Dr Clare Craig

Mandatory folic acid fortification of non-wholemeal wheat flour does not come into force until 13 December 2026 but folic acid has been in the food supply for some time without anyone being informed.

Millers began fortifying flour in September 2025 and by the end of October the vast majority of non-wholemeal wheat flour contained folic acid. That flour has been in bread, cakes, biscuits, batter and thousands of other foods ever since. The labels did not keep up.

The food industry’s own technical advisers told manufacturers that labels needed to change as soon as flour containing added folic acid entered the supply chain. The government said the same thing in 2022. There was no subsequent exemption from the labelling law. Instead, it was documented that it anticipated businesses would breach the law and told enforcement authorities to be proportionate about the resulting “non-compliance”.

The law was already clear

The law already requires prepacked food to carry a list of ingredients. The food labelling regulations state that “indication of the following particulars shall be mandatory: (a) the name of the food; (b) the list of ingredients”. They also state that the list “shall include all the ingredients of the food, in descending order of weight, as recorded at the time of their use in the manufacture of the food”. They further state that “food information shall not be misleading, particularly: (a) as to the characteristics of the food and, in particular, as to its nature, identity, properties, composition”. Government guidance confirms that vitamins and minerals added to flour must be declared in the ingredients list. Defra went further in its consultation response, saying that manufacturers would have to relabel products, “immediately after this is introduced in the product.”

The folic acid was added first

Industry were given two years to prepare for the December 2026 deadline. Millers chose not to wait and folic acid was added from September 2025.

They did not want to waste old packaging. Industry had already warned the government that some manufacturers held more than two years’ worth of packaging stock. UK Flour Millers’ own implementation document acknowledged what would result, “labelling misalignment is expected.”

The government knew consumers could be eating it unknowingly

In 2023, the Department of Health and Social Care asked the Food Standards Agency to assess the danger to people who might react badly to folic acid including from allergies when the folic acid in fortified flour was not declared on the packaging.

The FSA could not find data on how common hypersensitivity to folic acid was in the UK. There was no established allergen reference dose, meaning the standard method of assessing such a risk could not be used. It concluded that reactions would be very rare but could not be excluded, that their severity would be moderate and that there was medium uncertainty around its own assessment. Of course, there is no way of correlating what happened with this prediction because how would someone who had had a bad reaction know it was because of hidden folic acid?

Doesn’t the transition period allow this?

The obvious defence is that the new regulations contain a transitional provision. The regulations do not exempt labelling. The Explanatory Note describes a provision enabling “stocks lawfully placed on the market or labelled before 13th December 2026 to continue to be sold until exhausted”. The note is, in its own words, “not part of the Regulations”. The provision itself, the only transitional provision in the instrument, states that an enforcement officer “must not serve an improvement notice” where the notice “would relate to a product that was placed on the market or labelled before 13th December 2026” and “the matters constituting the alleged contravention would not have constituted an offence under the Bread and Flour Regulations as they applied immediately before 13th December 2026”. There is no mention of labelling, which is governed by the food labelling regulations and enforced separately under the Food Information Regulations 2014. Labelling law therefore still applies.

A formal labelling exemption was considered. In September 2023 the Committee on Toxicity recorded that transitional arrangements could mean a period of up to three months in which folic acid would not be reflected on the label, and that is what the FSA was asked to assess. No such compromise was written into the regulations. Instead we were left with enforcement discretion with no defined end date. The FSA assessment covered only three months. The unlabelled period began in September 2025 and a year on the issue with labelling continues.

From “immediately” to “proportionately”

In 2022, the government told consultees that manufacturers would have to change their labels “immediately” when folic acid was introduced into their products. It reassured consumers that existing labelling law meant they would know when folic acid was present. By March 2025 government guidance was instead discussing the expected “non-compliance”, how long it might last, how the risks might be mitigated and how enforcement authorities should respond to it in a graduated and proportionate way.

The law had not changed and there was no new exemption. All that changed was the government’s willingness to enforce the law.

If the government is willing to tolerate inaccurate ingredient lists because changing packaging is inconvenient or expensive, the obvious question is who are they actually representing?

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Dr Ros Jones

At the beginning of 2020, when the first rumours were circulating of 4 deaths from pneumonia in China (a country of 1.4 billion population), few people would have had any concept of the panic and rushed decisions that would be made only a few weeks later by governments from across the world.

Lockdowns were a novel concept, a word previously associated with prison riots or (in US dictionaries) with children locked into classrooms if a gunman entered the premises. But in no time at all, the likes of Neil Ferguson were noting that Italy had followed China into lockdown so ‘maybe we can get away with it’. Next information from our Chief Medical Officer and Chief Scientific Officer was that a vaccine would probably take 2 or 3 years, and given the low infection fatality rate (<1%) a rushed vaccine could not be justified. The public was initially led to understand that the frail and elderly should stay at home for 12 weeks but that after a short 3-weeks ‘to flatten the curve’ everyone should expect to catch the virus and obtain natural immunity.

But something changed and despite the WHO downgrading the emergency from its initial ‘High Risk’ category, it was suddenly full steam ahead with numerous companies competing to get a vaccine ready to market. The first out of the blocks was BioNTech, a small German biotech company with no products to its name, but who linked up with Pharma giant, Pfizer, to market its new modified mRNA product. Following not far behind was Moderna, also with an mRNA product and AstraZeneca using a viral-vector-DNA system. The mRNA technologies had never been used successfully in humans (Moderna had been trying for decades to make a cancer vaccine but found the lipid nanoparticles (LNPs) required to coat the genetic material to transport it into the cells, were too toxic for repeated dosage in cancer patients. It appears they just hoped that two doses approved under an emergency authorisation might just get them their first success). AZ’s DNA-based system had been used to make an ebola vaccine and a limited amount was used for vaccinating close contacts at very high risk of an infection with a high case fatality rate. Millions of doses were stock-piled in the Democratic Republic of Congo but never rolled out to a healthy population.

A bit further down the road were Valneva, with an inactivated whole virus vaccine and Novavax, using a recombinant spike protein. In Sept 2020, Valneva announced a Major COVID-19 Vaccine Partnership with U.K. Government. For many people worried about the lack of any medium or long-term safety data of the mRNA technology, a standard vaccine looked like a promising option, worth waiting for you might think. An option which, in autumn 2020, I was seriously considering - how times have changed!

By April 2021, we read Valneva Reports Positive Phase 1/2 Data for Its Inactivated, Adjuvanted COVID-19 Vaccine Candidate, VLA200 and Valneva Reports Positive Phase 1/2 Data for Its Inactivated, Adjuvanted COVID-19 Vaccine Candidate, VLA2001. All good you might think and certainly the people of Livingston in Scotland, where the vaccine was due to be made, were enthusiastic. Admittedly the results, like for so many drugs nowadays, were announced by the company rather than published in a peer-review journal.

But then to universal surprise, in Sept 2021, in response to questions from the local Scottish Nationalist Party (SNP) MP, health secretary Sajid Javid stood up in the House of Commons and confirmed the immediate cancellation of the UK’s contract for the Valneva covid vaccine. When asked why, Hansard quoted Mr Javid as saying “There are commercial reasons why we have cancelled the contract, but I can tell her that it was also clear to us that the vaccine in question that the company was developing would not get approval by the Medicines and Healthcare Products Regulatory Agency (MHRA) here in the UK.”

This statement was rebutted later that day by a statement from the MHRA (the UK’s medicines regulatory authority), who reported that the rolling programme of information submitted in the approval process was progressing as expected and they anticipated approval in the next few months. Interestingly, the Hansard report was later corrected to “but I can tell her that it was also clear to us that the vaccine in question that the company was developing has not yet gained approval by the Medicines and Healthcare products Regulatory Agency here in the UK, and may not [do so]”

News reports at the time were generally unquestioning of the reasoning behind the decision Government cancels contract with French vaccine-maker Valneva apart from some dispute about an unspecified agreement breach.

But only one month later in Oct 2021 Valneva Reports Positive Phase 3 Results for Inactivated, Adjuvanted COVID-19 Vaccine Candidate VLA2001.

A BMJ review and subsequent correspondence questioned many aspects of the decision to cancel the contract. Kate Bingham, the erstwhile ‘Vaccine Tsar’, weighed in in Dec 2021 by asserting UK Government ‘short sighted’ to scrap Scottish vaccine contract with Valneva and in Jan 2022 a letter to the BMJ commented that “This significantly raises the question of political interference into MHRA’s processes and predetermined bias, considering the Health Secretary made damaging comments before adequate results are made available.”

The Novavax protein-based vaccine was approved in February 2022 and was used for boosters though always way behind the Pfizer & Moderna market share. Finally, in April 2022 and contrary to Sajid Javid’s negative predictions, regulatory approval of COVID-19 Vaccine Valneva by MHRA went ahead and was followed in quick order by the European Medicines Agency (EMA). By June 2022, Valneva was the first covid-19 vaccine to receive full marketing approval by the EMA.

Valneva’s marketing approval was based on immune testing, i.e. antibody production, rather than any clinical measure of efficacy and there was no placebo, the control group receiving AstraZeneca, which of course had by then been effectively dropped (see above). One likely advantage of Valneva over AstraZeneca (and hence over Pfizer & Moderna too) was a good antibody response to the nuclear capsid protein as well as spike protein, which in theory should give broader cover. Further results from a randomised trial were published in the Lancet in December 2022, reporting that Valneva gave a higher immunoglobulin response than the comparator AstraZeneca in a phase 3 trial.

BBC News Scotland reported in 2023 that the scrapped covid vaccine deal with Valneva cost UK taxpayers £358m. It was not only the UK that cancelled contracts. The EU also dropped out and Valneva ceased production of the covid vaccine after making only 10 million doses and decided to concentrate their efforts on travel vaccines. More recently, they are laying off staff and selling production facilities as travel is down due to the geopolitical climate. Ironically the company has partnered with Pfizer to produce a Lyme disease vaccine - in theory they could flog that to stay-at-home dog walkers.

So this brings me back to the question in the title of this piece. Using the simplest principle of ‘follow the money’, it is clear that Moderna, in particular, and Pfizer to a lesser degree, both had a desperate commercial need for the mRNA vaccines to succeed. Moderna had been investing in modified-RNA research for almost two decades (hence the company’s name), in hopes of producing effective cancer vaccines. But they had never got anything to market, stymied particularly by the toxicity of repeated doses of the coating LNPs. An emergency use authorisation replicated worldwide, gave a perfect opportunity for a poorly tested gene-product to be given to literally billions of people. Lack of proper post-marketing surveillance provided the self-fulfilling prophecy of ‘Safe and Effective’. Sure enough, Moderna acquired UK government funding to build research and production facilities at Harwell near Oxford. This partnership was announced with much fanfare in December 2022 by which time AstraZeneca and Valneva had been shown the door.

If we assume that enforced lockdowns and the trashing of Vitamin D, ivermectin and hydroxychloroquine or even just standard antibiotic use, were required to maintain the demand for an urgent vaccine, then denigrating the slightly slower standard technology product in favour of the all singing all dancing new mRNA drugs would at least be logical.

The logic seems to be working. In 2024, the FDA approved Moderna’s new mRNA-based RSV vaccine, mResvia, although this is not yet licenced in the UK. It was licensed when trial participants had a median of 112 days follow-up, so further safety data post-approval will be vital (though unlikely to occur, judging by post-marketing surveillance or lack of for the covid vaccines). Now in August 2026, mFLUSIVA, Moderna’s mRNA-platform flu vaccine, has gained FDA approval, despite trials showing significantly higher adverse events than the standard technology comparator (grade 3 systemic effects rose 6-fold and deaths were more than doubled). Several other mRNA vaccines are in the pipeline against zika, chikungunya, ebola and heaven knows what else. All presumably following the ‘100 days to market’ aim. Results from a cancer vaccine against melanoma are hailed as promising. Of course, cancer vaccines is where Moderna started. Without prejudging the long-term results, at least in theory the recipients were already sick and in need of some treatment, unlike the huge numbers of healthy young people with irreversible damage from the mRNA covid-19 shots. Meanwhile, BioNTech’s bowel cancer mRNA vaccine trial has just been halted because of “a numerical imbalance in overall survival between the patient groups in the study” (presumably double speak for more deaths in the vaccinated than the placebo group!).

Moderna’s mission is “to deliver the greatest possible impact to people through mRNA medicines.” One can only pray that the impact is for better rather than worse.

As far as I am aware, neither Pfizer nor Moderna have yet carried out the proper carcinogenicity, teratogenicity and reproductive studies which would normally be required for a gene therapy as opposed to the simplified vaccine regulations. Even the basic pharmacology of where does this product go and how long does it persist in instructing the recipient to produce whatever protein it is coded for. Whether it is C-19’s ‘spike protein’ or RSV’s ‘prefusion F’, personally, I would want to see a reliable dose prediction with an OFF switch, before going anywhere near these products.

POSTSCRIPT: If any HART readers have any FOI material on emails etc surrounding the Valneva decision in September 2021, please get in touch. Unfortunately, Sajiv Javid seems to have looked after his diaries more carefully than either Matt Hancock or Anthony Fauci!

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Dr Clare Craig

Key points

• Canada claims the highest reduction in neural tube defects from folic acid fortification anywhere in the developed world – 46 percent.

• The United States with a near-identical programme claimed only 19 to 28 percent.

• The 46 percent comes from one study with no control group.

• The rate of neural tube defects in Canada was already falling steeply year on year but this decline was ignored in their calculations.

• The paper also claims that higher-risk provinces benefited more, but their data does not support this either

There are a wide range of claims of the effectiveness of what are very similar laws mandating folic acid on the reduction in neural tube defects. These range from 14.4 percent in Australia through 19 to 28 percent in USA right up to the bold claim of 46 percent in Canada.

The Canadian claim is based on one study published in the New England Journal of Medicine in 2007 by De Wals et al. It is a large surveillance study looking back at the impact on pregnancies and births. It is worth looking closely at how they reached their claimed figure.

What did they measure?

The investigators identified 2,446 affected pregnancies among about 1.9 million births in seven of the ten provinces between 1993 and 2002. All affected pregnancies were counted including live births, stillbirths and terminations. They selected three periods to examine and reported that incidence was 1.58 per 1,000 births before fortification and 0.86 in the full fortification period. The period when manufacturers made the change was excluded. That is the 46 percent reduction. The claimed fall of 7.3 per 10,000 pregnancies works out at 4.19 fewer terminations, 2.79 fewer affected live births and 0.32 fewer stillbirths.

The baseline

In order to claim something changed there needs to be an estimate of what would have happened otherwise. In this instance they selected a flat baseline from 1993 to 1997 before the law changed. That means they could assume that the rates would not have fallen at all without the government intervention.

The same researcher had already published a paper on the rate of pregnancies affected by NTDs in two regions of Quebec in 1992. De Wals and colleagues recorded the rate as 1.41 per 1,000 in 1992 and described it as a threefold reduction over the preceding three decades.

Yet, the study compared the apparently flat pre-fortification period with the apparently flat post fortification period and ignore the overall decline completely.

There is no national data that includes all pregnancies with which this baseline can be compared. The closest is to compare registered births but these may not be representative of the pregnancies during a time when the rate of terminations changes.

Figure 1: Incidence of neural tube defects at birth (blue line) and incidence in all pregnancies in NEJM study covering 55% of Canadian population (orange line) with 95% confidence intervals.

Falling births

From 1989 to 1997 there was a year on year decline in affected births which was seen across the western world. Roughly half of the decline in affected births from 1989 had happened before the mills changed. Could this have been an increase in terminations? That must be part of the reason. Ultrasound diagnostics was improving and becoming more readily available leading to terminations in early pregnancy.

The more gentle background decline is seen in births with a fall in 1996 and a continuing fall after 2000. Scaling the births to the study data shows this more clearly. If the proportion of affected pregnancies that became live births stayed constant then the two lines should track. The fact the align at the beginning and end of the period suggests this is a fair assumption. The live births figure for the whole country (in orange) shows a gradual decline. The figure from the paper shows a sudden uptick before a steeper decline. Ultimately the whole trajectory ends where you would expect it to if the only decline had been from the background falling rates that were evident before and after the period in question.

Figure 2: The same two series with the birth record scaled up by 72 percent so that the two averages match. Scaling by a single constant assumes that the ratio of pregnancies to births was constant i.e. that the proportion of affected pregnancies ending in termination held steady. Given the alignment at the beginning and end of the period that seems reasonable.

1998 to 2002

Ontario was not included in the study. The total rate of affected pregnancies there rose from 11.7 per 10,000 pregnancies in 1986 to 16.2 in 1995, then fell 47 percent by 1999. The decline began two years before the addition of folic acid began and was completed before the paper’s “full fortification” which started in April 2000.

Given the known earlier fall in Ontario of the same magnitude as the claim which was unrelated to folic acid, questions must be asked about how much of the later fall in the other provinces would have happened anyway.

It is worth noting that miscarriages were excluded from this data. If a woman had a pregnancy loss before a diagnosis then that pregnancy would not be included in the data. There is evidence that folic acid increases pregnancy losses creating an illusion of benefit.

End of the decline

Whatever had been causing the decline before fortification, once folic acid was added that decline ends. The same was seen in USA.

Conclusion

It is fair to say that affected pregnancies reduced during the period folic acid was introduced. However, it is bad science to make a claim of a measurement for that reduction while paying no attention to the underlying background decline. Even with a good measure of the size of the decline, the fact that pregnancy losses increase with folic acid exposure must also be accounted for.

This is “The Science” that Britain is following.

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Dr Clare Craig

Another article addresses the NEJM 2007 paper claiming Canadian neural tube defects fell by 46 percent after folic acid was added to the flour. The main figure is a before and after comparison with no control group to compare. To show causation rather than just correlation de Wals and colleagues reported that the size of the fall in each province was proportional to how high that province’s rate had been beforehand. The implication was that those with more of a problem benefitted the most. It is based on the idea that neural tube defects are caused by a folate deficiency and that adding it to flour brings women to a healthy level.

Figure 2 of the paper showing the strong correlation between the fall in the rate and the starting rate

Testing the correlation

If there was a true correlation then randomly assigning the rate after fortification to different provinces would make the correlation substantially weaker or even fall apart. Give Newfoundland’s result to British Columbia, British Columbia’s to Quebec, and so on. Those with a low starting rate might end up with a high fall and those with a high rate might have a low fall. That is not what happens.

In all 5,040 possible arrangements the correlation stays at 0.949 or above. Putting the real data in gives 0.951, where 1 would mean the two quantities were perfectly related to each other so the same increase in one was always matched by an identical increase in the other and 0 would mean no relationship between them at all. Of all the possible random combinations, 62 percent gave a stronger correlation than the actual data.

The same number is on both axes

The x-axis of Figure 2 shows each province’s rate before fortification. The other plots the fall in the rate i.e. the rate before fortification minus the rate after it. So the starting rate is a part of the number plotted on both axes. Plotting a difference against one of its own components is not always misleading. What makes it misleading in this case is the small size of the number being subtracted.

Before fortification the provincial rates ranged from 0.96 to 4.56. Afterwards they were compressed into a range of 0 to 1.26. Each plotted difference in rate comes from a starting rate which varied widely with a comparatively small number subtracted from it. If we randomly allocate those small numbers, little changes.

Figure 1: Rate of neural tube defects in Canadian provinces. Each grey bar is a province’s rate before fortification. The shaded band shows the full variation in the size of the fall when each provinces’ end result is randomly allocated. The diamond marks the actual fall. Rates from De Wals and colleagues (2007), Table 4.

For example, Newfoundland and Labrador recorded 4.56 per 1,000 before fortification and 0.76 after. The fall is therefore 3.80. Subtracting even the largest finishing rate in the study leaves 3.30, which is higher than any other province’s rate before fortification. Newfoundland holds the right-hand end of the graph under every one of the 5,040 arrangements. Lower down the bands overlap more. The random allocation can cause provinces to change order but not by much. The maximum change is only 1.26. The variation in the falls is inherited from the starting rates.

The combination with the lowest correlation looks like this:

As an analogy, imagine seven candles of very different heights. They are burnt down to stubs. Each candles starting height is then compared to the amount of height lost. It wouldn’t matter how you muddled up the stubs -- you would still see a correlation where the tallest candle was plotted with the greatest loss and the shortest with the least.

What the graph really shows

The provinces started with rates that were far apart and finished with them close together. This kind of convergence has more than one possible cause. A genuine benefit reducing the rates is only one possibility. Regression to the mean is another: a province recording an unusually high rate in one period will tend to record something nearer the average in the next as outliers tend to be rare.

The line on the graph has been offered as a way of predicting the scale of the benefit from folic acid fortification in another country but it is incapable of doing that.

The zero level that came from China

The line the researchers fitted hits zero benefit when the starting rate is 0.6 per 1,000. That was not extrapolated from the data collected in Canada. The Methods state that the model was constrained based on the assumption that no reduction is possible where the starting rate is 0.6 per 1,000 or less. This figure came from a study of Chinese regions.

The scientific evidence that forms the basis of the claim of folic acid efficacy is flawed in many ways.

27^th August 2026

Joint Letter from:

CCVAC – Children’s Covid Vaccines Advisory Council

HART – Health Advisory and Recovery Team

The Perseus Group

UKMFA – UK Medical Freedom Alliance

Doctors for Patients UK

To: The Right Honourable Andy Burnham, Prime Minister

Dear Mr Burnham,

Firstly, congratulations on becoming Prime Minister.

You have a huge opportunity to righ…

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28^th August 2026

To: The Right Honourable Andy Burnham, Prime Minister

Dear Prime Minister,

Congratulations on becoming Prime Minister.

Britain has spent six years arguing about the Covid pandemic. We do not believe the country needs another rehearsal of those arguments. But what it does need is answers.

A group of 160 doctors, scientists and health professionals have written to you asking you to do something your predecessors have repeatedly failed to do: commission an independent examination of outstanding questions about the safety of Covid-19 vaccines and ensure that those who believe they have been injured or bereaved are properly heard. The full letter is linked here.

We are not asking you to accept the conclusions.

We are asking you to ensure that the evidence is examined.

That distinction matters.

You have spoken powerfully about what happens when institutions become defensive and difficult questions are left unanswered. Britain has seen the consequences in Hillsborough, the infected blood scandal and the Post Office scandal. In each case, people raising concerns were dismissed for years before institutions were eventually forced to confront what had happened.

Whatever your own view of Covid vaccination, we ask you to ensure that the same mistake is not made again.

There remain legitimate and unresolved questions about adverse events following Covid vaccination, including cardiovascular events; increases in cancer, the causes of excess mortality and increased long-term sickness since the pandemic; the adequacy of systems for identifying vaccine injury; and whether those who believe they have suffered serious harm have been adequately investigated and supported.

Excess mortality and ill health are likely to have multiple causes, including delayed NHS treatment, the effects of lockdown, Covid infection itself and wider pressures on the health service. But we believe vaccination must also be permitted to form part of that investigation rather than being treated as a question that cannot be asked. This is ultimately an issue of public trust.

As a group of senior clinicians and public figures, we are asking you to take concerns raised in the letter extremely seriously and we ask your government to support a full and transparent examination of the outstanding evidence. The UK Covid-19 Inquiry chaired by Baroness Hallett stated that they would not look at the full evidence for the safety or efficacy of these products, as (remarkably) it was outside the scope of the Inquiry.

The pharmaceutical industry produces medicines that save millions of lives. But precisely because governments spend billions purchasing its products and depend upon its research, the relationship between industry, regulators, medical institutions and government must be transparent and subject to rigorous scrutiny.

Our testimonies raise a wider issue which we believe deserves serious political attention: the influence of the pharmaceutical industry over medical research, regulation and public health policy. The Pandemic Response All Party Parliamentary Group in 2024 concluded that the MHRA is failing to flag serious harms from the Covid vaccine. Several signatories to this letter have been invited to speak in Westminster on these issues.

No industry responsible for products affecting the health of billions of people should be beyond challenge. Nor should doctors or scientists fear professional or reputational consequences simply for raising legitimate questions about safety.

Some adverse effects of Covid vaccines are already officially recognised. The question is whether Britain’s mechanisms for identifying, investigating and compensating serious vaccine injury are adequate - and whether every credible safety signal has been investigated with sufficient independence and urgency. As one of the signatories to this letter stated under oath in the United States senate in June, he fears that millions of people may be at risk of premature heart disease and cancer.

There is another group whose voices should not be lost in the political argument: people who have been seriously injured by Covid vaccines and families who have been bereaved.

People who believe they have suffered harm should not have to choose between being ignored and becoming campaigners simply to have their cases heard.

That should be something on which people on every side of the Covid debate can agree.

Prime Minister, we are therefore asking you to answer two straightforward questions.

• Will you support a full examination of evidence concerning Covid vaccine safety and efficacy that we believe has not been adequately addressed by the UK Covid-19 Inquiry? This must include excess mortality and increased long-term sickness since 2021.

• Will you ensure that people who believe they have been seriously injured following Covid vaccination, and bereaved families who believe vaccination contributed to a death, have access to a credible system through which their cases can be properly investigated?

Until the outstanding safety questions have been independently examined, we believe the precautionary principle requires the Covid booster programme to be suspended.

We recognise that asking you to suspend the programme would be a significant decision. But you do not need to agree with us about suspension to agree that unanswered safety questions deserve independent scrutiny.

The reason for this lies beyond a fair hearing for those who believe they were injured by the vaccine. Public confidence in vaccination and medicine cannot be restored by insisting that people trust institutions. Institutions have to demonstrate that they are worthy of trust. That means publishing evidence, acknowledging uncertainty, investigating possible harms and being willing to change course when evidence demands it.

It also means recognising that questioning a medical intervention is not inherently anti-science. Proper science requires challenge, replication, disagreement and the willingness to test uncomfortable hypotheses.

The Covid years divided families, communities, doctors and politicians. Continuing to fight the same political battles will not heal those divisions.

Finding out what happened might.

You have an opportunity, at the beginning of your premiership, to approach this differently. We are not asking you to prejudge the evidence.

We are asking you to open the door to its independent examination.

If the concerns we and others have raised prove unfounded, a rigorous investigation should establish that. If they are justified, the public deserves to know.

Either way, transparency is the only sustainable route to restoring trust.

We thank you for taking these proposals seriously.

Yours sincerely

Dr Aseem Malhotra, MBChB, MRCP, Cardiologist

Dr Rosamond Jones, retired Consultant Paediatrician, Children’s Covid Vaccines Advisory Council

Dr Clare Craig, diagnostic pathologist, co-chair Health Advisory and Recovery Team

Dr Elizabeth Evans, retired doctor, CEO, UK Medical Freedom Alliance

Mr Nick Hunt, retired Civil Servant, MoD, Chairman, The Perseus Group

Dr Ayiesha Malik, General Practitioner, Executive Committee, Doctors for Patients UK

Professor Angus Dalgleish, MD, FRCP, FRACP, FRCPath, FMed Sci, Emeritus Professor of Oncology, City St Georges, University of London, Principal, Institute for Cancer Vaccines & Immunotherapy

Professor David Seedhouse, Honorary Professor of deliberative practice, School of Pharmacy, Aston University

Dr Alan Black, MBBS, MSc, DipPharmMed, retired pharmaceutical physician

Dr Alan Mordue, MBChB, FFPH. Retired Consultant in Public Health Medicine & Epidemiology

Dr Andrew McHutchon, MBChB, FRCA, retired Consultant Anaesthetist/Intensivist

Dr John Flack, BPharm, PhD, Retired Director of Safety Evaluation, Beecham Pharmaceuticals and Senior Vice-president for Drug Discovery SmithKline Beecham

Dr Henry Goodall, MBBS, FFOM, retired Consultant Occupational Health Physician, President of the Society of Occupational Medicine, 2011-12

Dr John Campbell, Nurse educator and broadcaster

Graham Phillips, BPharm, Dipp Comm Pharm, FRCPharm, Principal Pharmacist iheartpharmacy group, Founder of Prolongevity.co.uk

Dr Sabine Hazan, MD, Gastroenterogist

Molly Kingsley, writer and campaigner, cofounder UsForThem

John Vincent MBE, British restaurateur, entrepreneur and government food adviser

Gurinder Chadha OBE, Film Director

Dimitri Masceranas, England International Cricketer

Pat Cash, International tennis coach

Peter Fleming, Professional tennis player and sports commentator

Woody Harrelson, Actor

Rob Schneider, Actor & film maker

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Dr Clare Craig

There have been two randomised trials which have produced a signal of harm from folic acid. Neither was designed to measure harm.

The first was the Aspirin/Folate Polyp Prevention Study which gave 1,021 people 1 mg of folic acid a day or a placebo. All of them had already had a bowel polyp removed. The trial was testing whether folic acid stops polyps coming back. Advanced polyps appeared in 11.6 percent of those on folic acid compared to 6.9 percent in the placebo group. For three or more polyps the difference was 9.9 percent compared to 4.3 percent. They also found more cancers elsewhere in the body. A later analysis of the same men found prostate cancer at 2.6 times the placebo rate. The researchers ended their 2007 paper by understandably calling for safety trials to establish whether folic acid increases bowel cancer. That work has never been done.

The second is the Aberdeen trial between June 1966 and June 1967, which enrolled 2,928 pregnant women who were given 5 mg of folic acid a day, 0.2 mg or a placebo. The study aimed to measure whether low folate causes birth defects, anaemia and placental abruption. Cancer was not an endpoint. Thirty-five years later a different team linked the women’s records to Scottish registries and found cancer deaths 70 percent higher and breast cancer deaths twice as high in the 5 mg group, with 112 and 31 deaths respectively. A further follow up to 2013 did not find the same concerning increase. This is the only randomised data in the world that examined folic acid effects after decades but it was not designed to do that.

Both trials used higher doses of folic acid than the fortification level. It is widely accepted that different drug doses result in different benefits. The same is true for safety. For folic acid specifically, cancer risk is not evident above 1mg a day but at fortification doses there is a clear signal.

What gets funded

A study design that starts with a hypothesis of benefit is easier to fund. Funders are more attracted to research that would produce a positive and applicable outcome, even if reducing harm because of negative outcomes is clearly of great importance to the public. For example, seeing as high homocysteine is related to heart disease stroke and folic acid lowers homocysteine a hypothesis could be presented that folic acid could prevent heart disease strokes. Studies to answer that exact question were funded in seven countries. Thirty trials and 82,334 people have now tested folic acid for benefits in heart disease and stroke.

Manufacturers may support such studies in addition to other sources. CSPPT – Chinese Stroke Primary Prevention Trial, which produced the strongest evidence that folic acid might prevent stroke, gave 20,702 Chinese adults a single tablet combining enalapril with 0.8 mg of folic acid, or enalapril alone. It was sponsored by the manufacturer of that tablet, Shenzhen AUSA Pharmed.

By contrast, a hypothesis that starts in a negative way is less likely to be funded. Any researchers saying folic acid is synthetic, that the enzyme which converts it works slowly and gets overwhelmed, that unconverted folic acid circulates in the blood, that cancerous cell division might be amplified by it and that we should count cancers for twenty years to see what happens are going to struggle relatively to get funding. Cancer is slow and the effect is likely to be small. The situation is not helped by the fact that folic acid is treated as if it was folate and therefore a vitamin and therefore safe. Nor is it helped by the fact eighty countries already add it to their food. It is not just manufacturers who fail to fund such studies.

Folic acid is a drug

Companies that market medicines have a legal obligation to carry out safety monitoring, called pharmacovigilance. They must collect reports of side effects and submit reports at set intervals to the regulator.

Folic acid tablets are a licensed medicine in the United Kingdom so all that applies. However, folic acid when added to flour under the Bread and Flour Regulations is being treated as a food ingredient. The route of ingestion is what determines this distinction not the dose. There is no system for tracing food safety in the same way and there is no big company with a folic acid patent who could be held to account.

There is money available

The Global Alliance for Improved Nutrition was launched in 2002 with more than $70 million over five years. $50 million was from the Gates Foundation. The Food Fortification Initiative started the same year and is based at Emory University. It campaigns for vitamins and minerals to be added to milled wheat, maize and rice. The International Association of Operative Millers is one of its leading supporters. In 2023 the Gates Foundation gave the Food Fortification Initiative $300,000 to review the evidence on the impact of fortification across ten foods.

Campaigns staffed and funded by people who think it is heroic to add things to food are not going to fund research to establish the negative effects of folic acid. No organisation exists with a purpose to establish the negative impacts of folic acid at fortification levels.

The ethics problem

If a safety trial was proposed and funded it would run into a problem with the ethics committee. Given that SACN has recommended fortification and the government tells every woman who might become pregnant to take folic acid, an ethics committee would claim that further research, even much needed safety research, was unethical. Once authorities declare something safe it becomes “unethical” to question it.

There has never been a single trial of the effects of folic acid on children and yet no ethics committee is pointing this out and saying that mandating it in flour is unethical.

Timing is also a problem. Cancer takes decades to appear but research grants run for three to five years. The measurements used in the funded benefit trials are for outcomes that are quick: blood results, polyps, memory tests and brain scans. Slow harms do not fit into the funding cycle.

Monitoring instead

The plan is to monitor. If that were really the only option then the most ethical way to do that would be a standard design called a stepped wedge. The rollout begins in a particular region and the order in which regions receive it is randomised. Given the fact that it is being put into staple food and that our food provision is not regionalised this becomes impossible in practice.

That leaves monitoring a population after a uniform rollout as the only measure. SACN in 2009 estimated that the monitoring data available had a 13 percent chance of detecting a 10 percent rise in bowel cancer. A study with 13 percent power would miss a real effect seven times out of eight. That is not good enough. Worse, the Bread and Flour (Amendment) Regulations 2024 did not require safety monitoring at all.

In 2017 a Cochrane review tested whether any more trials were needed on cardiovascular deaths or deaths from any cause and concluded that enough had been done. The trials they considered were short with follow up for adverse events from 3.4 years to 7.3 years. Cancer takes far longer than that to appear. They also did not separate the evidence at fortification doses.

Eighty thousand people across seven different countries have been randomised over twenty-five years, at public expense, to find out whether folic acid prevents heart attacks, strokes, dementia, deafness, fractures, depression and polyps. That effort proves a safety trial could be done.

Now that folic acid is already in a huge variety of food ahead of the December 2026 mandate it is too late to do the safety trials. There is no clean placebo group to compare.

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Dr Clare Craig

The first trial to raise a question about bowel cancer risk from folic acid found an increased risk of pre-cancerous growths called polyps. A small proportion of these progress to cancer over years. Bowel screening tests for blood in the faeces and if present the person undergoes a colonoscopy at which polyps might be found. The level of blood needed to trigger the colonoscopy began to be reduced to two-thirds from February 2026, phased across England to March 2028. The number of polyps that will be found is about to rocket. As well as there being no monitoring of bowel outcomes there is also therefore no good way of measuring the impact of folic acid exposure secondary to the government mandating it in our food. The mandate comes in in December 2026, but most manufacturers complied well in advance of that deadline. One country, Chile, added folic acid to flour with no bowel screening at all. That is the best test of the impact there is but it has been ignored.

What the trial found

As with every folic acid trial the Aspirin/Folate Polyp Prevention Study was designed to see if folic acid would be beneficial. They gave 1 mg of folic acid a day to 1,021 people who had recently had pre-cancerous bowel tumours. Significantly more of the treated group had three or more adenomas on follow up. The risk was more than doubled with a confidence interval that ranged from a 15 to 321 percent increase. Advanced lesions were 67 percent more common but that finding was no longer significant after adjustments were made. It was this increased risk of polyps which caused the UK’s Scientific Advisory Committee on Nutrition (SACN) concern.

The trial itself illustrates the problem this article is about. Participants were recruited between 1994 and 1998. Voluntary fortification of American flour began in 1996 and became mandatory in 1998, so by the second phase of the trial the placebo group was eating fortified flour too. Any genuine effect would be diluted by treating the placebo group. SACN noted that the folic acid group were therefore taking more than the 1 mg a day the trial gave them.

The Chief Medical Officer asked the SACN to examine that signal in October 2007. They agreed it raised concerns but the pooled randomised evidence from trials all designed to look for benefit was too weak to draw conclusions. The trials had 13 percent power to detect a 10 percent higher risk of colorectal cancer, and the Committee on Carcinogenicity agreed there was no realistic way of reducing that uncertainty. SACN supported adding folic acid to our flour but said voluntary fortification should be restricted, supplements should be capped at 200 micrograms a day for the over fifties and for anyone with a history of adenomas, and there should be careful monitoring to measure adverse effects after the horse has bolted. One member dissented from this advice because of their concerns regarding colorectal cancer risk.

The safety test on the whole population

Having failed to carry out adequate safety testing, is the monitoring set up ready to show what impact folic acid has?

With the UK’s lower threshold for colorectal cancer screening many more people will be referred to colonoscopy. Modelling for the Department of Health and Social Care estimates that this change will result in 36 percent more positive tests and 2,017 more high risk polyps being detected along with 663 more bowel cancers every year. The short term effect is a rise. However, longer term the intention is that the detection and removal of polyps means that the proportion that would have become cancer never get a chance to and the number of cancers would then reduce. The reduction in cancer was estimated to be around 20 percent after 13 years in the NordICC trial. The rise then fall will happen independent of any effect of folic acid but could hide its impact.

There are three interacting variables here:

1. The change in the numbers of adenomas and cancers actually developing.

2. Changes to the tests used to detect them.

3. The number recorded in official data.

Screening changes the number detected even if nothing else changes.

Under these circumstances a simple before and after comparison of bowel cancer incidence cannot separate the effect of folic acid from the effect of screening.

The monitoring plan does not look

The published impact assessment covers neural tube defects, blood folate, vitamin B12 and intakes of calcium, iron, thiamin and niacin. No bowel polyp or cancer monitoring is planned even though colorectal cancer was one of the specific reasons SACN asked for careful monitoring of adverse effects. Asked in June 2026 how the policy would be assessed, the Government replied that it was still exploring how to evaluate the impact.

What happened elsewhere?

Perhaps we could look to other countries that have added folic acid to their flour and see what happened to their risk of colorectal polyps and carcinoma.

The idea that a mandate presents a sharp before and after date is not true. Manufacturers were given a two year lead in to change their processes in the UK and similar lead in times were present elsewhere.

In multiple instances, bowel cancer screening criteria changed right at the time that folic acid was introduced.

When fortification arrived in each country and what changed in bowel cancer detection alongside it.

The United States

Mason and colleagues reported that American bowel cancer incidence rose from 1996 and peaked in 1998. Part of that rise will be because of colonoscopy displacing sigmoidoscopy from about 1995. Medicare cover, which applies to all over 65 year olds, began on 1 January 1998, the day fortification became compulsory. It started with high risk people and expanded to everyone from July 2001.

SACN examined whether screening could explain the American and Canadian rise and set out exactly the mechanism described above: an immediate increase as cancers are found earlier, then a return to background, unless screening keeps increasing, in which case the return is delayed. They concluded that the available data were insufficient to confirm whether screening changes could explain what happened.

Australia

Australia extended their screening in 2008 and it is estimated that screening prevents 92,200 cases over 2015 to 2040. Every year had more screening than the year before. There is one study of the impact of folic acid by Van der Pols et al. They did not adjust for the increase in screening and concluded there was no evidence that the September 2009 mandate influenced bowel cancer incidence. The control period included voluntary fortification which had been permitted since 1996, so it was not clean.

Then there is what happened in the year of the mandate itself. Australia’s screening programme was suspended in May 2009 because the faecal occult blood test kits were faulty. It resumed in November 2009 and everyone affected was reinvited. Fortification became mandatory in September 2009, in the middle of that gap.

Incidence rose from 2009 to 2010 in exactly two age bands, 55 to 59 and 65 to 69, by 12 percent and 9 percent, both statistically significant. The authors attribute this to the suspension: fewer cancers found in 2009, then a catch up in 2010.

That explanation creates three problems for their own conclusion.

Having accepted that a six month interruption to screening can move national age-specific incidence by 9 to 12 percent, then the rest of the analysis must account for it. The continuous expansion of the same programme from 2008 onwards would have an effect. The screening issues cannot be applied only when the answer is convenient.

It does not fit the ages. The people eligible for screening in 2009 were those turning 50, 55 and 65. All three groups were affected by the suspension and the reinvitation. Two of the three age bands rose. The paper reports that other age groups changed very little, so the 50 to 54 band, which contains the third eligible age, did not show the effect at all.

It puts the pivot of the analysis on an artefact. Their evidence of safety is that the decline in incidence accelerated after 2010, from 0.4 percent a year to 2.2 percent a year. The joinpoint sits at 2010. If 2010 was inflated by catch up screening, as they themselves argue, then the decline measured from that inflated year is steeper than the truth.

The authors also note that the lag between exposure and a colorectal cancer diagnosis is estimated at anywhere between 4 and 20 years, which they use to argue that an effect in 2010 would be surprising. Their reassurance rests on the seven years from 2010 to 2016, the very bottom of that range.

New Zealand

New Zealand mandated fortification in August 2023. Its national screening programme finished rolling out in 2022, so the preventive effect of removing polyps was only just beginning when the flour changed. The starting age has since been lowered from 60 to 58 and is due to fall again to 56 in September 2026. Given a latency of at least 4 years, there is nothing to see yet, and the screening programme will have changed twice more before there is.

We have found no study of the population impact of folic acid on bowel cancer that controls for changes in screening.

Is there any control group?

Canada and Chile both introduced folic acid without a step change in their bowel screening.

Canada

The key provincial programmes providing access to screening did not arrive until 2007 and 2008, nine years after the November 1998 mandate. A national survey in 2003 found that endoscopy use had risen roughly six-fold over the preceding decade. There was no particular stepwise change like in the USA. There is therefore still a confounding issue but nevertheless an age-stratified analysis of Canadian bowel cancer incidence controlling for endoscopy usage has never been done.

Chile

There was no bowel cancer screening in Chile when they introduced their folic acid mandate in 2000. The first pilot screening programme did not begin until 2007 and colonoscopy coverage among 50 to 75 year olds was only 8.7 percent a decade after fortification. The problem is Chile had no cancer registry to record cancer incidence. Hirsch and colleagues therefore compared hospital discharges for colon cancer before and after and found a rise. Discharges were 2.6 times higher in those aged 45 to 64 and 2.9 times higher in those aged 65 to 79. This is the largest rise that has been reported related to folic acid and none of the rise can be blamed on screening. The same analysis found breast cancer discharges rising too, which the authors attributed to new breast cancer programmes. SACN’s working group reviewed the paper in 2009 and agreed that no conclusions could be drawn from it, because of methodological limitations, missing information and the unclear way the results were presented. They did not offer another explanation to explain the rise.

The Chile data is important and no-one has commissioned better. Nothing has been published in the seventeen years since.

Chile is the closest thing to an unconfounded test of the effect of folic acid on bowel cancer that the world has produced. It showed a 2.6-fold increase.

The Australian data showed a null result when it was confounded by the effects of a screening programme but it gets cited as reassurance. By contrast, Chile’s rise was free of the confounding effect of screening and gets dismissed as inconclusive. Why is evidence suggesting harm held to a different standard to evidence suggesting safety?

Instead of carrying out a full safety trial the UK is mandating the addition of folic acid amidst this immense uncertainty of the size of the risk. By changing the bowel screening at the same time, it is doing it in a way that harm will not be measurable.

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Dr Clare Craig

There has never been a trial designed to determine the safety of folic acid at any dose, let alone specifically focused on fortification doses. The evidence that exists is always second hand from trials designed to show a benefit; includes other vitamins alongside folic acid and uses doses higher than the fortification dose. The effects of drugs differ by dosage so what happens at a high dose may be different to what happens at a low dose. The limited trial data that exists for people with heart stents is concerning as explained below.

Earlier this year the NHS removed from its warnings on “who cannot take folic acid” the words “if you…have a stent in your heart”. Asked in Parliament why, the minister defended the cut saying the page had been shortened and simplified. The warning has since been restored. The live NHS page again lists a coronary stent among the circumstances in which folic acid “is not suitable”.

Figure 1: NHS website advice before amendments saying “have a stent in your heart”

Figure 2: NHS website advice after amendments to shorten and simplify saying “you have a coronary stent (a small metal mesh tube inserted into the artery that leads to your heart)”

A similar caution can be found in the product information details published by the drug regulator. The Summary of Product Characteristics from 2018 for Folic Acid at a 5mg dose states that folic acid (which they called folate) “should not be routinely used in patients receiving coronary stents”.

The evidence base for that caution comes largely from a randomised trial published by Helmut Lange and colleagues in 2004. Between 1998 and 2000, 636 patients who had just received a bare-metal coronary stent were allocated to placebo or to an intravenous bolus of 1mg of folic acid along with 5mg of vitamin B6 and 1mg of vitamin B12. They were then given six months of oral folic acid at 1.2mg a day along with 48mg of vitamin B6 and 60µg of vitamin B12. The expectation was that giving vitamins would be beneficial to the patients and it was part funded by the vitamin manufacturer. It did not prove beneficial.

The participants had a follow-up angiogram to measure the narrowest point of their heart vessels. The treatment group had a smaller minimum luminal diameter and the change in the size of the lumen since the procedure was also worse for them. Both findings were clearly statistically significant, at p=0.008 and p=0.004. These are the most convincing results and are both measures the trial set out to measure.

Overall, a narrowing of half or more of the blood vessel diameter, which is the definition of “restenosis”, had occurred in 34.5 percent of lesions in the treatment group compared to 26.5 percent in the placebo group. That amounts to a 30 percent increased risk, at p=0.05, the threshold for conventional statistical significance.

The study also measured interventions that occurred before the follow up angiography. At 165 days a repeat intervention to revascularize the treated vessel had been needed in 7.6 percent of the treatment group compared to 4.4 percent of the placebo group, which was not statistically significant. By 250 days, after the follow up angiography and counting procedures that were undertaken because of findings from it, the figures were 15.8 percent compared to 10.6 percent, again at p=0.05 and again on the threshold. Major adverse coronary events, which included these interventions as well as heart attacks and death, were 16.8 percent compared to 10.9 percent at 250 days, at p=0.03. Deaths (one in each arm) and infarctions (3 vs 2) were too few to see a noticeable difference.

The study needed to be larger to get a full understanding not least because the follow-up angiography was undertaken by only 76 percent of participants. The authors of this industry sponsored study (which kept referring to folic acid as folate) concluded

“Our data do not provide any evidence that folate therapy for the primary or secondary prevention of coronary artery disease is potentially harmful, since the folate group did not have an increased incidence of death or infarction… If, however, physicians decide to administer folate therapy to patients with coronary artery disease and moderate hyperhomocysteinemia even before the results of prospective prevention studies are known, they should exercise caution in the use of this therapy for patients who have just received a stent.”

The trial was not restricted to that group of patients and the caution therefore should be wider.

As well as being too small the trial gave three vitamins together, included intravenous dosing and used bare metal stents which are now a small minority of what is implanted. Metal stents were replaced by drug-eluting stents which work by releasing a drug whose purpose is to suppress the growth of new cells inside the stent. Whether folic acid interacts with those drugs has never been studied.

The Lange study was undertaken after results of a Swiss trial suggested a benefit. The Swiss trial, published in 2001, gave 205 patients the same three vitamins after angioplasty. They found restenosis in 19.6 percent of the treatment group compared to 37.6 percent in the placebo group. Only just over half of those patients had a stent. In the stented subgroup the difference was 20.6 percent in the treatment group compared to 29.9 percent in the placebo group and was not statistically significant.

A 200-patient Iranian trial is the only one to have tested folic acid alone. It found restenosis in 10 percent in the treatment group compared to 5 percent for the placebo group but was too small to reach statistical significance.

A Norwegian trial, NORVIT, gave 3,749 patients who had just had a heart attack one of four daily treatments:

• 0.8mg of folic acid with 0.4mg of vitamin B12 and 40mg of vitamin B6;

• folic acid with B12;

• vitamin B6 alone; or

• placebo.

The negative outcomes that were measured included fatal or non-fatal heart attack, fatal or non-fatal stroke, and sudden death attributed to coronary heart disease, over a median of 40 months. Patients on all three vitamins had a 22 percent higher risk. The authors concluded:

“the NORVIT trial demonstrated that intervention with folic acid, with or without high doses of vitamin B6, did not lower the risk of recurrent cardiovascular disease or death after an acute myocardial infarction. Such therapy may even be harmful after acute myocardial infarction or coronary stenting and should therefore not be recommended.”

A second Norwegian trial, WENBIT, was running in parallel. It recruited 3,090 patients on the identical four-arm design. When preliminary results were presented from NORVIT in September 2005 they raised a possible increase in cancer. The following month WENBIT stopped its treatment early, which shortened the exposure it was able to test.

A substudy of WENBIT reported on the effect after stenting. Of 456 eligible participants, 365 had detailed measurement of their arteries by angiography at six to twelve months, including 509 bare-metal stents. Restenosis occurred in 17.9 percent of lesions with no difference between the groups. This is the strongest evidence against a harmful effect. It was presented at the World Congress of Cardiology in 2008. Eighteen years later there is still no publication of the full results.

A later substudy from the same trial also found no significant difference between the groups in how the arteries changed overall. However, a difference was seen in “rapid progression” of the unstented lesions in the treatment group in an analysis carried out after the event. It was published in the American Journal of Cardiology in 2010. Oddly, in this peer reviewed publication they did not report the restenosis rate or the ultrasound measurement of the narrowing.

All the trials above gave between 800-1200 µg a day. For the majority, flour related exposure is expected to be lower than this. A lower dose cannot be assumed to be safer. Drugs have different effects at different doses and each dose needs to be studied in its own right.

It is high time that a large safety study of folic acid at fortification doses was carried out to measure outcomes that matter, like heart attacks and death. There is no intention to do that. Instead almost the whole UK population is going to be exposed through the mandatory addition of folic acid to flour, which removes the one thing such a study would need: a comparable group of British consumers who are not exposed.

Was there a change in restenosis rates when countries added folic acid to flour?

If there really was a signal then the data on restenosis rates should show it. However, any comparison over time is a problem because of numerous changes over the same time course. The first is that the stents themselves changed, from bare metal to drug-eluting and further upgrades, each cutting restenosis risk. The stented population themselves have aged, have more diabetes and more complex heart disease. Comparisons between countries are hampered by differing definitions of what is recorded in the data. There are measures of all procedures treating a narrowing of a stented lesion but these cannot be compared to a count of procedures for any kind of restenosis. Also, some countries report as a percentage of all interventions done, which itself could change over time, while others give absolute numbers of interventions.

What has not been researched

Any registry analysis of restenosis across a fortification date, adjusted for stent generation and case mix

A randomised trial of folic acid alone, at a fortification-relevant dose, in patients receiving modern drug-eluting stents, with identical angiographic follow-up in both arms

Folic acid alone at doses below 1 mg a day in stented patients, at any stent generation

Interaction between folic acid and the antiproliferative drugs released by drug-eluting stents

Unmetabolised folic acid measured at the time of stenting and related to restenosis at follow-up, which no stent study has done

Restenosis in carotid, renal, peripheral or intracranial stents in relation to folic acid intake

The effect of folic acid exposure lasting longer than the six months Lange measured

Whether Lange’s subgroup pattern, with harm concentrated in men, in those without diabetes and in larger vessels, is real or chance

A full publication of the WENBIT stent result, which remains a conference abstract eighteen years on

Any registry analysis of restenosis across a fortification date, adjusted for stent generation and case mix

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Dr David White

Part 1. The Healthy vaccinee effect.

The UK Covid-19 Inquiry Module 4 report (Vaccines and Therapeutics) was published in April and much has been written about it by HART and others. One major criticism of Baroness Hallett and her team has been their lack of critical approach to the information given to them by government, regulatory bodies and the pharmaceutical industry regarding the safety and efficacy of the vaccines.

The clearest example of this was in her press briefing and the executive summary which picked on the largest published estimate of lives saved, namely 475,000 in England and Scotland. Against this huge apparent success, picked up and amplified by all the mainstream media, lay the “tragic” but “rare” or indeed “extremely rare” vaccine injuries, sacrificed for the ‘greater good’.

So what is the basis of this claim and can it all be explained by the ‘healthy vaccinee effect’?

Figure 1. Four scenarios that may inflate observational estimates of vaccine effectiveness against death. The first 3 illustrate the healthy vaccinee effect — those well enough to be vaccinated are less likely to die of pneumonia or any cause in the near future.

• The healthy vaccinee effect (HVE), a form of selection bias, is a recognised source of bias in observational data.

• HVE biased studies report implausible findings - reductions in non-target deaths in the vaccinated and very early benefit, both before the target virus is circulating and before a biological effect is plausible.

• The Inquiry’s estimate is underpinned by vaccine effectiveness estimates from observational studies. Two provided enough data to allow residual bias to be identified and corrected to produce a bias-adjusted estimate.

• If non-Covid-19 deaths are used as a negative control outcome to correct residual bias in these 2 observational studies, apparent vaccine effectiveness against Covid-19 death reduces from more than 80% to about 22.7% and 41.6% respectively.

• It is likely that even the corrected VEs are still confounded by misclassification bias (scenario 4 above) and a novel form of bias - acute disease-specific healthy vaccinee bias, caused by vaccinating during outbreaks (scenario 3). Here infection status determines both vaccination status and outcome.

• Both of these biases have a plausible mechanism with the potential power to account for all of the benefit remaining after correction using a negative control.

• Due to their susceptibility to bias, observational studies cannot be used with any confidence to estimate that any lives were saved by vaccination.

The Inquiry’s estimate is taken from a modelling paper published in The Lancet Respiratory Medicine. The module 4 report states:

‘Analysis of data from the World Health Organization estimated that, by March 2023, the lives of about 475,000 people aged 25 years or older had been saved as a result of Covid-19 vaccinations in England and Scotland.’

Figure 2. What the estimate says would have happened without vaccines.

The red line in figure 2 is a simplified visualisation showing the magnitude of the counterfactual estimate relative to observed deaths. It is not reproduced from the original Lancet publication. The Inquiry’s estimate has been added in red to an Our World in Data graph of cumulative Covid-19 deaths in the UK.

The randomised trials were not powered (not enough participants or time) to demonstrate an effect on mortality. Instead, the modellers used 24 mostly observational studies with their built in susceptibility to bias, to estimate vaccine effectiveness (VE) against death. Their estimate of the number of lives saved is largely based on their estimates of VE – a model based on a model. This review looks at healthy vaccinee bias, both frailty-related and acute infection specific, together with bias in attributing cause of death whether by death certification or PCR testing, and which of these biases in observational data can be corrected.

What is the healthy vaccinee effect (HVE)?

Descriptions include - those that receive vaccination being in better health, healthier, more health conscious, or when those who are unwell delay vaccination.

For frailty-related HVE to bias an observational study on mortality, two things need to happen. Firstly the frail and already near to death must be more likely to die from the infection being vaccinated against, than the well. Secondly either more than half of the well must be in the vaccinated group or more than half of the frail must be in the not-vaccinated group. In the hypothetical outbreak of virus X shown in figure 3, the frail are evenly distributed but the well are more likely to be vaccinated than unvaccinated.

Figure 3. Simplified example for illustration showing how the HVE might work in care homes when the majority (89%) of the well are vaccinated but only 50% of the frail. The hypothetical outbreak is caused by virus X, with an infection fatality rate (IFR) of 2% in the well and 20% in the frail. 10% of the population are assumed frail, and overall vaccination rate is 85%. The vaccine is an inactive placebo. Other assumptions could lead to a higher apparent VE. If ¾ of the frail remained unvaccinated in the example, apparent VE would be 74%.

The same hypothetical virus X infection, care home population, and no true vaccine effect, is also considered in figure 4. Both uptake proportions now vary independently: columns = % of well residents vaccinated, rows = % of frail residents vaccinated.

If the rate of vaccination in the well is higher than in the frail, apparent VE is positive, if it is lower, VE is negative. If the rates are the same apparent VE =0%. Apparent VE increases as the percentage of well that are vaccinated increases and the percentage of frail that are vaccinated decreases.

Figure 4. Apparent VE% as a joint function of vaccination uptake in the well and frail. Hypothetical virus X outbreak in care home population: 10% frail with IFR 20%, 90% well with IFR 2%. Vaccine is an inactive placebo.

Functional limitations in the elderly and frailty are not confined to care homes. In England and Wales in 2011 3.2% of those aged 65 years and over were living in a care home. For those aged 85 and over the figure was 13.7%. The majority of elderly people live in their own homes, some with considerable support especially in the last years of life. This may be provided by family, local authority or independent sector home care companies. Local authorities spend ⅓ of their budget for older adult care on community based care and ⅔ on care homes. Although I have used care homes in the example, a similar argument applies to elderly people living in their own homes, the main differences being the proportion of frail in the population living in their own homes is likely to be lower, together with variations in testing and vaccination route.

Why a healthy vaccinee effect would be expected

The weeks preceding death due to old age frailty are often characterised by declining mobility, poor appetite, reluctance to drink, increasing dependence, taking to bed and periods of confusion or agitation. If offered a vaccination during this time it would not be surprising if it was declined. If living in their own home they likely wouldn’t want or be able to attend a vaccination centre. If living in a care home - family, carers, nurses or doctors may advise deferral of the vaccination. As health worsens and they are confined to bed, they may develop terminal pneumonia (whether initiated by SARS-CoV-2 or any other virus circulating at the time).

The Green Book states: ‘If an individual is acutely unwell (for example with a fever above 38.5 C), immunisation may be postponed until they have fully recovered. This is to avoid wrongly attributing any new symptom or the progression of symptoms to the vaccine.’

The problem is that in an observational study, the control group, or reference group, is not randomly allocated (which is needed if confounding is to be minimised) but is made up of individuals who choose not to be vaccinated or are advised to defer their vaccines, and this includes those at the end of life who are too sick to be vaccinated and most likely to die of pneumonia in the near future. Vaccination protocols that recommend deferral during acute illness inevitably create the potential for healthy vaccinee bias in observational comparisons.

The HVE and counterfactual modelling

How many lives did the placebo vaccine save in the care home outbreak in figure 3?

We can use the unvaccinated as a reference group to estimate counterfactual deaths in the vaccinated residents as stipulated in the Lancet modelling paper. Because 0.8% (12 out of 1500) of the unvaccinated residents died of infection with virus X, the number of counterfactual virus X deaths that would be predicted to have occurred in the vaccinated residents without vaccination is also 0.8% so 68 out of 8500 residents. As only 26 died in the scenario, 42 lives could be estimated to have been saved by the placebo vaccine.

Or we could use the formula

Estimated lives saved = Number vaccinated x death rate in unvaccinated x VE

or estimated lives saved = Nv x Ru x VE = 8500x0.008x0.618 = 42

The HVE predicts that placebo vaccines with no biological effect against Covid-19 death would show the following characteristics in observational studies:

• one dose to appear surprisingly effective at preventing death not only from Covid-19 but from all causes;

• fast onset of protection as soon as the frail unvaccinated start dying of pneumonia but rapid waning as the frail unvaccinated die out;

• different vaccines would appear to be equally effective;

• the greater the number of healthy people taking them - the more effective the vaccine would appear to be;

• boosting would appear to be recurrently effective until about half of the healthy declined them.

The HVE in influenza vaccination

In influenza vaccine observational studies: vaccination was found to prevent 50% of all deaths when only 5% of deaths were related to influenza in an average winter; the largest difference in mortality occurred before the influenza season; the HVE is strongest immediately after vaccination and declines with time; those with more functional limitations such as requiring assistance for bathing were less likely to be vaccinated; and adjustment for diagnosis code variables did not control for this bias.

The HVE in Covid vaccination

There are numerous studies where healthy vaccinee effect could account for apparent Covid vaccine effectiveness:

1. An early analysis by Public Health England reported a reduction in Covid-19 mortality within the first 14 days after vaccination (HR 0.74), a period during which a biological effect is unlikely to explain the observation.

2. A study from Qatar specifically designed to assess the healthy vaccinee effect reported substantially lower non-Covid mortality among vaccinated individuals, with adjusted hazard ratios as low as 0.35 (95% CI 0.27–0.46) in the first six months following two doses, consistent with a pronounced healthy vaccinee effect.

3. Humphreys et al. found: ‘vaccinated individuals had a reduced risk of death unrelated to COVID-19 compared to the unvaccinated population. Among those aged 65–79 years, aHR’ … for non-Covid-19 mortality … ‘ranged from 0.36 to 0.58, and from 0.35 to 0.70 among those aged ≥ 80 years-old.’

4. The ONS addressed the issue of bias in 2023:

‘As coronavirus (COVID-19) vaccination should not provide protection against non-COVID-19 mortality, we can use non-COVID-19 mortality as a control outcome to assess the amount of confounding left in our model’ ……also ….’even when including all adjustments for confounding factors, we observe a reduction in risk of non-COVID-19 death for vaccinated groups compared with the unvaccinated population.’

Even after full adjustment of its observational data, the ONS reported a reduction in non-Covid-19 mortality in the vaccinated which reached almost 50% after dose 3. with the apparent protection continuing beyond 3 months post dose.

5. The Lancet modelling paper quoted by the Inquiry based its estimate largely on vaccine effectiveness estimates derived from 24 mainly observational studies (about 5 were test-negative studies), leading it to reach VE estimates of 67-95% . The range represents different doses and variants. Two of the papers, Hulme et al. and Kaura et al. both from England, reported on both Covid-19 and non-Covid-19 or all-cause deaths. Each shows the same order of magnitude (over 80%) reduction in risk of death from non-Covid-19 causes as from Covid-19, a feature consistent with significant HVE bias.

6. Effectiveness of BNT162b2 booster doses in England: an observational study in OpenSAFELY-TPP Hulme et al.

Among 4,352,417 BNT162b2 booster recipients matched with unboosted controls, estimated effectiveness of a booster dose compared with two doses only was …. 88.5% (85.0-91.1) for COVID-19 death, and 80.3% (79.0-81.5) for non-COVID-19 death.

Two time periods were analysed and show a VE against Covid-19 death of 81% (days 1-28) and 93% (days 29-70). Such a high degree of genuine biological protection would not be expected during the earlier time period, and again supports that it is predominantly HVE bias that is being measured not VE.

In this study, features suggestive of HVE bias are apparent even though those in care or nursing homes, those receiving end of life care and those medically housebound were excluded. The study used national death registry records from the Office for National Statistics (ONS), which is based on data from death certificates.

7. Kaura et al. collected data from North-West London, in individuals aged 16 and older, and looked at a matched cohort on days 14-84 after the first dose. A Covid-19 death was defined as a death within 28 days of a positive PCR test. The 2 groups were well matched by the number of comorbidities. The not-vaccinated had a higher prevalence of anxiety and depression but a lower prevalence of asthma, diabetes, ischaemic heart disease, cancer and obesity. A profound reduction in all-cause mortality in the vaccinated again mirrors the reduction in Covid-19 mortality. VE was reported as 86% against Covid-19 mortality at 84 days follow up. The reported incidence-rate ratios for Pfizer-BioNTech were 0.14 for Covid-19 mortality and 0.18 for all-cause mortality, again a remarkably similar reduction in both outcomes suggesting confounding.

Kaura et al. reported mortality, expressed as incidence rate per 1,000 person-years (PY) (Figure 5). Non-Covid-19 deaths in the not-vaccinated can be calculated from figures in table 2 to be 8.08 per 1000 PY, and non-Covid-19 deaths in those vaccinated with Pfizer-BioNTech to be 1.46 per 1000 PY, giving an RR of 0.181 and a VE against non-Covid-19 death of 82% — a finding essentially indistinguishable from the reported 86% VE against Covid-19 mortality itself.

Figure 5. Table of results from Kaura et al.

If observational studies showed profound reductions in non-Covid deaths after vaccination, can we test if this is a real benefit?

We can test this by using the observational data to estimate how many counterfactual all-cause deaths it would predict in the Pfizer-BioNTech randomised trial.

Kaura et al. reported an incidence-rate ratio (IRR) for all-cause mortality of 0.18 (95% CI 0.10–0.30) in vaccinated individuals. In the Pfizer-BioNTech trial there were 14 all-cause deaths in the placebo group and 15 in the vaccine group. Before applying Kaura’s estimate, Pfizer’s counting window for deaths needs to be adjusted to fit Kaura’s ie. deaths between days 14 and 84 after dose one. This can be done using data from table 16.2.7.7 ‘Listing of Deaths’ included in the FDA/Pfizer documents which Judge Pittman ordered to be released - giving 9 and 7 all-cause deaths respectively.

Applying Kaura’s IRR of 0.18 to the vaccine arm’s observed mortality gives the counterfactual rate that arm would be expected to show without vaccination (if Kaura’s effect size represented a real reduction in all-cause deaths) as 7 ÷ 0.18 ≈ 39. But as this data is from a randomised trial we can directly compare the counterfactual estimate of 39 deaths without vaccination, with the randomised trial’s own placebo arm mortality data, which recorded only 9 deaths.The observational data findings of reduced non-Covid and all-cause deaths are not consistent with the randomised data, and the apparent benefit is not confirmed, suggesting the apparent all-cause benefit is due to bias.

A similar counting window corrected comparison can’t be made for Covid-19 deaths as the only vaccine group death was on day 110, leaving a numerator of 0 within Kaura’s counting window, but an uncorrected comparison using Kaura et al.’s IRR of 0.14 would predict 7 Covid-19 deaths in the placebo group, not the single placebo-only death seen in the randomised trial.

Why the early Covid vaccine rollout environment may have amplified healthy vaccinee bias and introduced other sources of bias

• Vaccination started during an active pandemic wave, making infection shortly after the vaccination decision more likely.

• Vaccination took place in care homes during outbreaks.

• Vaccination began in care homes, where frailty was concentrated.

• Intensive outbreak testing increased opportunities for differential misclassification.

1. Vaccination into a pandemic wave.

The HVE is strongest when exposure to the pathogen occurs shortly after the vaccination decision, when the imbalance in baseline mortality risk between vaccinated and unvaccinated individuals is greatest. As time passes after the vaccination decision, frail unvaccinated individuals die from their underlying conditions, reducing the imbalance between groups. As 53% of care homes in England experienced an outbreak in January or February 2021, it is likely that many care homes had a Covid-19 outbreak shortly after the first dose was administered.

The HVE after the Covid-19 vaccine rollout would therefore be expected to be larger than after an influenza vaccine rollout as the latter is given before the influenza season and not into a wave of influenza infection. After influenza vaccination there is more time for the frail unvaccinated to die before encountering the infection.

2. Vaccinating during a care home outbreak.

Vaccinating into a wave also led to the situation of vaccinating care home residents during an outbreak in their care home. This added a novel variant of HVE, target-disease-specific healthy vaccinee bias. A January 2021 guidance letter sent out by NHS England stated:

‘We are aware of there being some uncertainty around vaccination in care homes where there are COVID-19 cases or an outbreak. However vaccination should still take place in care homes with outbreaks.’

When a vaccinator arrived at a care home during an outbreak, those who were too unwell to be vaccinated would now include those with a SARS-CoV-2 infection who would go on to die of Covid-19. These residents would have Covid-19 on their death certificates and a positive PCR test, and were not-vaccinated. It’s difficult to imagine a more effective way of feeding bias directly into mortality observational data. If 1 or 2 residents were already on end of life care when the vaccinator called, an apparent vaccine benefit could be seen in observational data in as little as a couple of days.

Figure 6. Care home deaths during the first and second waves in Scotland, with first dose rollout to care homes added in green window to the Care Inspectorate’s graph.

3. Starting the rollout with care home residents.

A vulnerable elderly population can readily trigger the HVE as there will always be unvaccinated residents in their last weeks of life who are at risk of terminal pneumonia. As care home residents were the first to be vaccinated and the most likely to die of Covid-19 or any cause, their deaths strongly influenced results from the first data collections onwards. The early mortality data collections likely influenced important policy decisions.

Giddings et al. found over January and February 2021 in England, 53% of LTCF (long-term care facilities for adults aged over 65) experienced a Covid-19 outbreak with a mean duration of 48 days, 12.67% of residents were infected during an outbreak (a mean of 5 residents per home), and the proportion of residents dying from Covid-19 in an outbreak at this time was 3.32%. This gives an implied IFR (infection fatality rate) of about 26% (3.32/12.67=0.262)

Life expectancy in a care home is short due to age, frailty and existing illness. A Scottish pre-covid study found median survival after entering a care home was approximately 1.7 years, with 3.2% of residents dying within one month. In pre-Covid England, there were 391,972 occupied care home beds in 2019, and 131,149 residents died. This implies that a persistent fraction of residents are in the last weeks of life at any given time, and could be considered as frail in the weeks or months before death (on average about 2.8% die per month although there is also seasonal variation with deaths about 9% higher in winter). When an outbreak strikes a care home, these approximately 3 per 100 residents will die per month anyway, whether they are infected with Covid-19 or not. As an average outbreak in England lasted 48 days, the proportion of residents expected to die anyway during that time would be about 4.5%.

4. Testing

In England, care home staff were having weekly PCR tests and residents tested monthly. All residents and staff were PCR tested on days 1 and between days 4 and 7 of an outbreak, and at the end of the outbreak 14 days after the last positive test. LFTs were being increasingly used especially for staff testing in January 2021. Testing could establish the presence and scale of an outbreak, but establishing cause of death in an individual is more nuanced.

Extensive outbreak testing increased the opportunity for incidental SARS-CoV-2 detection among unvaccinated residents already approaching death from another cause, introducing a potential source of differential misclassification. A small Spanish study during the 2016-17 influenza season found 47% tested PCR positive for a respiratory virus immediately after death.

The possibility that there was differential testing or testing bias - in which the unvaccinated were tested more often than the vaccinated - is raised by the findings of a qualitative assessment report which stated:

‘The accuracy of RT-PCR was highlighted as a problem, especially for the initial PHE tests. The rate of false negatives was reported as high by clinicians, resulting in re-testing (and/or ignoring a negative test result), when COVID-19 was highly clinically suspected.’

This also raises the possibility of differential misclassification of cause of death. In the Pfizer-BioNTech trial there were 5 deaths from pneumonia before the data cutoff, only 3 of which were due to Covid-19. If negative tests were ignored in the unvaccinated with pneumonia, with repeat testing or a death diagnosis of Covid-19 regardless of testing, then there was the potential to substantially increase the number of deaths attributed to Covid-19 pneumonia on death certificates in the unvaccinated.

5. Staff shortages in care homes

In December 2020, during the second pandemic wave when early observational data was being collected, and on which important decisions would be based, the BBC interviewed one Somerset nursing home proprietor about the situation. She described the unfolding tragedy as follows:

“And then it just hit us and just went around the home like wildfire. It was horrific.”

Nearly half of the home’s residents died and at one point 80% of the staff were sick or having to isolate.

At one point she decided the home was so unsafe it should close, but was told there was nowhere else for her Covid-positive residents to go. “So literally, I had no choice.”

“It was a living hell, I can’t make it sound anything better than that.”

Severe staff shortages may have increased mortality through mechanisms unrelated to SARS-CoV-2 infection, including dehydration, lack of nutrition, falls, pressure sores and delayed recognition of illness. If such deaths occurred during recognised outbreaks, there was potential for some to have been incorrectly attributed to Covid-19.

The magnitude of any such effect remains uncertain but the implications of these conditions are profound. The factors affecting life and death in a care home at this time were clearly multiple, complex and powerful and this alone would make any observational data collected on vaccine effectiveness against death highly questionable.

Conclusion to part 1

The Inquiry’s estimate of lives saved is based on vaccine effectiveness estimates derived from observational studies. Such studies show vaccination produces not only an apparent reduction in Covid deaths, but also an implausible reduction in non-Covid deaths of similar magnitude. Figure 7 shows an example of vaccination associated with an apparent reduction in non-Covid deaths of 72%.

Observational data on Covid-19 and non-Covid-19 deaths in the boosted and not-boosted, based on Hulme et al, for individuals aged under 65, days 29-70 following first booster, with rates adjusted to per 100,000 person-years (PY)

Covid-19 deaths

per 100,000 PY

Non-Covid-19 deaths

per 100,000 PY

Boosted

10

153

Not-boosted

49

545

Deaths apparently prevented by vaccination

39

392

% of deaths apparently prevented by vaccination

80%

72%

Figure 7. Comparing Covid and non-Covid deaths in the boosted and not-boosted, in those under 65 years old.

Healthy vaccinee bias is the proposed mechanism for the confounding, while negative-control outcomes are the empirical evidence that substantial residual confounding remains after statistical adjustment.

Part 2 will consider how identification of residual bias can be formalised, and how newly emerging methods of using non-Covid deaths as a control can correct for frailty-related HVE bias to produce a bias adjusted estimate.

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Dr Clare Craig

Another article addresses the NEJM 2007 paper claiming Canadian neural tube defects fell by 46 percent after folic acid was added to the flour. The main figure is a before and after comparison with no control group to compare. To show causation rather than just correlation de Wals and colleagues reported that the size of the fall in each province was proportional to how high that province’s rate had been beforehand. The implication was that those with more of a problem benefitted the most. It is based on the idea that neural tube defects are caused by a folate deficiency and that adding it to flour brings women to a healthy level.

Figure 2 of the paper showing the strong correlation between the fall in the rate and the starting rate

Testing the correlation

If there was a true correlation then randomly assigning the rate after fortification to different provinces would make the correlation substantially weaker or even fall apart. Give Newfoundland’s result to British Columbia, British Columbia’s to Quebec, and so on. Those with a low starting rate might end up with a high fall and those with a high rate might have a low fall. That is not what happens.

In all 5,040 possible arrangements the correlation stays at 0.949 or above. Putting the real data in gives 0.951, where 1 would mean the two quantities were perfectly related to each other so the same increase in one was always matched by an identical increase in the other and 0 would mean no relationship between them at all. Of all the possible random combinations, 62 percent gave a stronger correlation than the actual data.

The same number is on both axes

The x-axis of Figure 2 shows each province’s rate before fortification. The other plots the fall in the rate i.e. the rate before fortification minus the rate after it. So the starting rate is a part of the number plotted on both axes. Plotting a difference against one of its own components is not always misleading. What makes it misleading in this case is the small size of the number being subtracted.

Before fortification the provincial rates ranged from 0.96 to 4.56. Afterwards they were compressed into a range of 0 to 1.26. Each plotted difference in rate comes from a starting rate which varied widely with a comparatively small number subtracted from it. If we randomly allocate those small numbers, little changes.

Figure 1: Rate of neural tube defects in Canadian provinces. Each grey bar is a province’s rate before fortification. The shaded band shows the full variation in the size of the fall when each provinces’ end result is randomly allocated. The diamond marks the actual fall. Rates from De Wals and colleagues (2007), Table 4.

For example, Newfoundland and Labrador recorded 4.56 per 1,000 before fortification and 0.76 after. The fall is therefore 3.80. Subtracting even the largest finishing rate in the study leaves 3.30, which is higher than any other province’s rate before fortification. Newfoundland holds the right-hand end of the graph under every one of the 5,040 arrangements. Lower down the bands overlap more. The random allocation can cause provinces to change order but not by much. The maximum change is only 1.26. The variation in the falls is inherited from the starting rates.

The combination with the lowest correlation looks like this:

As an analogy, imagine seven candles of very different heights. They are burnt down to stubs. Each candles starting height is then compared to the amount of height lost. It wouldn’t matter how you muddled up the stubs -- you would still see a correlation where the tallest candle was plotted with the greatest loss and the shortest with the least.

What the graph really shows

The provinces started with rates that were far apart and finished with them close together. This kind of convergence has more than one possible cause. A genuine benefit reducing the rates is only one possibility. Regression to the mean is another: a province recording an unusually high rate in one period will tend to record something nearer the average in the next as outliers tend to be rare.

The line on the graph has been offered as a way of predicting the scale of the benefit from folic acid fortification in another country but it is incapable of doing that.

The zero level that came from China

The line the researchers fitted hits zero benefit when the starting rate is 0.6 per 1,000. That was not extrapolated from the data collected in Canada. The Methods state that the model was constrained based on the assumption that no reduction is possible where the starting rate is 0.6 per 1,000 or less. This figure came from a study of Chinese regions.

The scientific evidence that forms the basis of the claim of folic acid efficacy is flawed in many ways.

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Dr Clare Craig

Multiple countries have already added folic acid to their food but the decisions differ in terms of the dosage and the types of food affected.

Table 1: What each country mandates, which foods it applies to and ability to opt out

The dosage being put into British food is 62 percent more than the United States, 67 percent more than Canada and 25 percent more than the Australian and New Zealand minimum. How was the decision reached for Britain to have the highest mandatory concentration of these five nations? The British policy also has minimal opt outs with only Canada covering all white flour and everything made from it in the same way, albeit at a considerably lower dosage.

Three wildly different claims about benefit

Despite all these countries aiming to achieve broadly similar daily exposure to folic acid, when scientists measured what was delivered they produced very different results. Furthermore, the claimed reductions in neural tube defects later attributed to folic acid differ dramatically.

Table 2: Target dose, achieved dose and claimed benefit by country (links to evidence here)

There are differences in how the benefit was measured. For example, USA counted affected live births and left out terminations while Canada included live births, stillbirths and terminations. Australia compared eighteen months of fortification against a single point estimate for the pre-fortification period. None included the background year on year fall that has been seen for decades in their sums.

Rather than compare the three claims with each other, each country’s dose can be put into the British model to see what that predicts compared to what that country reports.

The UK impact assessment includes the equation the British benefit is calculated from. The estimate for neural tube defects per 1000 pregnancies is calculated as 37.5 divided by the square root of the folic acid intake. That equation is the basis of the claimed reduction of 20 percent for the UK. If we assume that the UK average of 251 micrograms of natural folate per day is uniform across the countries then a like for like comparison can be made with only the folic acid dose changing.

Table 3: The effect of each country’s delivered dose according to the UK model and the outcome that government claims

The USA data suggests two values for how much folic acid ends up in people. At the lower end, the model claims it should equate to a 16 percent reduction in neural tube defects and at the higher end a 29 percent reduction. The latter fits the government’s claim. The exposure rate in Australia would be predicted to result in a 22 percent reduction if the model could be trusted but the government claim only 14.4 percent. Canada is the real outlier with a claimed reduction that is four times the size of the model prediction.

How can the discrepancy be explained? One way is to suggest there was a big difference in background dietary folate intake. Ordinary diets supply between 200 and 300 micrograms per day. For the American figure to fit, American women would need to have been consuming between 108 and 260 micrograms of folate a day before fortification. The upper end is an ordinary figure and entirely plausible. For the Australian figure to fit, Australian women would need to have been eating about 439 micrograms a day. That is near impossible without folic acid in the food. For the Canadian figure to fit, Canadian women would need to have been consuming about 29 micrograms of folate a day prior to fortification which is far too low for any diet. A woman eating 29 micrograms a day would be severely deficient and starving.

The evidence from Canada is often held up as a cut and dry success story referenced by the UK government. The model is relied on to make the 20 percent reduction claim but the same model cannot compute what happened in Canada.

Caution about overdosing

USA. When the FDA modelled dosages they used three levels, 70, 140 and 350 micrograms per 100 grams of flour. They chose 0.7 milligrams a pound for enriched flour, which works out at 154 micrograms per 100 grams, slightly above their middle dose in their modelling. Activists asked for 250 or 350, arguing that this was well within the limits of safety. The FDA refused because of the risk that at 210 or above the heaviest consumers of grain products would exceed the recommended safety level of a milligram a day, saying,

“There simply is no evidence in the record that such a fortification program would keep folate intakes within the safe upper limit.”

That cut-off only relates to one adverse effect, the masking of vitamin B12 deficiency while permanent neurological damage progresses undetected. The FDA concluded that 140 was the maximum level that would be safe for all groups. It even calculated how many injuries would cancel any benefit, putting the figure at between 386 and 1,228 cases a year of masked B12 deficiency progressing to neurological damage. It therefore capped voluntary fortification of breakfast cereals at 400 micrograms a serving and wrote into the rule that if the share of cereals fortifying at that level rose it would reconsider. How can the FDA decide that 210 micrograms per 100g of flour was not safe, yet the Uk government are mandating 250 micrograms?

Canada. Higher levels were also considered and rejected in Canada because of concern about exceeding the recommended upper intake of 1,000 micrograms a day. The level is a single figure of 150 micrograms per 100 grams of flour with no maximum. That is the same rule Britain has used.

Australia. Food Standards Australia New Zealand, the regulator for both countries, decided on a minimum of 200 micrograms per 100 grams but included a restriction of a maximum of 300. They also restricted it to only wheat flour for bread-making. Organic flour is exempt. Notably, FSANZ accepted that some children would exceed their upper limit so set up monitoring to check on this. Since then, reports have appeared on bread composition, on intakes, on folate status and on neural tube defect rates. They have not published a follow-up on the specific concern of children exceeding the limit.

New Zealand. New Zealand approved mandatory fortification jointly with Australia in 2007. In 2009, when Australia went ahead New Zealand deferred. In 2012, they revoked the requirement in favour of a voluntary scheme. However, in 2021, New Zealand approved it again and it was brought in on 14 August 2023. New Zealand fortifies at the Australian level and targets the same foods. The Ministry for Primary Industries has said, “Organic bread and flour were excluded from the mandatory fortification scenarios because it can no longer be marketed as organic if it contains folic acid. This also allows for some consumer choice for those not wanting to consume folic acid.”

Britain. The UK modelling report did express concern about overdosing. They suggested there should be a cap introduced on exposure from voluntary fortification and supplements. The law has not introduced such a cap. There is also no legal commitment to any monitoring in the regulations.

What foods are included

In 1940s, the FDA decided it would not require mandatory fortification for any food product and that policy is still active. What was introduced in 1996 was a rule to change what food labelled “enriched flour” should contain. Millers are free to sell plain flour or organic flour with no additions. In reality, most flour sold and eaten in USA is enriched so the CDC describes the change that came into force in 1998 as a mandate. Ultimately, enriched flour ends up in a lot of American food products.

Australia and New Zealand mandate fortification only in wheat flour intended for bread-making. As well as organic flour being exempt, cakes, biscuits, pastry and sauces fall outside the mandate entirely.

The Canadian Food and Drug Regulations have the broadest reach in terms of the quantity and range of food containing folic acid. They require that all white flour, and all foods containing it, contain folic acid.

Britain has chosen, not only the highest dose, but the broadest reach akin to Canada but going further because of the mandatory inclusion of folic acid in imported and organic flour, as made clear in their response to our petition. All products manufactured in the UK from non-wholemeal flour will have to have folic acid. The consequence is that it is already in a huge range of products including many products people would not think to check. Wholemeal flour has been exempted but the exemption applies to the flour. Many loaves, advertised as wholemeal, contain white flour and therefore folic acid.

It is also important to note than when estimating dosing the impact assessment assumed the addition of folic acid “would only apply to UK-produced flour”. Therefore 11.3 percent was deducted to account for imports. The regulations require additions to all flour sold here including imported flour. Every exposure in their sums should therefore be adjusted upwards to account for imported flour.

Why has Britain chosen both the highest dose and the widest exposure? Canada had the most draconian policy before, sparing neither organic nor imported flour, but it only demanded 150 micrograms per 100 grams of flour and not the 250 micrograms Britain is demanding.

Why not start at 150?

The UK modelled situations with 0, 100, 200, 250, 300, 350 and 450 micrograms per 100 grams. The American and Canadian levels fall between 100 and 200 and yet this level was never modelled.

On the government’s own estimates, every 100 micrograms per 100 grams raises intake across the population by 40 micrograms a day on average. Looking back at table 1 it is hard to know where that estimate came from. The measured estimates are far higher ranging from 70 to 240 micrograms delivered into people.

Based on their extremely low 40 microgram rise the population would be exposed to 60 micrograms a day with a law demanding 150 micrograms be added. 60 micrograms is the bottom of the target range that the Food Standards Agency had set. It is therefore incredibly odd that this level was not modelled.

If 150 micrograms per 100 grams is used in the government’s own equation, it produces a claimed reduction in neural tube defects of about 10 percent. Remember, that since 1998 USA have used that level and claim a 28 percent reduction and Canada has also used it and they claim a 46 percent reduction [link to Canada paper].

If the British equation is right, the North American results are three to five times too large. Either, the countries whose experience is cited as proof that fortification works have been overstating what it achieved or Britain’s model is very wrong.

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Dr Clare Craig

Neural tube defect births in England and Wales have almost vanished. In the mid-1960s roughly 1 baby in every 270 was born with anencephaly, spina bifida or encephalocele. By 2004 the figure was closer to 1 in 3,300. The question is what caused that change and when.

Births or affected pregnancies

A birth prevalence figure counts the babies delivered but it excludes the terminations. With the development of new tests, the proportion of affected pregnancies which were terminated rose steeply through the late 1970s and 1980s. By 1990 it had reached about 80 percent and has remained that high since.

A falling birth count could mean fewer affected pregnancies but it could also mean no change in pregnancies just more terminations. There is a data series for England and Wales which includes terminations and covers the period from 1964 to 2004.

The upper line on the graphs shows the total affected pregnancies i.e. births plus terminations plus late fetal losses. The researchers adjusted the termination data to account for 56 percent not being recorded as being due to a neural tube defect – in 1964 it was 3.7 per 1,000. It then drifts up slightly to around 4.1 in the early 1970s, and then falls almost continuously from the mid-1970s. By 1990 it is 1.6 per 1,000.

The Department of Health issued its advice that women planning a pregnancy should take folic acid in 1992, following the MRC Vitamin Study published the previous year. From that point the line plateaus.

That same plateau has been recorded by eight congenital anomaly registers in England and Wales, a national Scottish study and twenty-eight EUROCAT registries across nineteen countries. All these countries gave advice to take folic acid from 1992.

What caused the fall?

The authors of the study that produced the graph, Morris and Wald, proposed rising dietary folate as one explanation for the decline in incidence but the evidence to support that is poor. Voluntary fortification of some breakfast cereals began in the mid-1980s, too late for the start of the fall.

Given that the great British reduction in neural tube defects had already happened before the folic acid policy began it cannot have been the policy that was driving the fall. Something else must have been changing that was reducing the risk. The reality is that the cause of neural tube defects is complex and dietary folate is an inadequate explanation.

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Dr Clare Craig

KEY POINTS

● The UK government model gives an expected benefit of fortification of 624 quality adjusted life years (QALYs) per year of fortification.

● Half of the harm from one problem – gestational diabetes – is enough to wipe out this benefit in terms of QALYs.

● Adding the complications and consequences of gestational diabetes would make the balance even worse.

An Australian group measured gestational diabetes recruited before and after mandatory folic acid fortification. It tripled. From 5% to 15%. Furthermore, there was a clear dose response relationship where risk increased stepwise for each increase in a marker of the mother’s folic acid intake. The evidence is set out in a companion article. The study’s own authors call for urgent assessment of the safety of folic acid in pregnancy.

If Britain sees anything like what Australia saw, how much of the rise would have to be caused by folic acid before the harm from gestational diabetes alone outweighs the claim made for benefit based on government modelling?

The answer is only a half.

What is the claimed benefit?

The most optimistic claim is that adding folic acid to our food will prevent around 200 neural tube defects a year.

The government assessment carried out at the time the regulations were put through covers England only and is more specific. It takes an average of 165 babies born alive with a neural tube defect each year (2.75 per 10,000 births, which implies about 600,000 births a year in England) and applies a 19 percent reduction in risk. That estimate of 19 percent is the average of predictions from two other models -- 15.4 percent and 22.4 percent. The claimed potential benefit is 31 fewer affected live births a year: 24 spina bifida, 4 encephalocele and 3 anencephaly, which is fatal within hours of birth. The remaining benefit is in reduced terminations.

The assessment assumed a baseline of about 800 affected pregnancies a year in England. The English registry recorded only 621. The number has been falling for years. The reasons the assessment’s figure is too high are set out elsewhere. For the sums here the registry figure is used, which reduces every case count by a fifth (621 ÷ 800 = 0.78).

On the corrected figures, England alone would have 118 fewer affected pregnancies (19% of 621) which equates to a fall of 2.0 per 10,000. Australian surveillance recorded a fall of 1.5 per 10,000 (44 fewer across 290,000 births). There are numerous reasons to think the British claim is optimistic, but, to be conservative, the full benefit is taken here for the purposes of comparing with the harm.

Balancing benefit and harm

To compare benefit against harm, healthcare economists use quality adjusted life years, or QALYs. One QALY is a full year of totally healthy life. A year lived with illness or disability counts as a fraction of a QALY.

The government’s assessment puts the whole life of a healthy newborn at 41.9 QALYs, which works out at being 81 years of life discounted at the Treasury’s 1.5 percent rate for health effects. It then works out what each neural tube defect costs against that.

Table 14 of the assessment: QALYs lost by each affected child that could be prevented if benefit claim were true

The earlier 2019 consultation assessment valued prevented terminations as equivalent to stillbirths i.e. the whole full life for a fatal case. However, in the final assessment terminations were not included in the health costs and counted as part of the economic analysis based on the cost of the procedure avoided i.e. £500 to £1,600 each.

Applying these valuations to the claimed reduction in cases gives an annual benefit of 803 QALYs (28 surviving cases × 24.2, plus 3 fatal cases × 41.9). Correcting the case count to the registry baseline gives 624 QALYs (28 × 0.78 = 21.7 surviving cases × 24.2, plus 3 × 0.78 = 2.3 fatal cases × 41.9).

Any harm in the whole population that exceeds 624 QALY per year will wipe out the optimistic gain from putting folic acid into the flour.

Quantifying the harm

For the mother, a diagnosis of gestational diabetes at 26 to 28 weeks gestation will result in about thirteen weeks of diabetes management with four finger-prick tests a day. Of women diagnosed, 43 percent receive insulin while 8.1 percent receive oral medication.

The thirteen weeks of testing, restricted eating and the insulin injections (for those who need them), lived at about 92 percent of full health, comes to 0.02 QALYs per case, or about one week of healthy life lost.

Based only on this one harm, if England saw the same rise in incidence of gestational diabetes that Australia saw, a rise of 10.2 percentage points (5.0 percent to 15.2), that would be 61,200 additional diagnoses a year (600,000 births × 10.2 percentage points).

The comparison

It would take 31,200 cases of gestational diabetes at 0.02 reduction in QALYs to equal the 624 claim of benefit. That could be expressed as 51 percent of the 61,200 more cases that Australia saw.

If folic acid accounted for half of an Australian-sized rise in gestational diabetes the burden of the disease and its treatment would cancel the whole claimed benefit in terms of neural tube defects.

It is impossible to know what fraction of the rise in Australia was directly due to folic acid. When the researches took a conservative view of the impact of folic acid and compared the rate among women with folate levels in the normal range and the rate for the whole cohort, they estimated 26 percent could be due to folic acid. However, they had no actual control group. The “normal” women were also exposed to folic acid. It would take a randomised controlled trial to measure it properly. But taken at face value, if 51 percent cancels the benefit then 26 percent takes us half way there without a single complication from gestational diabetes being counted.

What about the complications?

The 0.02 QALY estimate only includes the mother’s management of the diagnosis. The complications, for mother and child, are excluded. For the baby the sum excludes the induced labours, the caesarean sections, the large babies and the shoulder injuries and birth trauma that come with them, the newborns with low blood sugar, the jaundice, the admissions to special care and the future risk of impaired glucose tolerance. For the mother it excludes her cardiovascular risk and the raised risk of type 2 diabetes in the decades afterwards, which is the best documented long-term consequence of the condition.

For each of those complications the QALYs lost mount up. The later maternal diabetes alone would change the balance dramatically such that only a few percent of the increase would have to be due to folic acid.

There are plenty of other harms

Evidence of other types of harm swing the pendulum further still away from justifying the intervention. The 41 percent excess of multiple births in the Hungarian trial is a serious complication which leads to a variety of pregnancy and neonatal complications. The same study found statistically significant increases in illness in the children and these also haven’t been costed. The mothers in that trial were never followed up. The excess fetal losses in that trial, nine for every claimed prevention are not costed either. The cancer risk and risk to those with heart stents and with vitamin B12 deficiency are not included either despite these groups representing millions of people.

The burden of proof

The decision on folic acid is to add a licensed drug to a staple food eaten by an entire population. It was once widely accepted that the standard that applies to a measure like this is that its proposer must demonstrate that it is safe. Its critics are not required to demonstrate that it is harmful. On this single measure of one harm, the sums do not survive. A risk benefit analysis of the health impact was never done. A debate in the House of Commons was never had. The regulations that were passed make no legal requirement that any of these harms should be measured and monitored.

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Dr Clare Craig

The measurement of the effect of folic acid in pregnancy has been confined to neural tube defects but the effects are far wider. There are adverse effects in the mother with multiple births and with gestational diabetes, which tripled across the introduction of fortification in Australia and rose stepwise with folate level, along with all the complications that both of those bring. It also has effects on the fetus and the impact of that can determine whether that baby ends up fed formula milk. Some of the highest folic acid exposures per kilogram in the population are in formula fed premature babies. So does folic acid in pregnancy increase the risk of formula exposure and further folic acid exposure?

Overview
● Tongue tie, prematurity, twinning and the delivery complications of gestational diabetes, have all been suggested as being associated with maternal folic acid. The evidence differs enormously in quality and some of it is contradictory.
● All these are risk factors for formula feeding.
● Formula must by law contain more folate per calorie than breast milk and it almost always uses folic acid.
● Premature babies receive far more folic acid per kilogram via formula than term babies.
● No tolerable upper level exists for infants under four months.
● Formula containing natural folate has been trialled and made lawful in Britain but only one mainstream British brand uses it.

Babies get the biggest dose

The European Food Safety Authority is the body that sets nutrient limits for the European Union and its limits have been carried into British law after Brexit. Its tolerable upper level for adults is 1,000 micrograms of folic acid a day based on an average male of 70 kilograms with a mature liver. That works out at 14 micrograms per kg per day. A term newborn on formula takes in 12 to 17 micrograms of folic acid per kilogram per day depending on volume eaten. A 1.5 kilogram premature baby on hospital preterm formula takes in about 52 micrograms per kilogram per day, three to four times the term rate.
There is no safety limit. EFSA has set no tolerable upper level for any infant under four months. For 4 month olds right up to 3 year olds the limit is set at 200 micrograms a day, which is the same as the entire recommended daily folate intake for an adult.
A British cohort published in 2024 tested premature infants across several neonatal units. None showed evidence of deficiency. However, it found concentrations above the study’s reference threshold in 31 percent of infants at the first measurement and 42 percent at the second. The worst affected were receiving fortifier, parenteral nutrition or supplements. The authors called for research into the consequences of exceeding the threshold but nobody has done that research.

How much is in there?

Aptamil says it contains folate at 13 micrograms per 100 millilitres. SMA contains folic acid at 11 micrograms. A parent would read those as nearly the same quantity of the same thing. Unless she knows the regulatory conversion, she has no way to see that one figure is folic acid by weight and the other is folate equivalents, a unit that counts folic acid at 1.7 times its mass. Both declarations are lawful.
The conversion sits in a footnote to the law that governs formula composition, assimilated Commission Delegated Regulation 2016/127: one microgram of dietary folate equivalents equals 0.6 micrograms of folic acid from formula. The convention comes from the American Institute of Medicine, which in 1998 judged synthetic folic acid taken with food to be 1.7 times as available to the body as the folate in food itself. Cow & Gate is the one brand that declares both figures, 10 micrograms of folic acid and 17 of folate per 100 millilitres, and there is the 1.7 ratio, printed on the tin for anyone who looks.

The same footnote mentions the legal range of 15 to 47.6 micrograms of dietary folate equivalents (DFE) per 100 kcal, which is 9 to 28.6 micrograms of actual folic acid.

Table 1: The four leading British first infant milks, the range the law permits and breast milk itself, in both units the labels use.

On the regulatory conversion the legal minimum for formula is 15 micrograms of folate equivalents per 100 kcal compared to the approximately 12.7 in breast milk. No formula may lawfully be sold containing as little folate per calorie as the actual breast milk it is meant to replicate.

The 1.7 multiplier exists because folate is poorly recovered from vegetable sources, so more of it is needed for the same effect. Breast milk folate is bound to folate binding protein, which protects it through the gut and delivers it efficiently. The conversion therefore makes little sense in this context.

The smallest babies get the most

The milk given to premature babies has no upper limit for folic acid because neonatal products are foods for special medical purposes and the limits for formula composition therefore do not apply.

Aptamil Nutriprem 1, given to babies of 1 to 1.8 kilograms and supplied to hospitals only, declares 34.8 micrograms of folic acid per 100 millilitres at 80 kcal. That is 43.5 micrograms per 100 kcal, half as much again as the 28.6 the law permits for a healthy full-term baby. A 1.5 kilogram baby fed at the usual 150 millilitres per kilogram takes 180 kcal a day and with it 78 micrograms of folic acid. Using the EFSA adult upper limit and scaling down for weight would suggest an upper limit for a 1.5 kilogram baby of 56 micrograms a day. The sickest and smallest patients receive the most concentrated product.

A premature baby that is managing to breast feed is still given human milk fortifier, which in a recent British cohort added 30 micrograms of folic acid per 100 millilitres. Since 2018 UK guidance has even added a 50 microgram daily oral supplement for exclusively breastfed preterm infants. Those babies on intravenous nutrition are given 10 to 40 micrograms per kilogram per day. The European Society for Paediatric Gastroenterology, Hepatology and Nutrition, which writes the feeding guidelines used across British neonatal units, recommends a range running from 23 to 100 micrograms per kilogram per day of folate rather than folic acid. The studies underlying it measured the correction of deficiency based on blood tests. None of these studies was designed to detect harm from excess.

That 56 microgram upper limit is not a safety limit because the research required to ensure safety has never been done. The number is instead a result of scaling the adult limit, which itself is based only on masking of B12 deficiency, to a smaller body. By contrast to the 56 microgram upper limit, a 1.5 kilogram baby on Nutriprem 1 at ordinary feed volumes takes in 78 micrograms a day and on fortified breast milk 68.

The same scaling method gives 106 micrograms a day as an upper limit for a term baby at 3.5 kilograms and the leading products deliver 41 to 58. It is clear that preterm babies are exposed far more than term babies.

Does the mother’s dose fill the bottle?

Folic acid in pregnancy may even increase the risk that a baby is exposed to the folic acid in formula. Babies with tongue ties, prematurity, twins or triplets or a delivery complicated by gestational diabetes or pre-eclampsia all have a higher risk of formula exposure. There is evidence for each of these that exposure to folic acid in pregnancy increases the risk, though it varies in strength from a randomised trial for twinning to a single case-control study for tongue tie.

In 2020 an Israeli group compared 85 infants who had undergone frenotomy for a tongue tie in Jerusalem with 148 controls. Regular pre-conceptional folic acid use was reported by 54.1 percent of case mothers against 25.7 percent of controls, an odds ratio of 3.41, with weaker results in the looser exposure categories, 1.45 for any use and 1.67 for most days. The effect size is large, but the study was small and retrospective and exposure depended on maternal recall. A separate group in Palembang measured maternal serum folate rather than asking about tablets and found an association in the same direction, an odds ratio for tongue tie of 2.13 among 144 mothers, though that work remains an unreviewed preprint.

On prematurity the evidence is contradictory. A 2019 meta-analysis of thirteen cohorts found supplement users had 10 percent less preterm birth. But supplement users are older, richer, better educated, non-smoking planners of their pregnancies and every one of those lowers preterm birth by itself, so residual healthy-user confounding could plausibly account for a modest protective association of that size. The Norwegian Mother and Child Cohort set out to minimise that problem, excluding every known risk pregnancy and adjusting for eleven maternal variables across 66,014 singleton pregnancies. It found folic acid begun more than eight weeks before conception carried an 18 percent increase in spontaneous preterm delivery, with confidence intervals suggesting the true rise was between 5 to 32 percent. The association strengthened when the analysis was restricted to first pregnancies and to women who conceived within a month.

The only randomised trial that could address the question is not clear because of how it was analysed. Czeizel randomised 5,502 confirmed pregnancies to a multivitamin containing 0.8 mg of folic acid or to a control group given trace elements. It reported a significant increase in multiple births in the supplemented arm and also reported no significant change in risk of preterm birth in the singletons. Multiple pregnancies carry a substantially higher risk of preterm delivery, so by restricting the prematurity analysis to singletons the analysis of prematurity risk may have been biased. The overall rate of preterm delivery across all the randomised pregnancies including twins and triplets has never been reported.

The randomised evidence on twinning is stronger than it is usually reported to be. When the rate is calculated per pregnancy rather than per baby, which is the correct unit, Czeizel’s trial gives a rate ratio of 1.49 with a confidence interval from 0.94 to 2.38. That figure comes from the authors of the study most often cited against him. A 49 percent increase that just fails to reach significance in a trial of this size is an underpowered result, not a negative one. A study of Swedish registry data found more twin deliveries in folic acid users after adjusting for fertility history, Czeizel found the same in the Hungarian case-control surveillance data, and American studies agreed.
The one large study that did not is treated as the refutation. Li and colleagues followed 242,015 Chinese women taking 400 micrograms of folic acid a day and found multiple births in 0.59 percent of users against 0.65 percent of non-users, a rate ratio of 0.91. The direction is the first difficulty. No proposed mechanism has folic acid reducing twinning, so a 9 percent reduction points to differences between the two groups rather than to an effect of the pill.

Also, the two groups differed. Women who took folic acid were 16 months younger and far more likely to be first-time mothers, 92.3 percent against 72.2 percent. Maternal age and parity are two of the strongest determinants of dizygotic twinning and both were higher in the unexposed group, which inflates the unexposed rate and would hide any impact from folic acid. No adjustment was made for parity, and the adjustment that was made for education had a disproportionate impact, moving the rate ratio from 0.91 to 0.98, suggesting the two groups were poorly matched from the outset.

The second difficulty is precision where it matters. The mechanism at issue is dizygotic twinning, which requires two eggs. In this cohort dizygotic twinning ran at 2.5 per 1000 pregnancies, against 10 to 20 per 1000 in Europe and North America. The cleanest marker for it is the opposite sex twin pair, and the study found 304 of them. The rate ratio for opposite sex twins was 0.95 with a confidence interval from 0.76 to 1.19, so the study is compatible with a 19 percent increase in dizygotic twinning. The authors’ power calculation is for a 40 percent increase in all multiple births, which is not the quantity in dispute. They also record that the MTHFR 677C to T variant is common in Chinese populations and that this variant reduces dichorionic twin pregnancy. The population was, on their own account, genetically selected against the outcome being measured.

This does not mean the Chinese study is wrong. It tested a different dose of a different preparation in a population with among the lowest dizygotic twinning rates in the world, and it reported a null whose confidence interval does not exclude a modest increase. It is a genuine null. It is not a refutation.
Gestational diabetes and pre-eclampsia both delay milk coming in which increases the likelihood of formula feeding. Australian data show gestational diabetes tripling across the introduction of mandatory fortification, rising stepwise with red cell folate, and in 3,196 Adelaide pregnancies pre-eclampsia was more common in women taking under 800 micrograms of folic acid daily, 10.3 percent, than in women taking none, 6.1 percent.

What is the alternative?

Formula does not have to contain folic acid. Folic acid is the synthetic oxidised form. Formula can instead be made with the reduced folate L-5-methyltetrahydrofolate, the form the body actually uses. A trial has been run on 240 term infants randomised to one or the other. They showed identical growth and the methylfolate babies had markedly less unmetabolised folic acid circulating. EFSA assessed the ingredient and found it safe and it has been lawful in British formula since 2023.

HiPP, one of Europe’s largest formula manufacturers, already uses calcium L-methylfolate in its infant formulas, listed on the tin as Metafolin. Three years after Britain made it lawful, this is the only mainstream British formula which contains it. Even there the label has to read folic acid, with the actual substance in brackets after it, because folic acid is the nutrient name the law recognises. Folic acid is preferred by manufacturers because it is cheap and exceptionally stable on the shelf, which methylfolate is not, so switching means more careful dosing and ensuring stock is fresh.

It is shocking that the highest folic acid exposures are seen in babies for whom there is no upper safety limit. When reduced folates are available in formula, why does folic acid remain the default.

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Dr Clare Craig

For close to seventeen years, folic acid has been added to almost all bread-making flour in Australia and eaten across the population. Britain has begun to do the same with a mandate from 13 December 2026.

There has been only one randomised trial of a modest dose in low-risk women, which tested a multivitamin containing 0.8 mg of folic acid. It recorded about nine excess fetal losses for every neural tube defect prevented. It also found a 41 percent increase in multiple births and, years afterwards, more illness in the children. The mothers were never followed up at all.

Australia now supplies an additional warning of risks to pregnant women.

What was found

Researchers in Adelaide compared two large pregnancy cohorts recruited at the same hospital under near identical entry criteria. The first was recruited in the years before the 2009 fortification mandate and the second six to nine years after. Both excluded women who already had diabetes. Both were scored for gestational diabetes against the same diagnostic threshold. Gestational diabetes, meaning diabetes first recognised in pregnancy, tripled between the two cohorts, from 5.0 percent of women to 15.2 percent. Other pregnancy complications were stable or falling and none of the other differences were statistically significant.

Pregnancy complications in the two Adelaide cohorts, before and after fortification, with the p value for each difference.

Across the whole of Australia, gestational diabetes rose from 5.6 percent of pregnancies in 2010 to 19.3 percent in 2022. That is 13.7 more women diagnosed in every hundred and the national rise matched the trajectory seen in the study.

What else might explain the rise?

Diagnosis. Australia adopted new diagnostic criteria for gestational diabetes in 2015. The new thresholds require lower blood sugar levels for a diagnosis, so inevitably there have been more diagnoses. Both the study’s cohorts were scored against the same threshold and when the earlier cohort was rescored on the new criteria its rate only moved from 4.4 percent to 5.0. The authors accept that the criteria change explains part of the national rise but not its magnitude or its trajectory.

Demographics. The later cohort was older and heavier. The researchers adjusted for maternal age, weight, ethnicity, socioeconomic status and metabolic syndrome together, and the tripling remained significant after all of them. Metabolic syndrome, the cluster of raised blood pressure, blood sugar, blood fats and waist measurement that most strongly predicts gestational diabetes, was in fact half as common in the later cohort, 8.6 percent against 17.2. The women in the later cohort had a lower predicted risk yet developed three times the disease.

General metabolic decline. If Australians generally were becoming more diabetic, diagnosed type 2 diabetes in the wider population would be expected to climb a comparable curve. It has not. Age-standardised type 2 prevalence has been broadly stable for the past decade and the incidence rate has been falling steadily since 2000, while gestational diabetes tripled. Whatever is driving this change from 2009, it acts on pregnancy rather than on glucose metabolism generally.

What changed

2009 is the year Australia mandated folic acid in flour. It takes many hours for the body to remove folic acid but when it does it turns it into folate the body can use. The measure of blood stores of folate, red cell folate, therefore reflects intake over the preceding months. It was measured in 1,191 women in the post-fortification cohort and, because the earlier cohort was not tested, in a separate group of 410 women recruited at the same hospital in the same pre-fortification years. Across those two measurements the median rose from 561 nmol/L to 1,490, against a clinical reference range of 360 to 1,400. Those with the lowest stores fell from 22.7 percent of women to 0.6. Levels above the normal reference range rose from 0.5 percent to 57.6. A large share of post-fortification samples were recorded as 1,790 nmol/L, which is the highest figure the laboratory assay can register, so the true rise is larger than the measured one. The authors rightly called this “maternal folate excess”.

Supplement exposure was also high. Reported use of supplements containing 800 micrograms of folic acid or more, twice the recommended dose, rose from 25.9 percent of women to at least 60 percent.

There was a clear dose response relationship. The post-fortification cohort showed a correlation with those with higher folate being more likely to have gestational diabetes. After the same adjustment for age, weight, ethnicity, socioeconomic status and metabolic syndrome, every 500 nmol/L increase in red cell folate raised the risk of gestational diabetes by 34 percent. The risk was 12.5 percent for those with folate within the normal range, 16.2 for those above it and 18.5 for those at or beyond the assay ceiling. Women whose folate was too high to measure had 48 percent more gestational diabetes than women in the normal range, a difference too large to be put down to chance. A dose response relationship is a core piece of evidence of causation in epidemiology.

The study’s own authors conclude that maternal folate status is an independent risk factor for gestational diabetes which has likely contributed to the national rise. They called for urgent assessment of the safety of folate excess in pregnancy. That call comes seventeen years after the exposure began.

How much of the rise did folic acid cause?

Since 2009 there has been no unexposed Australian population left to compare against, so no attributable fraction can be estimated from these data.

Start with the lower end. In the two cohorts, gestational diabetes went from 5.0 percent of women to 15.2, a increase of 10.2. The women who remained within the reference range of folate levels still saw an increase in risk. Instead of a risk of 5.0, these women were affected at a rate of 12.5 percent. In theory it could be argued that other factors were causative for these women. Taking that conservative view we can assume that all women in the cohort would have been affected at a rate of 12.5 percent in a folic acid free environment. Based on that assumption only the difference between 12.5 and the actual average of 15.2 would be attributed to folic acid i.e. 2.7 percent. It is worth remembering that the women within the reference range were still exposed to folic acid but may have handled it differently and the 12.5 figure is an observed category rate rather than a true control baseline. Nevertheless, this is a reasonable lower end scenario.

At the other extreme, if we attribute to folic acid the whole residual increase in risk once the diagnostic criteria change and demographic drift are removed, then the causal share of the increase that can be attributed to folic acid rises to about 80 percent (10.9 of the 13.7 percentage point rise). This would assume every other unmeasured change across the period that could impact on prevalence remained static. Nevertheless, it gives a useful upper estimate.

The honest position is that the causal share sits somewhere between zero and four-fifths, and that the evidence for it being well above zero is the clear dose-response relationship.

What a diagnosis means for a woman

Australia has about 290,000 births a year, so a rise of 13.7 percentage points represents roughly 39,700 women a year being diagnosed who would not have been diagnosed at the old rate. On the lower scenario about 10,300 of those diagnoses would be attributable to folic acid. On the upper scenario it would be about 31,800.

A diagnosis at 26 to 28 weeks means about thirteen weeks of diabetes management with four finger-prick tests a day. Of women diagnosed, 43 percent receive insulin and 8.1 percent oral medication. On the lower scenario that is about 4,400 additional insulin-treated pregnancies a year, 3.8 million finger-prick tests (10,300 × 13 weeks × 7 days × 4 tests) and 2,600 woman-years of restricted diet, every year the policy runs. On the upper scenario it is 13,700 insulin-treated pregnancies, 11.6 million tests and 7,900 woman-years.

Gestational diabetes also results in more induced labours, more caesarean sections, more large babies with the shoulder injuries and birth trauma that follow, and more newborns with low blood sugar, jaundice or an admission to special care. Afterwards it carries a substantially raised risk of type 2 diabetes in the mother, a raised cardiovascular risk and impaired glucose tolerance in the child.

Nobody is looking

Britain begins fortifying in December 2026, at 250 micrograms per 100 grams of flour, above the 200 microgram minimum Australia set. Nothing in the regulations monitors for gestational diabetes. If Britain sees what Australia saw, nothing is in place to notice.

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Dr Clare Craig

Mandatory fortification with folic acid depends on two beliefs. The first is that these defects arise because women do not get enough folate from their food. The second is that raising folate intake across the whole population will therefore prevent them. Both the claim about cause and the claim about remedy must be true to justify the intervention.

Folic acid at pharmaceutical doses does reduce recurrence of neural tube defects in women who have already had an affected pregnancy. The trials were clear about that. However, that is not enough to support the idea that folate deficiency is the cause. Trials of lower doses in women at ordinary risk also reported fewer affected births, however, researchers in that study pointed out that whole effect could have been because of the increased risk of pregnancy loss. What none of these trials establishes is that the defects arose in the first place because the mothers were short of folate.

Nevertheless, the international resolutions and national policies on folic acid fortification are framed as the correction of micronutrient deficiency. At a minimum that is an oversimplification. For a start, the World Health Organization’s own guidance accepts that low folate cannot account for every case.

What would falsify it

If these defects are principally a disease of dietary folate shortage, these things ought to be true.

1. High risk folate deficient group. There should be a group of women who are short of folate. The affected pregnancies should be concentrated in that group.

2. Low risk folate deficient group. Women with the highest stores of folate should be protected. Affected pregnancies should not occur at the top of the distribution. While there is a correlation between folate stores and risk there is no level that provides protection.

3. Rescue. An intervention, giving extra folic acid, should impact women with low folate levels rather than all women.

4. Other exposures. The effect of folic acid should be consistent not conditional on other exposures.

5. Toxicity. High folic acid exposure should never be associated with a higher risk.

Let’s check each against evidence that already exists in the medical literature.

High risk folate deficient group

For decades researchers looked for the women with a folate deficiency who ought to have proved the theory. They could not find them. Most mothers of affected pregnancies had plentiful folate. High risk countries had good diets and every attempt to identify a deficient cohort failed, as a companion article sets out.

Low risk folate deficient group

What emerged instead, eventually was an analysis of an Irish cohort of more than 56,000 pregnancies. Daly et al showed a correlation. Risk fell steadily as red cell folate stores rose. Affected pregnancies occurred at the very top of the distribution. Three decades on there is still no agreement that the curve has a meaningful at risk cut off. The World Health Organization nonetheless adopted a red cell folate concentration as a population target, while stating that it cannot predict any individual woman’s risk.

This shows that folate deficiency is neither necessary nor sufficient for these defects. There is no discrete deficient subgroup to account for them. It could be evidence that folate modifies risk. It could be evidence that folate stores correlate with a third factor that is causative. It is not evidence of a deficiency disease.

Public Health authorities argue that increasing folate must reduce the risk for every group of women and is therefore justified. Where is the evidence that that is the case?

Rescue

If giving folic acid prevented neural tube defects solely by replacing a dietary deficiency then it should not be possible to produce the defect with a known toxin and still prevent it with folic acid. It is possible, and the experiment has been done. This indicates that folic acid is behaving as a drug not a food.

Moulds on maize produce a type of toxin, a mycotoxin called fumonisins. They inhibit an enzyme, ceramide synthase, which the cell needs to build specialised fats in its outer membrane. Folate receptor alpha sits in a patch of those fats, which holds it in shape and allows it to work. Fumonisin degrades the patch and the receptor stops taking folate into the cell. Folate receptor alpha is critical for getting folate into developing brain cells and preventing neural tube defects. When fumonisin B1 was given to laboratory mice across the two days of neural tube closure 79 percent of exposed fetuses developed a neural tube defect. When the mothers were given folic acid the rate was reduced but not restored to normal. When they were instead given GM1, one of the fats that makes up the patch, folate levels inside the cells recovered and the defects were almost entirely prevented.

Here the initiating cause is known and it is a toxin. Folic acid partly rescues it and an agent treating the actual lesion rescues it better. The mothers were not short of folate in their diet. The toxin created the shortage inside the cells by disabling the receptor, and folic acid was acting here as a drug forcing more folate through a damaged system.

This is not just true in mice. Along the Texas border with Mexico the prevalence of these defects doubled in 1990 and 1991, in the same crop year as fumonisin outbreaks in livestock, with risk tracking tortilla consumption. That is a suggestive parallel to the animal work. Together this evidence indicates not only that folic acid has a drug effect but also that toxins can be the causative factor.

Other exposures

Valproate taken in early pregnancy is associated with a ten to twentyfold increase in risk. No doctor claims that is because of a dietary deficiency. The standard teratogen guidance states that attempts to mitigate with higher-dose folic acid have not helped. Pre-existing diabetes, obesity and early-pregnancy fever are all maternal factors that increase the risk with strong supporting evidence. None of them can be reduced to a shortage of folate in the diet.

Then there are the genetic causes, which are a major component and the least often mentioned. Closure is a mechanical process. A sheet of cells must lengthen, bend and fuse on time and a great many genes play a part in that choreography. Disrupt any of them and the tube fails to close in an animal with entirely normal folate. In humans this appears as the syndromic and chromosomal cases, and as a recurrence risk after one affected pregnancy running many times the population rate. That inheritance is not dietary. Of the 621 affected pregnancies recorded in England in 2022, 57 were recorded with an associated genomic condition.

Some of these defects can be prevented with other nutrients. The curly tail mouse is the classic model of a folate-resistant defect. Folic acid does not prevent it and inositol does, acting through an entirely separate signalling system that controls how fast the cells of the developing tail bud divide. In a folate-responsive animal model inositol is not protective. Mice lacking the gene Grhl-3 develop neural tube defects that cannot be prevented with either. In mice deficient in the iron transporter ferroportin, folate levels were measurably low but folic acid did not prevent the defects and high iron did.

In the American national study of pregnancies conceived after mandatory fortification, taking folic acid supplements was not associated with any further reduction in risk, and neither was dietary folate. The authors interpreted this as fortification having already treated any folate-responsive cases. This does not fit with a model where the problem lies entirely in inadequate dietary folate.

In Bangladesh an estimated seventy million people drink arsenic-contaminated groundwater. A study of 294 cases of spina bifida divided these women into low and high arsenic exposure groups measured by the arsenic in their toenails, which records exposure over the preceding months rather than on a single day. In the low arsenic group folic acid was associated with half the odds of the malformation, an estimate whose confidence interval reached exactly 1.00. In the high arsenic group there was no association at all. The two groups were not formally compared, so the difference between them is suggestive rather than demonstrated, and only about a fifth of these women took folic acid, so the numbers in each group are small. An earlier study by the same group showed the protective association fading as arsenic in drinking water rose. Arsenic and folate interact on the same pathway. Folate supplies methyl groups, the small chemical tags the body uses to switch genes on and off, and the body disposes of arsenic by attaching methyl groups to it. Chick embryos exposed to arsenic develop the defects with demonstrated depletion of that methyl supply.

Toxicity

Five mouse strains carrying mutations that cause neural tube defects were given high folic acid doses across generations. Three of the five were negatively affected. Two showed a higher rate of neural tube defects and the third showed increased loss of the affected embryos before birth. In one, the defect rate rose from 18 percent to 58 percent. In another, which had no defects at all on the ordinary diet, 16 percent were affected on the high dose. How can something which can prevent the defect produce it instead, depending on genotype? A shortage being corrected does not behave like that. Correcting a shortage helps those who are short and does nothing to the rest. It does not reverse direction and cause the disease it was given to prevent.

The same mouse studies showed embryonic loss before closure as an adverse response. Long-term supplementation substantially reduced the survival of the affected embryos. If an embryo is lost there is the possibility that the defect did not appear because the embryo died. When the same possibility was raised in 1997 about a human trial in which nine pregnancy losses accompanied every defect apparently prevented, it was treated as speculation and never properly investigated. The mouse work shows the mechanism is real in animals.

It is quite possible that certain human genotypes are more sensitive to folic acid toxicity than others but this has not been investigated.

What can we conclude?

These defects are clearly heterogeneous not due to one causal mechanism. Some are caused by genetic lesions, drugs and maternal metabolic disease. Importantly, no deficient subgroup has ever been identified and one large study in an already fortified population found no further reduction from supplements or dietary folate.

Prevention by folic acid does not identify the initiating cause which can include toxins. Some experimental defects are folate-resistant and preventable through other pathways. Responsiveness to folic acid depends on genotype and it can prove toxic.

Given this we should be asking:

● How much disease can folic acid actually prevent?

● What causes the remainder?

● What is the consequence of exposing everyone?

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Dr Clare Craig

On 13 July 2026, the Irish Minister for Public Health, Jennifer Murnane O’Connor, launched a public consultation on the mandatory fortification of non-wholemeal flour with folic acid. It closes on 5 October. The stated aim is to reduce neural tube defects (NTDs), a group of conditions including spina bifida and anencephaly that arise in early pregnancy.

Ireland and the United Kingdom have some of the highest rates of these defects in western Europe since at least the 1970s. Low folate does raise the risk, and a share of affected pregnancies occur in women whose stores are low, but it cannot account for the rest. The relationship runs as a continuous gradient across the whole range of folate levels, so affected pregnancies still occur in women who are amply supplied, and most mothers whose baby has an NTD are not deficient. The World Health Organization’s own guidance concedes that low folate cannot explain every case. When rates fell across the British Isles the fall did not track the modest rise in dietary folate. The most direct test of that idea is what happens to these defects during a famine, and it does not support it; the evidence is set out in a companion article.

This July consultation comes only five months before the United Kingdom’s own mandate, under the Bread and Flour (Amendment) Regulations 2024, takes effect on 13 December 2026. Given that 70% of Irish flour is imported from the UK, is this a reaction to simplify processes in the UK or is it really aimed at Irish benefit?

WHO is pushing this?

The WHO’s World Health Assembly agreed a resolution in 2023 to accelerate the prevention of micronutrient deficiencies through food fortification. The World Health Organization and global nutrition bodies promote fortification as a means of meeting Sustainable Development Goal targets, in particular the nutrition target under Goal 2 and the health target under Goal 3. The impetus comes from a global timetable running to 2030.

The western European outlier

Across Europe folic acid fortification has remained voluntary. Manufacturers may fortify their products, but no government has required it, and most rely instead on advising women to take supplements before and during early pregnancy. The United Kingdom is the first country in western Europe to break from that position and mandate fortification. The only other European country to have legislated for it is Moldova. Every other nation on the continent, faced with the same evidence, has declined. Ireland now proposes to become the second country in western Europe to follow the British lead.

Why the choice is already half made

Ireland grows some of the highest-yielding wheat in the world, yet it has almost no milling capacity left. Since the closure of the Odlum’s mills the country imports nearly all of its flour. In 2023, 69 per cent of it came from the United Kingdom. British mills count the Republic as their largest export market, sending roughly 180,000 tonnes a year across the Irish Sea.

When UK fortification begins in December, folic acid will be present in the non-wholemeal flour British mills already supply to Ireland. The Food Safety Authority of Ireland has told Irish consumers to expect it, advising that breads, biscuits, cakes and pastries made with UK flour will carry folic acid on the Irish market shortly afterwards. A large part of the Irish bread and bakery supply will be fortified whether or not Ireland passes a law of its own.

The road not taken

Ireland has alternatives. It could source non-wholemeal flour from other European mills, or rebuild the domestic milling capacity it once had. Instead the direction of travel is towards writing the British requirement into Irish law and extending it to all non-wholemeal flour sold in the country. A decision taken by legislators in Westminster, without a parliamentary debate, is, through the supply chain, becoming the default for a population in another country.

Ireland had previously rejected this policy. A national committee recommended mandatory fortification in 2006, and the plan was put on hold in 2009 while the safety evidence was reviewed, after trial results raised questions about folic acid and the recurrence of colorectal adenomas. The consultation reopens the policy without the safety review that paused it having reached a conclusion.

The effect of the UK decisions to mass medicate its own population is that it is prescribing even for people outside of its jurisdiction.

Ireland can buy its flour from any country and grows plenty of wheat but is preparing to add a drug to their daily bread because of a decision taken in the UK. The fact that Ireland and the UK have had above average neural tube defect rates historically has never been explained in terms of diet or folate deficiency. The benefits have been overplayed and the risks ignored. Meanwhile, Ireland is being asked to adopt a British policy that was never debated in parliament and that really originated with the WHO.

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Dr Clare Craig

AMMENDMENT: N.B. This article has been edited. It had implied all chapatti flour (atta) was wholemeal which is wrong. Much of the atta sold in Britain is white or blended. The error came from mis-reading a December 2024 Lords debate. In answer to a question about fortifying chapatti flour the response came that all non-wholemeal flour would be fortified and consideration would be given to chapatti flour.

Key points

• Neural tube defect risk is highest among women of Indian and Bangladeshi origin. They are also the least likely to take a folic acid supplement before pregnancy.
  

• Despite their higher risk these groups only account for about one in fourteen affected pregnancies. Around seven in eight are to White mothers.
  

• The mandate is justified partly as a way to reach women who do not supplement. That description fits these women on both risk and uptake.
  

• Suggestions have even been made that rice should be fortified with folic acid.

The clearest recent estimate of how neural tube defect risk varies by ethnicity in Britain comes from a study of congenital anomaly registers in England and Wales. After adjustment for deprivation and maternal age, mothers of Indian ethnicity were 1.84 times as likely as White mothers to carry a pregnancy affected by a neural tube defect, and Bangladeshi mothers 2.86 times as likely. The excess among Indian mothers was concentrated in anencephaly and in cases occurring alongside other anomalies, which the authors linked to possible genetic factors rather than to folate intake. Findings for Pakistani mothers have varied between regions.

These same groups take folic acid before pregnancy least often. Among nearly half a million women screened in London, 35 per cent of White women reported taking a supplement before conception, against 20 per cent of South Asian women.

It is important to note that the elevated rate translates into a small number of cases. In the register data used for the ethnicity analysis, 52 of 748 affected pregnancies were to mothers of Indian, Pakistani or Bangladeshi ethnicity, about one in fourteen, with roughly seven in eight to white mothers.

The justification for a mandate in food has been based on the claim that is what is required to reach women at risk who do not take supplements. In December 2024, when a peer asked that folic acid reach chapatti flour so the policy did not widen inequalities, the minister replied that fortification applied to non-wholemeal products, that wholemeal was already a higher source of folate, and that chapattis would be considered along with all other products.

The Bread and Flour (Amendment) Regulations 2024 require folic acid in non-wholemeal wheat flour only. Non-wholemeal chapatti flour is is included in that. For Bangladeshi women, rice is a more common staple than for Pakistani and Indian women. Experts have already written in the BMJ advising that rice as well as bread should be fortified.

What is of importance here is that there may be a reason why this group has the highest risk which could help unravel the underlying mechanism. Instead of investigating, the government have reached for a blanket policy of mass medication that exposes millions to benefit only a few.

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Dr Clare Craig

Key points

• The same molecule at different doses can produce different effects and sometimes opposite ones.

• Regulators expect different efficacy by dose including non-linear dose responses

• Safety assessment is built around finding the dose at which harm begins as the dose rises.

• The folic acid safety signals are seen below 1 mg, which is the range fortification will deliver. The trials claiming safety at 4 mg cannot be used to dismiss them.

• Lifelong repeated low dose exposure through food has never been tested.

In 1983, in Science Ian Zagon and Patricia McLaughlin published a result that should have transformed safety testing. They gave naltrexone, a drug that blocks opioid receptors and is used to treat opioid and alcohol dependence, to mice inoculated with cells from a cancer called a neuroblastoma which every untreated mouse went on to develop. There were three key observations: the percentage who developed a tumour; the time before a tumour developed and the percentage that survived the experiment. At the low dose of 0.1 milligrams per kilogram, a third developed the tumour; the time before a tumour appeared nearly doubled and overall survival rose by 36 per cent. At a much higher dose of 10 milligrams per kilogram, every mouse developed a tumour, tumours appeared sooner than in the untreated controls and survival fell by 19 per cent. Conventional medical thinking that more drug has more effect should have been abandoned that day. Here was a result showing that the same molecule, in the same strain of mouse had the opposite effect on the same tumour depending entirely on the dose.

The following year the same authors discovered why. The low dose only blocked opioid receptors for four to six hours a day while the high dose blocked them continuously. The intermittent blockade led to a rebound response in the animal’s own opioid signalling which restrained tumour growth. However, continuous blockade removed that signalling altogether. The dose mattered because of the timing of its effect on the target receptor.

The low dose is now prescribed off licence as a treatment in its own right for its anti-inflammatory effects, and its anti-cancer potential is under investigation on the strength of results like these. The high dose does not help in these scenarios. The two doses are pharmacologically unique in their actions. They are not just proportional effects of a higher dose.

Folic acid is very similar in terms of dosage effects. In the randomised trial evidence cancer incidence was increased in trials of less than one milligram a day. However, at doses over one milligram there is no cancer signal. In addition, in the only large trial of a modest dose in women at ordinary risk of having a baby with a neural tube defect, there was an excess of fetal deaths. The trials at four milligrams did not show a significant excess, though the largest of them was not able to rule one out. The lack of a signal at higher doses is used to dismiss the signal seen at lower doses. This is not good science. It is also terrible public health when the entire country is about to be exposed on a daily basis to the lower dose.

Different efficacy at different doses

Naltrexone is not a one-off. There are numerous drugs which show different effects depending on doses.

For example, doxycycline is an antibiotic but it has an unrelated indication. At 20 milligrams twice a day it cannot inhibit bacteria but does dampen collagen-degrading enzymes so it is licensed for reducing gum disease. Trials at that dose have found no detectable antibacterial effect and therefore no emergence of resistant organisms.

Quetiapine is an example where there are more than two doses of interest. At 25 milligrams the prominent action is blockade of histamine receptors causing sedation. At higher doses serotonin receptors are occupied in the brain, although this is not used as a treatment. Once we reach several hundred milligram doses dopamine receptors are occupied and it can be used to treat psychosis. The molecule stayed the same but there was one of three outcomes in terms of effects in the body based only on dosage.

These are quite separate treatments that happen to use the same molecule.

Why can dosage have such a huge effect?

Bodies are complex systems. Drugs tend to interact by binding to receptors on cells. There are often multiple potential binding sites in the body and they differ in how tightly the drug binds to them. At low concentration only sites with the strongest binding are occupied. As the concentration rises the molecule binds to other sites where binding is less strong and the resulting effect that predominates therefore changes.

Rather than think of drugs as having a linear reaction on the body the effect is the sum of everything the molecule is doing at every binding site it reaches, combined with whatever the body does in response. The body is full of buffering systems such that when a threshold is reached the response changes. Therefore, different dosages can lead to entirely different responses.

All of that is accepted as true when assessing drug efficacy. There is a guideline which sets the standard: E4 of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, adopted by the regulators of Europe, Japan and the United States in 1994. This sets out what must be known about dosage before a medicine can be registered. E4 does not assume that increasing doses increases the benefit. It recommends that study designs look to see whether lower doses are in fact more efficacious than higher ones.

Toxicology is a field which treats problems as linear. At an extreme it measures the lethal dose 50 in animals – the dosage needed to kill half of those given it. At the other end, they make attempts to determine the highest dose at which no adverse effect is seen. The level that gets described as “safe” is determined by starting with doses that do cause harm, reducing it until a level is reached where what is being measured is no longer observed, then dividing by an uncertainty factor to give the safety limit. The methods used mean that any hazard that appears only at lower doses cannot be detected.

E4 says harm should be measured across the range of doses that might be efficacious as well but it only ever treats harm as something which increases as the dose rises. Nowhere does it suggest that a smaller dose might do more damage than a larger one. As with all toxicology the approach taken is to raise the dose and stop where side effects become unacceptable. The lower dose is assumed to be safer throughout this process. The assumption that lower doses are harmless is embedded so deeply that when the guideline does describe adverse effects occurring more often at a lower dose, it calls the excess “spurious”. E4 may have been correct in that the study gave the same people increasing doses and let them drop out once they had an adverse event. That meant susceptible people were never exposed to high doses. It would make more sense to test different people with different doses and follow them all up for a reasonable period of time and that is what E4 recommends but it is rarely done. The design of current studies cannot show whether lower doses cause particular adverse reactions. Because the dosage question is approached from the point of ensuring optimal efficacy the dose comparison trials are small and short. A typical study to compare doses checks three or four dosages on groups of around fifty people for about twelve weeks. These groups are far too small for any measure of safety. The approach to toxicology is not well placed to detect low dose harm.

With regards to folic acid, when the MRC Vitamin Study reported in 1991, its own investigators noted that a trial with enough power to demonstrate efficacy usually lacks the power to settle safety, so that “a judgment on safety needs to be taken on wider grounds”. No such safety study has ever been done. On dosage they observed that a lower dose such as 0.36 milligrams was likely to be effective as well, though possibly less so, and that a very large trial would be needed to compare the two.

The cancer concerns were dismissed after a 2013 Lancet meta-analysis pooled results from trials which included doses of a fraction of a milligram per day up to forty times that amount. They then reported a single average. That is a legitimate answer to the question of how much cancer there was overall, but it cannot answer whether the effect differs by dose. E4 says that the differences between separate trials usually make such an approach “unsatisfactory”.

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What the folic acid data actually show

The limited evidence on folic acid safety indicates that the harm may not be greater at the larger dose. This is true for both the cancer data and the fetal death data.

Firstly, the cancer trials studying exposure below one milligram a day show cancer incidence about 20 per cent higher than in the placebo groups. However, trials on doses higher than this show no excess. Secondly, the only large randomised trial of a modest dose of folic acid in women at ordinary risk, recruited while planning a pregnancy, reported no significant effect on any category of fetal death. That is accurate only when each category is examined separately. From the trial’s own table the total number of pregnancy losses was 374 among 2,793 pregnancies in the treatment group against 304 among 2,660 in the placebo group, significant at a p value of 0.028. That total includes every pregnancy loss after a positive pregnancy test. Counting only later losses still results in an excess but it is no longer statistically significant. The treatment group were given a multivitamin so the excess cannot be attributed to the 0.8 milligrams of folic acid alone. The only other trial to use a dosage below 1 mg, and the only one at that dose with an arm giving folic acid without other vitamins, was too small to see a safety signal and was stopped before reaching its target size because recruitment had slowed. The researchers pooled what little data they had to report a benefit but did not pool the same data when reporting pregnancy loss. When a Cochrane review pooled it in 2015 the miscarriage rate was 31 per cent higher on folic acid, on twenty five events in total, such that it was not statistically significant.

Three of the four randomised trials in women who had already had an affected pregnancy used 4 milligrams. The largest of them, the MRC trial, found that the excess of miscarriage was not statistically significant with a relative risk of 1.06 but a confidence interval from 0.79 to 1.43. It therefore could not exclude an effect of the size the Hungarian trial recorded. It could be that the size of the trial was the issue rather than that there were no excess pregnancy losses at the higher dose. In 1997 Judith Hall declared that it would be unethical to repeat the trials, so this remains the full extent of the data available.

Both safety signals appear in evidence from doses below 1 milligram a day and neither appears at higher, medicinal dosing. The intended mandatory fortification will expose the population eating ordinary quantities of wheat to doses under 1 mg a day. A medicine is prescribed at a particular amount each day for a period of time. Fortification results in variable dosing each day and over a lifetime.

In 1997 Nicholas Wald, who had coordinated the MRC trial, reanalysed its miscarriage figures to see whether there was evidence that folic acid causes fetal loss. He concluded it did not and defended that conclusion by saying that the trial had used about ten times the dose proposed for the population, suggesting that evidence “adds further weight against the miscarriage hypothesis”. Remember, it was his same paper which had said six years earlier that comparing 4 milligrams with 0.36 milligrams would need a very large trial to ensure the right dose for efficacy. That was never done.

What happens in the body at higher doses

The effect of folic acid on blood folate stores at different doses has been measured. Women of reproductive age were given either 1.1 milligrams or 5 milligrams of folic acid daily for thirty weeks. The higher dose produced about twice the plasma and red cell total folate concentrations, despite a more than fourfold increase in the amount taken. Circulating levels of unmetabolised folic acid did not differ significantly between the two groups. The researchers suggested there may be mechanisms by which the body can adapt to high folic acid intakes and limit exposure to unmetabolised folic acid. If that is true, that the body handles it differently at different doses, that has huge implications for safety testing.

There are several interactions of folic acid in the body that would account for such an observation. The principle can be thought of as like a pipe that bursts and causes a flood. Such an incident is noticed and dealt with within hours. However, there are not the same systems to deal with a pipe that leaks insidiously and that can rot a joist over two years because it causes harm below the radar.

At therapeutic doses, absorption from the gut, enzyme saturation and renal spill all limit what acts on other tissues. Fortification doses do not reach the thresholds for absorption or renal spill, but they do exceed the capacity of the enzyme. At the fortification dose the body therefore produces unmetabolised folic acid while neither of the mechanisms that shed it is yet in play. That is a low dose window, in which a modest amount is handled differently rather than a scaled down version of the effect seen with a medicinal dose.

Timing

Almost every trial in the folic acid safety literature was based on a daily tablet. The result is a daily peak that is then cleared. Folic acid in flour will be in bread, pasta, biscuits and sauces, arriving at breakfast, at lunch, at supper and at points in between. Exposure could be for a lifetime.

Intermittent large doses are cleared by the body but continuous low doses are not cleared in the same way. Naltrexone showed that the duration of occupancy of a receptor can determine the effect. Folic acid binds folate receptor alpha more tightly than the natural reduced folates do, so where it is present it competes for the receptor. Unmetabolised folic acid was found in 38 per cent of US adults aged sixty and over in the 2001 to 2002 national survey, after an average ten hour fast (routine fortification of flour with folic acid was introduced in the US in 1998). A later national survey covering all ages found it in more than 95 per cent of people, despite using a test that could only detect higher levels. These surveys were not picking up temporary peaks after a meal. Taking folic acid as a pill creates a single large peak which the body clears. Being exposed through fortification seems to leave unmetabolized folic acid in the blood continuously. The studies to show how much that matters have not been done for folic acid. Importantly, methotrexate, which is a drug used as an immune suppressant and as chemotherapy and is carried by the same transporters as folate, is absorbed more completely when the same total dose is given as repeated small amounts. Safety testing for repeated low dose exposure to folic acid in a healthy population simply has not been done.

Deciding the upper safety limit

The upper limit of 1 milligram per day for safety was decided on the basis of a single chosen endpoint, namely case reports of neurological deterioration in people with undiagnosed B12 deficiency. Other possible harms were reviewed but the evidence was judged too weak to include or unrelated to a particular dose. The upper limit therefore should not be considered to be a level below which safety has been shown. Different doses will result in different concerns. Worryingly, the only work on safety of fortification prior to the change to the regulations has been a calculation of how many people might exceed this hypothetical upper limit. That is not a good way of assessing the dangers.

Burden of proof

It is not for people with concerns about safety to have to prove that folic acid is definitely unsafe in all people. When governments decide to mandate adding a drug to a staple food, the onus is on them to have carried out proper safety testing beforehand. They did not.

From 13 December 2026 folic acid exposure will become universal in the United Kingdom. It also becomes far harder to study safety at that point because any potential placebo group would be exposed through their diet.

Pharmacology has understood for more than forty years that doses and their effects on the body are not linear. Safety testing needs to account for different negative impacts at different doses too.

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