19.
Figure 11. Early treatment is more effective. Meta-regression showing efficacy as a function of treatment delay in COVID-19 studies from 161 treatments.
Details of the patient population including age and comorbidities may
critically affect how well a treatment works. For example, many COVID-19
studies with relatively young low-comorbidity patients show all patients
recovering quickly with or without treatment. In such cases, there is little
room for an effective treatment to improve results, for example as in
López-Medina et al.
Efficacy may depend critically on the distribution of
SARS-CoV-2 variants encountered by patients. Risk varies significantly across
variants54, for example the Gamma variant shows significantly
different characteristics55-58. Different
mechanisms of action may be more or less effective depending on variants, for
example the degree to which TMPRSS2 contributes to viral entry can differ
across variants59,60.
Effectiveness may depend strongly on the dosage and treatment regimen.
The quality of medications may vary significantly between
manufacturers and production batches, which may significantly affect efficacy
and safety. Williams et al. analyze ivermectin from 11 different sources,
showing highly variable antiparasitic efficacy across different manufacturers.
Xu et al. analyze a treatment from two different manufacturers, showing 9
different impurities, with significantly different concentrations for each
manufacturer.
Across all
studies there is a strong association between different outcomes, for example
improved recovery is strongly associated with lower mortality. However,
efficacy may differ depending on the effect measured, for example a treatment
may be more effective against secondary complications and have minimal effect
on viral clearance.
The
distribution of studies will alter the outcome of a meta analysis. Consider a
simplified example where everything is equal except for the treatment delay,
and effectiveness decreases to zero or below with increasing delay. If there
are many studies using very late treatment, the outcome may be negative, even
though early treatment is very effective.
All meta analyses combine heterogeneous studies, varying in population,
variants, and potentially all factors above, and therefore may obscure
efficacy by including studies where treatment is less effective. Generally, we
expect the estimated effect size from meta analysis to be less than that for
the optimal case.
Looking at all studies is valuable for providing an overview of all research,
important to avoid cherry-picking, and informative when a positive result is
found despite combining less-optimal situations. However, the resulting
estimate does not apply to specific cases such as
early treatment in high-risk populations.
While we present results for all studies, we also present treatment time and
individual outcome analyses, which may be more informative for specific use
cases.
For COVID-19, delay in clinical results translates into
additional death and morbidity, as well as additional economic and societal
damage. Combining the results of studies reporting different outcomes is
required.
There may be no mortality in a trial with low-risk patients,
however a reduction in severity or improved viral clearance may translate
into lower mortality in a high-risk population.
Different studies may report lower severity, improved recovery, and lower mortality,
and the significance may be very high when combining the results.
"The studies reported different outcomes" is not a good reason for
disregarding results.
Pooling the results of studies reporting different outcomes allows us to use
more of the available information. Logically we should, and do, use additional
information when evaluating treatments—for example dose-response and
treatment delay-response relationships provide additional evidence of efficacy
that is considered when reviewing the evidence for a treatment.
We present both specific outcome and pooled analyses.
In order to combine the results of studies reporting different outcomes we use
the most serious outcome reported in each study, based on the thesis that
improvement in the most serious outcome provides comparable measures of
efficacy for a treatment. A critical advantage of this approach is
simplicity and transparency.
There are many other ways to combine evidence for different outcomes, along
with additional evidence such as dose-response relationships, however these
increase complexity.
Trials with high-risk patients may be restricted due to ethics for treatments
that are known or expected to be effective, and they increase difficulty for
recruiting. Using less severe outcomes as a proxy for more serious outcomes
allows faster and safer collection of evidence.
For many COVID-19 treatments, a reduction in mortality logically
follows from a reduction in hospitalization, which follows from a reduction in
symptomatic cases, which follows from a reduction in PCR positivity. We can
directly test this for COVID-19.
Analysis of the the association between different outcomes across studies from
all 161
treatments we cover confirms the validity of pooled outcome analysis for COVID-19.
Figure 12 shows that lower hospitalization is very strongly associated
with lower mortality (p < 0.000000000001).
Similarly, Figure 13 shows that improved recovery is very strongly associated
with lower mortality (p < 0.000000000001).
Considering the extremes, Singh et al. show an association between viral clearance and
hospitalization or death, with p = 0.003 after excluding one large
outlier from a mutagenic treatment, and based on 44 RCTs including 52,384
patients.
Figure 14 shows that improved viral clearance is strongly associated
with fewer serious outcomes. The association is very similar to
Singh et al., with higher confidence due to the larger number of
studies. As with Singh et al., the confidence increases
when excluding the outlier treatment, from p = 0.00000011 to p = 0.0000000048.
Figure 12. Lower hospitalization is associated with lower mortality, supporting pooled outcome analysis.
Figure 13. Improved recovery is associated with lower mortality, supporting pooled outcome analysis.
Figure 12. Improved viral clearance is associated with fewer serious outcomes, supporting pooled outcome analysis.
Currently, 53 of the treatments we analyze show statistically significant efficacy or harm, defined as ≥10% decreased risk or >0% increased risk from ≥3 studies. 90% of these have been confirmed with one or more specific outcomes, with a mean delay of 4.8 months. When restricting to RCTs only, 55% of treatments showing statistically significant efficacy/harm with pooled effects have been confirmed with one or more specific outcomes, with a mean delay of 7.3 months.
Figure 15 shows when treatments were found effective during the
pandemic. Pooled outcomes often resulted in earlier detection of efficacy.
Figure 15. The time when studies showed that
treatments were effective, defined as statistically significant improvement of
≥10% from ≥3 studies.
Pooled results typically show efficacy earlier than specific
outcome results. Results from all studies often shows efficacy much earlier
than when restricting to RCTs.
Results reflect conditions as used in trials to date, these depend on the
population treated, treatment delay, and treatment regimen.
Pooled analysis could hide efficacy, for example a treatment that is
beneficial for late stage patients but has no effect on viral clearance may
show no efficacy if most studies only examine viral clearance. In practice, it
is rare for a non-antiviral treatment to report viral clearance and to not
report clinical outcomes; and in practice other sources of heterogeneity such
as difference in treatment delay is more likely to hide efficacy.
Analysis validates the use of pooled effects and shows significantly faster
detection of efficacy on average.
However, as with all meta analyses, it is important to review the different
studies included. We also present individual outcome analyses, which may be
more informative for specific use cases.
Publishing is often biased
towards positive results, however evidence suggests that there may be a negative bias for
inexpensive treatments for COVID-19. Both negative and positive results are
very important for COVID-19, media in many countries prioritizes negative
results for inexpensive treatments (inverting the typical incentive for
scientists that value media recognition), and there are many reports of
difficulty publishing positive results81-84.
For vitamin B9, there is currently not
enough data to evaluate publication bias with high confidence.
Funnel
plots have traditionally been used for analyzing publication bias. This is
invalid for COVID-19 acute treatment trials — the underlying assumptions
are invalid, which we can demonstrate with a simple example. Consider a set of
hypothetical perfect trials with no bias. Figure 16 plot A
shows a funnel plot for a simulation of 80 perfect trials, with random group
sizes, and each patient's outcome randomly sampled (10% control event
probability, and a 30% effect size for treatment). Analysis shows no asymmetry
(p > 0.05). In plot B, we add a single typical variation in COVID-19 treatment
trials — treatment delay. Consider that efficacy varies from 90% for
treatment within 24 hours, reducing to 10% when treatment is delayed 3 days.
In plot B, each trial's treatment delay is randomly selected. Analysis now
shows highly significant asymmetry, p < 0.0001, with six variants of
Egger's test all showing p < 0.0585-92.
Note that these tests fail even though treatment delay is uniformly
distributed. In reality treatment delay is more complex — each trial has
a different distribution of delays across patients, and the distribution
across trials may be biased (e.g., late treatment trials may be more common).
Similarly, many other variations in trials may produce asymmetry, including
dose, administration, duration of treatment, differences in SOC,
comorbidities, age, variants, and bias in design, implementation, analysis,
and reporting.
Figure 16. Example funnel plot analysis for simulated perfect trials.
Pharmaceutical drug
trials often have conflicts of interest whereby sponsors or trial staff have a
financial interest in the outcome being positive. Vitamin B9 for COVID-19
lacks this because it is off-patent, has multiple manufacturers, and is very low cost.
In contrast, most COVID-19 vitamin B9 trials have been run by
physicians on the front lines with the primary goal of finding the best
methods to save human lives and minimize the collateral damage caused by
COVID-19. While pharmaceutical companies are careful to run trials under
optimal conditions (for example, restricting patients to those most likely to
benefit, only including patients that can be treated soon after onset when
necessary, and ensuring accurate dosing), not all vitamin B9 trials
represent the optimal conditions for efficacy.
Summary statistics from
meta analysis necessarily lose information. As with all meta analyses, studies
are heterogeneous, with differences
in treatment delay, treatment regimen, patient demographics, variants,
conflicts of interest, standard of care, and other factors. We provide analyses for specific
outcomes and by treatment delay, and we aim to identify key characteristics in
the forest plots and summaries. Results should be viewed in the context of
study characteristics.
Some analyses classify treatment based on early or late
administration, as done here, while others distinguish between mild, moderate,
and severe cases. Viral load does not indicate degree of symptoms — for
example patients may have a high viral load while being asymptomatic. With
regard to treatments that have antiviral properties, timing of treatment is
critical — late administration may be less helpful regardless of
severity.
Details of treatment delay per patient is often not available.
For example, a study may treat 90% of patients relatively early, but the
events driving the outcome may come from 10% of patients treated very late.
Our 5 day cutoff for early treatment may be too conservative, 5 days may be too late in many cases.
Comparison across treatments is confounded by differences in
the studies performed, for example dose, variants, and conflicts of interest.
Trials with conflicts of interest may use designs better suited to the
preferred outcome.
In some cases, the most serious outcome has very few events,
resulting in lower confidence results being used in pooled analysis, however
the method is simpler and more transparent. This is less critical as the
number of studies increases. Restriction to outcomes with sufficient power may
be beneficial in pooled analysis and improve accuracy when there are few
studies, however we maintain our pre-specified method to avoid any
retrospective changes.
Studies show that combinations of treatments can be highly
synergistic and may result in many times greater efficacy than individual
treatments alone63-79.
Therefore standard of care may be critical and benefits may diminish or
disappear if standard of care does not include certain treatments.
This real-time analysis is constantly updated based on
submissions. Accuracy benefits from widespread review and submission of
updates and corrections from reviewers. Less popular treatments may receive
fewer reviews.
No treatment or intervention is 100% available and
effective for all current and future variants. Efficacy may vary significantly
with different variants and within different populations. All treatments have
potential side effects. Propensity to experience side effects may be predicted
in advance by qualified physicians. We do not provide medical advice. Before
taking any medication, consult a qualified physician who can compare all
options, provide personalized advice, and provide details of risks and
benefits based on individual medical history and situations.
1 of 12 studies
combine treatments. The results of
vitamin B9
alone may differ.
None of the RCTs use combined treatment.
Currently all studies are peer-reviewed.
Srivastava et al. also suggests potential benefits of
vitamin B9 for COVID-19. We have not reviewed this paper in
detail.
SARS-CoV-2 infection and replication involves a complex
interplay of 100+ host and viral proteins and other
factors22-29, providing many therapeutic
targets.
Over 9,000 compounds have been predicted to reduce COVID-19
risk30, either by directly
minimizing infection or replication, by supporting immune system function, or
by minimizing secondary complications.
Figure 17 shows an overview of the results for vitamin B9
in the context of multiple COVID-19 treatments, and Figure 18 shows a plot
of efficacy vs. cost for COVID-19 treatments.
Figure 17.
Scatter plot showing results within the context of multiple COVID-19 treatments.
Diamonds shows the results of random effects meta-analysis.
0.6% of 9,000+ proposed treatments show efficacy106.
Figure 18. Efficacy vs. cost for COVID-19 treatments.
Meta analysis using the most serious outcome reported shows
8% [-18‑41%] higher risk, without reaching statistical significance.
6 sufficiency studies analyze outcomes based on serum levels,
showing 22% [7‑34%] lower risk for patients with higher vitamin B9 levels.
Results to date are contradictory. Several studies show higher mortality, however counfounding by indication may be significant — patients prescribed folic acid may have significantly higher risk on average. Studies independent of prescriptions based on patient condition show positive results1,2, as do sufficiency studies. Folic acid may not be the most effective or safest form for supplementation3. Studies show that a significant fraction of people have genetic variations limiting the ability to convert folic acid to the active form.
Retrospective 81 pyschiatric inpatients in the UK, mean age 76, showing no significant difference in COVID-19 mortality with folate deficiency.
Retrospective 10,000 adults in Qatar, showing higher risk of COVID-19 cases with vitamin B9 supplementation, without statistical significance. Authors do not analyze COVID-19 severity.
Retrospective 9,748 COVID-19 patients in the USA showing no significant differences with vitamin B9 use, without statistical significance.
Retrospective 8,570 individuals in Spain and Italy, showing higher mortality with combined vitamin B9 and B12 supplementation. Adjustments only considered age.
Analysis of 7,766 adults in France, showing higher intakes of vitamin C, folate, vitamin K, dietary fibre, and fruit and vegetables associated with lower seropositivity.
Retrospective 70 COVID-19 cases and 70 non-COVID-19 controls in Turkey, showing no significant differences based on folic acid levels.
Cluster RCT 526 healthcare workers in Egypt, showing lower COVID-19 cases with folic acid supplementation, and a dose-response relationship. Each wave of health care workers was randomized within 14 day isolation periods, introducing potential confounding by time.
Retrospective 529 hospitalized COVID-19 patients in Turkey showing lower serum folic acid levels associated with longer hospitalization and higher mortality. Folic acid deficiency and insufficiency were common. There was no significant association for vitamin B12 levels and outcomes. Authors hypothesize that folic acid may support the immune response against SARS-CoV-2 and reduce inflammation.
Retrospective 15,968 COVID-19 hospitalized patients in Spain, showing no significant difference in mortality with existing use of folic acid. Since only hospitalized patients are included, results do not reflect different probabilities of hospitalization across treatments.
Retrospective 26,121 cases and 2,369,020 controls ≥65yo in Canada, showing no significant difference in cases with chronic use of vitamin B9.
Retrospective 333 hospitalized patients in Israel, showing no significant difference in outcomes with low folate levels or with folic acid supplementation.
Retrospective 60 hospitalized pediatric COVID-19 patients showing deficiencies in vitamin D, folic acid (B9), zinc, and selenium associated with higher mortality.
PSM retrospective 3,712 hospitalized patients in Spain, showing lower mortality with existing use of azithromycin, bemiparine, budesonide-formoterol fumarate, cefuroxime, colchicine, enoxaparin, ipratropium bromide, loratadine, mepyramine theophylline acetate, oral rehydration salts, and salbutamol sulphate, and higher mortality with acetylsalicylic acid, digoxin, folic acid, mirtazapine, linagliptin, enalapril, atorvastatin, and allopurinol.
Retrospective 2,148 COVID-19 recovered patients in Jordan, showing lower risk of severity and hospitalization with vitamin B9 prophylaxis, without statistical significance.
UK Biobank retrospective showing higher cases and mortality with folic acid supplementation.
Prospective study of 57 consecutive hospitalized COVID-19 patients in Switzerland, showing lower risk of mortality/ICU admission with vitamin B9. Adjustments only considered age.
Retrospective 600 pregnant women in an urban area of China showing a significantly lower risk of SARS-CoV-2 infection in late pregnancy with higher gestational ozone exposure levels. Ozone exposure, driven by photochemical reactions, is strongly correlated with sunlight in this urban population. There was a non-significant trend towards lower risk of COVID-19 with folic acid supplementation.
We perform ongoing searches of PubMed, medRxiv, Europe PMC,
ClinicalTrials.gov, The Cochrane Library, Google Scholar, Research
Square, ScienceDirect, Oxford University Press, the reference lists of other
studies and meta-analyses, and submissions to the site c19early.org.
Search terms are vitamin B9 and COVID-19 or SARS-CoV-2. Automated searches are performed twice daily, with all matches reviewed for inclusion.
All studies regarding the use of vitamin B9 for COVID-19 that report
a comparison with a control group are included in the main analysis.
This is a living analysis and is updated regularly.
We extracted effect sizes and associated data from all studies.
If studies report multiple kinds of effects then the most serious
outcome is used in pooled analysis, while other outcomes are included in the
outcome specific analyses. For example, if effects for mortality and cases are
both reported, the effect for mortality is used, this may be different to the
effect that a study focused on.
If symptomatic
results are reported at multiple times, we used the latest time, for example
if mortality results are provided at 14 days and 28 days, the results at 28
days have preference. Mortality alone is preferred over combined outcomes.
Outcomes with zero events in both arms are not used, the next most serious
outcome with one or more events is used. For example, in low-risk populations
with no mortality, a reduction in mortality with treatment is not possible,
however a reduction in hospitalization, for example, is still valuable.
Clinical outcomes are considered more important than viral test status. When
basically all patients recover in both treatment and control groups,
preference for viral clearance and recovery is given to results mid-recovery
where available. After most or all patients have recovered there is little or
no room for an effective treatment to do better, however faster recovery is
valuable.
If only individual symptom data is available, the most serious symptom has
priority, for example difficulty breathing or low SpO2 is more
important than cough.
When results provide an odds ratio, we compute the relative risk when
possible, or convert to a relative risk according to107.
Reported confidence intervals and p-values were used when available,
using adjusted values when provided. If multiple types of adjustments are
reported propensity score matching and multivariable regression has preference
over propensity score matching or weighting, which has preference over
multivariable regression. Adjusted results have preference over unadjusted
results for a more serious outcome when the adjustments significantly alter
results. When needed, conversion between reported p-values and
confidence intervals followed Altman, Altman (B), and Fisher's exact
test was used to calculate p-values for event data. If continuity
correction for zero values is required, we use the reciprocal of the opposite
arm with the sum of the correction factors equal to 1110.
Results are expressed with RR < 1.0 favoring treatment, and using the risk of
a negative outcome when applicable (for example, the risk of death rather than
the risk of survival). If studies only report relative continuous values such
as relative times, the ratio of the time for the treatment group versus the
time for the control group is used. Calculations are done in Python
(3.13.3) with
scipy (1.15.3), pythonmeta (1.26), numpy (2.2.6), statsmodels (0.14.4), and plotly (6.0.1).
Forest plots are computed using PythonMeta111
with the DerSimonian and Laird random effects model (the fixed effect
assumption is not plausible in this case) and inverse variance weighting.
Results are presented with 95% confidence intervals. Heterogeneity among studies was
assessed using the I2 statistic.
Mixed-effects meta-regression results are computed with R (4.4.0) using the metafor
(4.6-0) and rms (6.8-0) packages, and using the most serious sufficiently powered outcome.
For all statistical tests, a p-value less than 0.05 was considered statistically significant.
Grobid 0.8.2 is used to parse PDF documents.
We have classified studies as early treatment if most patients
are not already at a severe stage at the time of treatment (for example based
on oxygen status or lung involvement), and treatment started within 5 days of
the onset of symptoms. If studies contain a mix of early treatment and late
treatment patients, we consider the treatment time of patients contributing
most to the events (for example, consider a study where most patients are
treated early but late treatment patients are included, and all mortality
events were observed with late treatment patients).
We note that a shorter time may be preferable. Antivirals are typically only
considered effective when used within a shorter timeframe, for example 0-36 or
0-48 hours for oseltamivir, with longer delays not being effective48,49.
We received no funding, this research is done in our spare
time. We have no affiliations with any pharmaceutical companies or political
parties.
A summary of study results is below. Please submit
updates and corrections at https://c19early.org/b9meta.html.
Effect extraction follows pre-specified rules as detailed above
and gives priority to more serious outcomes.
For pooled analyses, the first (most serious) outcome is used, which may
differ from the effect a paper focuses on.
Other outcomes are used in outcome specific analyses.
Effect extraction follows pre-specified rules as detailed above
and gives priority to more serious outcomes.
For pooled analyses, the first (most serious) outcome is used, which may
differ from the effect a paper focuses on.
Other outcomes are used in outcome specific analyses.
| Akbar, 11/7/2023, retrospective, Qatar, peer-reviewed, mean age 40.3, 9 authors, study period March 2020 - September 2020. | risk of case, 18.0% higher, OR 1.18, p = 0.29, treatment 316, control 9,684, adjusted per study, multivariable, model 2, RR approximated with OR. |
| Bejan, 2/28/2021, retrospective, USA, peer-reviewed, mean age 42.0, 6 authors. | risk of death, 9.0% lower, OR 0.91, p = 0.87, treatment 353, control 8,853, adjusted per study, RR approximated with OR. |
| risk of mechanical ventilation, 1.0% lower, OR 0.99, p = 0.99, treatment 355, control 8,874, adjusted per study, RR approximated with OR. | |
| risk of ICU admission, 17.0% lower, OR 0.83, p = 0.70, treatment 356, control 8,911, adjusted per study, RR approximated with OR. | |
| Bliek-Bueno, 11/10/2021, retrospective, multiple countries, peer-reviewed, mean age 67.7, 15 authors, study period 4 March, 2020 - 17 April, 2020, this trial uses multiple treatments in the treatment arm (combined with Vitamin B12) - results of individual treatments may vary. | risk of death, 87.4% higher, OR 1.87, p < 0.001, combined, RR approximated with OR. |
| risk of death, 170.0% higher, OR 2.70, p < 0.001, Campania, RR approximated with OR. | |
| risk of death, 59.0% higher, OR 1.59, p < 0.001, Aragon, RR approximated with OR. | |
| Deschasaux-Tanguy, 11/30/2021, retrospective, France, peer-reviewed, 95 authors. | risk of case, 16.0% lower, OR 0.84, p = 0.02, RR approximated with OR, per standard deviation change. |
| Farag, 11/20/2022, Cluster Randomized Controlled Trial, Egypt, peer-reviewed, mean age 37.5, 9 authors, study period 17 May, 2020 - 30 June, 2020, trial PACTR202005599385499. | risk of case, 87.6% lower, RR 0.12, p < 0.001, treatment 4 of 224 (1.8%), control 20 of 139 (14.4%), NNT 7.9, 1000µg. |
| risk of case, 65.9% lower, RR 0.34, p = 0.005, treatment 8 of 163 (4.9%), control 20 of 139 (14.4%), NNT 11, 500µg. | |
| Loucera, 8/16/2022, retrospective, Spain, peer-reviewed, 8 authors, study period January 2020 - November 2020. | risk of death, 1.5% lower, HR 0.99, p = 0.88, treatment 624, control 15,344, Cox proportional hazards, day 30. |
| MacFadden, 3/29/2022, retrospective, Canada, peer-reviewed, 9 authors, study period 15 January, 2020 - 31 December, 2020. | risk of case, no change, OR 1.00, p = 1.00, RR approximated with OR. |
| Meisel, 3/2/2021, retrospective, Israel, peer-reviewed, 8 authors, study period 27 January, 2020 - 23 November, 2020. | risk of death, 27.0% lower, OR 0.73, p = 0.54, treatment 23, control 310, RR approximated with OR. |
| risk of death/intubation, 6.0% lower, OR 0.94, p = 0.88, treatment 23, control 310, RR approximated with OR. | |
| Monserrat Villatoro, 1/8/2022, retrospective, propensity score matching, Spain, peer-reviewed, 18 authors. | risk of death, 132.0% higher, OR 2.32, p = 0.003, RR approximated with OR. |
| Nimer, 2/28/2022, retrospective, Jordan, peer-reviewed, survey, 4 authors, study period March 2021 - July 2021. | risk of hospitalization, 27.7% lower, RR 0.72, p = 0.23, treatment 16 of 213 (7.5%), control 203 of 1,935 (10.5%), NNT 34, adjusted per study, odds ratio converted to relative risk, multivariable. |
| risk of severe case, 28.2% lower, RR 0.72, p = 0.16, treatment 19 of 213 (8.9%), control 241 of 1,935 (12.5%), NNT 28, adjusted per study, odds ratio converted to relative risk, multivariable. | |
| Topless, 8/24/2022, retrospective, United Kingdom, peer-reviewed, 6 authors. | risk of death, 164.0% higher, OR 2.64, p < 0.001, adjusted per study, multivariable, model 2, RR approximated with OR. |
| risk of case, 51.0% higher, OR 1.51, p < 0.001, adjusted per study, multivariable, model 2, RR approximated with OR. | |
| Zhang (B), 12/20/2024, retrospective, China, peer-reviewed, 3 authors, study period 3 November, 2022 - 6 January, 2023. | risk of case, 40.0% lower, OR 0.60, p = 0.23, treatment 566, control 34, RR approximated with OR. |
Viral infection and replication involves attachment, entry, uncoating and release, genome replication and transcription, translation and protein processing, assembly and budding, and release. Each step can be disrupted by therapeutics.
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