©Alexandra Chambers | Neurotopia CIC | September 2025
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Abstract
This investigative research critically re-evaluates the widely accepted attribution of reduced neural tube defect (NTD) rates in Canada to folic acid fortification. Drawing on a parallel timeline analysis, the study identifies and contextualises several significant pharmacological and regulatory changes – specifically the concurrent withdrawal or restriction of known teratogenic anticonvulsants – that occurred during the implementation of fortification policy. The analysis integrates historical prescribing data, known teratogenic mechanisms, and the chronological overlap of drug market exits with declining NTD incidence. Evaluation reveals that these co-occurring variables represent substantial confounding factors. In addition, the paper incorporates a research synthesis on the biochemical limitations of synthetic folic acid, including the role of unmetabolised folic acid (UMFA), differential receptor binding, and genetic utilisation variance. The collated findings challenge the prevailing narrative that fortification was responsible for improved NTD outcomes and suggest an ongoing triple hit hypothesis; involving MTHFR susceptibility, anti-seizure medication (ASM) exposure, and hidden folate and B12 insufficiency as a plausible driver of paradoxical neural tube defect trends in the UK. This compilation highlights that a reassessment of causality is required in population-level nutrition policy to safeguard public health. Pharmacogenomic and nutritional profiling, including assessment of B12 and folate sufficiency, should be prioritised in women of reproductive age before the prescribing of anti-seizure medications. This analysis underscores the need for rigorous pharmacological context in public health modelling and offers an evidence-based call for transparency in attributing outcomes to broad scale interventions.
Introduction
The 2007 paper titled Reduction in Neural-Tube Defects After Folic Acid Fortification in Canada by De Wals et al.¹ overlooks major confounders in its methodology: the phased withdrawal of teratogenic anti-seizure medications (ASMs) such as paramethadione and trimethadione.2-3 Both in circulation since the 1940s and both discontinued by 1995, with reduced prescribing prior to the fact – a standard response due to known teratogenic risk.4 This reduction in foetal exposure would have resulted in falling neural tube defect (NTD) rates, independent of fortification. This paper presents a timeline of these pharmacological changes to demonstrate that these events were not only relevant, but critically unaccounted for.
This research synthesis also challenges the safety of ongoing folic acid fortification by examining key biochemical mechanisms, including the accumulation of unmetabolised folic acid (UMFA) and the variety of associated health indications. Through examining the dualistic masking of both folate and vitamin B12 insufficiency, anti-seizure medication (ASM) usage and the influence of MTHFR polymorphisms, a biologically plausible triple-hit model emerges. This hypothesis seeks to increase mechanistic understanding regarding the increased incidence of anencephaly in the UK. The importance of pharmacogenomics and an individualised approach is underscored for both clinical practice and the determination of national policy.
Omitted Pharmacological Confounders
· Sodium Valproate/ Depakene (valproic acid) / divalproex sodium (Epival) / Ratio-Valproic
The Independent Medicines and Medical Devices Safety Review (IMMDSR) 2020 sodium valproate timeline demonstrates prescribing changes that occur with increased awareness of risk, to reduce incidence of NTDs. These include coordinated restriction of teratogens via guideline changes, PIL (Patient Information leaflet) updates, and reduced prescribing to women protocol prior to additional anti-seizure drug withdrawals.4-5 Additionally, two long-standing anticonvulsants were withdrawn – paramethadione (Paradione)2 and trimethadione (Tridione)3 – widely known for their teratogenicity, causing severe congenital malformations including neural tube defects.4,6-8
1. Paramethadione: (Paradione):
Listed as discontinued by Abbvie (formerly Abbott); prescribing declined up to cessation in the mid-1990s and records show the final production batch was in 1989.2 The FDA formally withdrew the new drug application (NDA) in 2004 once Abbott’s original patent had ended.9
2. Trimethadione (Tridione):
Also listed as discontinued by Abbvie (formerly Abbott) by the FDA; marketing of this drug finally ceased in 1995,10 though the NDA has remained active for several years.3
Timeline of Pharmacological Confounders
To contextualize the decline in neural tube defects (NTDs), the following table on page 5 presents a parallel timeline of folic acid fortification efforts, alongside pharmaceutical events that contributed to the observed data outcomes.
Year
Fortification/ Trial Progress: De Wals et al., 20071
Pharmaceutical/ Prescribing Events
Expected Pharmaceutical Based Data Impact (Independent of Fortification)
1993–1997
Baseline data window
(Pre – Fortification)1
Paramethadione and trimethadione usage already in decline. Prescribing restrictions underway in clinical practice.2-4,10
Baseline elevated due to decades of teratogenic drug exposures; restrictions ongoing; decline underway,2-4,10
1994–1995
Still baseline/ pre-fortification1
Trimethadione discontinued in 1995.10 Paramethadione ceased by mid-1990s (final batch 1989).2
NTD rates continue declining, reflects reduced prescribing and previous withdrawals.2-4
1996–1998
Mandatory folic acid fortification introduced in Canada1
Simultaneous tightening of sodium valproate prescribing; regulators advising reduced use in women of childbearing potential.4
Observed reductions align with pharmaceutical prescribing changes.2-4
Late 1990s–2000s
Post fortification period in De Wals et al. dataset1
Further sodium valproate/ Depakene / divalproex/ Epival/ Ratio-valproic restrictions: guideline changes, PIL updates, reduced prescribing to women of childbearing potential.4
Additional NTD decline sustained by prescribing changes, creating appearance of causal link with fortification. Correlation, not causation.4
2007
De Wals et al. published, concluding that folic acid fortification is associated with a significant reduction in NTDs.1
Health Canada recall/discontinuation of Depakene® 500 mg and ratio-VALPROIC® 500 mg.5
Decline presented as effect of folic acid fortification; data significantly influenced by major drug prescribing restrictions & consecutive withdrawals.2-5,10
Geographic Heterogeneity
De Wals et al.’s paper concluded that “food fortification with folic acid was associated with a significant reduction in neural-tube defects in Canada. Furthermore, the risk reduction appeared greatest in regions in which the rates were highest before the fortification program was implemented”.1 While attributed to fortification, this gradient is more consistent with regional variation in prescribing and withdrawal of teratogenic drugs.2-5,10 However, this explanation was not modelled or considered.
Biochemical Distinction
Scientific discourse frequently uses the terms ‘folate’ and ‘folic acid’ interchangeably, for example the Goossens et al, 2021 paper titled Properties and Reactivity of the Folic Acid and Folate Photoproduct 6-Formylpterin11. Regardless, folate confers to naturally occurring reduced vitamers in food, whereas folic acid (pteroylmonoglutamic acid) is the fully oxidised synthetic form used in supplements and fortification.12 Incidentally, 5-MTHF (natural folate) is relatively light-stable on its own, except in the presence of riboflavin, a strong photosensitizer.13 Riboflavin has also been added to fortified foods in the US – its degradation is greatly accelerated under ordinary UVA/visible light, leading to oxidative breakdown products. This undermines Goossens et al.’s blanket attribution of 6-formylpterin to ‘folate’ and exposes another fortification practice that significantly erodes nutritional value.
In 1988 Mason & Selhub demonstrated that folic acid can be highly absorbed intact via protein at the intestinal brush border,14 however, this does not ensure effective metabolic utilisation. The superior bioavailability of folic acid is a categorical error: it is not absorption into the bloodstream that benefits, but the conversion into active folates. Dihydrofolate reductase (DHFR) is so limited that folic acid accumulates unmetabolised in circulation, paradoxically competing with natural folate.12 This has many varied documented adverse effects, such as functional folate deficiency and subsequent downstream health problems.16-17 Therefore, the common metric assessed to justify fortification (serum folate levels) is misleading, since it reflects circulating synthetic folic acid rather than true metabolic utilization.
Population exposure: UMFA has been detected in umbilical cord blood, confirming placental transfer and foetal exposure15, and nearly all serum samples from US children, adolescents and adults,18 and fasting plasma.17 As one carbon metabolism underpins DNA methylation, this raises the possibility that intake constitutes an epigenetic risk factor, with potential long-term adverse effects.12,19-21 Zsigrai et al. (2022) also revealed that folic acid directly alters gene expression in colorectal cancer cells, demonstrating both epigenetic and oncogenic concerns.23
Early-Onset Colorectal Cancer (EOCRC)
· US: Ages 20–29 saw annual CRC increases of 1.7-4.9% between 2004-2016.24-25
· England: Incidence in ages 20-29 rose from 0.8/100,000 (1993) to 2.8/100,000 (2014).26
Pattern: Persistent increases across cohorts/geographies. Screening may account for increased awareness.27 However, this does not explain the continued ongoing increase; a spike-then-plateau would be expected if detection were primary.
Implication: EOCRC trends are consistent with environmental exposure risk – synthetic folic acid being time-aligned and biologically plausible.
Prostate Cancer and Serum Folate
· Meta‑analysis: In their 2014 study, Tio et al. confirmed high circulating folate is linked to prostate cancer; whilst confirming this was not through dietary folate,28 and Figueirodo et al. (2009) implicated folic acid specifically.29
· UK data: Since the early 1990s, prostate cancer incidence in males has increased by 53% (2017-19) and is projected to rise by a further 15% by 2038-40, reaching around 85,100 new cases annually.30
· US data projection: Approximately 313,780 new prostate cancer cases are expected in 2025, with incidence in younger men showing a rising trend in recent years.31
Implication: Elevated levels of serum folate – and particularly UMFA from fortification or supplements – offer a coherent biological mechanism for the observed rise in prostate cancer incidence.
International Data Variations
International implementation of folic acid fortification demonstrates a consistent pattern of erasing baseline clarity. In some countries, voluntary industry adoption was widespread years before mandates were enacted, effectively removing a clean pre-fortification reference point.32 Such structural variability makes fortification appear unfalsifiable, while obscuring the contribution of contemporaneous pharmacological withdrawals2-5,10 that align with observed declines in NTDs.
In the United Kingdom, flour fortification has been effectively in place for many years through voluntary measures, despite the absence of a legal mandate.33 The 2000 Committee on Medical Aspects of Food and Nutrition Policy (COMA) report states that 80–90% of breakfast cereals and many breads were already fortified with folic acid by the late 1990’s.
In November 2024 the UK government announced legislation requiring mandatory folic acid fortification of non-wholemeal wheat flour, due to take effect by the end of 2026.34 The long-standing voluntary exposure complicates baseline interpretation and obscures any potential clean before-and-after data comparison.
Recent surveillance data further challenge the assumption that fortification has delivered continuing protective benefit. In England, neural tube defect (NTD) prevalence rose from 12.1 per 10,000 births (2010–2014) to 13.6 per 10,000 (2015–2019), with the increase driven largely by anencephaly.35 Scotland presents a similar picture: overall NTD prevalence showed no significant decline between 2000 and 2021, while anencephaly rates increased significantly after 2013.35-36 The UK is established in this data by Broughan et al. as unfortified prior to 2021. However, as stated, widespread voluntary folic acid fortification has been in place in the UK for decades. This means the population has already been exposed to folic acid without informed consent or genomic understanding. Framing this period as unfortified is inaccurate; and serves as a misrepresentation that shields both government and industry from accountability, and risks misattributing future changes in neural tube defect prevalence.
Folate & B12 Insufficiency
Low maternal vitamin B12 is a well-established independent risk factor for neural tube defects, particularly anencephaly, with women in the lowest quartile of B12 facing a two- to five-fold higher risk, irrespective of folate intake.37-38 B12 deficiency impairs one-carbon metabolism, elevates homocysteine, and disrupts DNA methylation required for neural tube closure.39-40
Importantly, long-term reliance on synthetic folic acid does not resolve these B12-dependent pathways and may exacerbate both functional folate and B12 deficiency by masking haematological symptoms.41-42 This mechanism offers a plausible explanation for why anencephaly rates have risen in certain fortified populations, suggesting that folic acid exposure may obscure – rather than prevent – underlying vulnerability.
MTHFR and Pharmacological Vulnerability
UMFA related harms disproportionately affect genetic subgroups with MTHFR C677T polymorphisms, such as autistic individuals.43 The MTHFR C677T polymorphism, reduces the efficiency of folate metabolism and subsequently raises homocysteine levels.44 Those with other MTHFR variants that are also relatively common in the general population are also at risk.44-45
In summary, folic acid has been shown to disrupt gene expression21, interfere with methylation processes22, and impair immune surveillance mechanisms such as natural killer cell function.17,19, Excess serum folate from folic acid, particularly in the absence of sufficient vitamin B12, has been linked to neurological impairment, haematological abnormalities,41-42 and suboptimal cognitive outcomes.46-47 Unmetabolised folic acid is now detectable in the vast majority of serum samples in fortified populations,18 reinforcing concerns about chronic systemic exposure. Epidemiological data show temporal associations between fortification policies and rising colorectal and prostate cancer rates 24–26, with additional studies directly linking circulating unmetabolised (serum) folic acid specifically to increased prostate cancer risk.28-29
Epilepsy: An Additional Risk factor
Several meta-analyses show that people carrying the T allele have a higher chance of developing epilepsy, with the risk strongest in those who inherit two copies (TT genotype).48-49 These same variants also influence treatment outcomes; in patients with high homocysteine, the C677T polymorphism has been linked to poorer seizure control and reduced response to antiseizure medication.50
Pharmacogenomic studies confirm that MTHFR and related polymorphisms contribute to variability in both drug effectiveness and side-effects.51-52 Mechanistic studies support this connection: individuals with MTHFR variants who take antiseizure medications show greater depletion of folate and vitamin B12, alongside elevated homocysteine, which is itself a pro-convulsant metabolite.53-55 In rare but severe cases, complete MTHFR deficiency has been reported to cause familial epileptic encephalopathy.56 This creates a paradox; the very demographics who are genetically more likely to develop epilepsy are also those most vulnerable to the metabolic side-effects of the drugs used to prevent seizures. In women of reproductive age, this dual vulnerability is especially critical: folate antagonism, high-dose synthetic folic acid, and unrecognised B12 insufficiency present an at-risk state. This can converge with impaired one-carbon metabolism, compounding both seizure-related risks and teratogenic risks such as neural tube defects.
Hispanic populations also carry a disproportionately high prevalence of the MTHFR C677T polymorphism, known to reduces enzyme activity and impair one-carbon metabolism.57 Analysis of the 1000 Genomes Project estimated the allele frequency at approximately 47% among Hispanics, compared with 36% in Europeans, 30% in East Asians, 12% in South Asians, and 9% in Africans. In Mexican Mestizo populations, homozygosity for the TT genotype occurs in around 25% of individuals, and in certain Amerindian groups it reaches 57%.58 This high genetic prevelance is biologically relevant, as reduced MTHFR function is a well-established risk factor for neural tube defects (NTDs) in the context of folate and B12 imbalance.39-40 Consistent with this genetic susceptibility, U.S. surveillance data from 1999–2011 show that Hispanic women had consistently higher prevalence of NTD-affected pregnancies compared to non-Hispanic whites and blacks.59 During this period, spina bifida prevalence was 4.17 per 10,000 births among Hispanics, compared with 3.22 in non-Hispanic whites and 2.64 in non-Hispanic blacks.
The convergence of genetic, nutritional, and pharmacological evidence highlights a high-risk subgroup that has been overlooked in current policy. MTHFR polymorphisms are associated with both epilepsy susceptibility and impaired folate metabolism,48-49 while vitamin B12 deficiency is an independent and well-established risk factor for anencephaly.38,42
Lamotrigine: A Missing link?
Lamotrigine (Lamictal), is termed a ‘newer’ generation anti-seizure medication, most frequently prescribed to women with epilepsy, particularly in the UK and much of Europe.60 US biomarker studies of lamotrigine monotherapy, conducted after the introduction of folic acid fortification and routine periconceptional supplementation, have generally reported no major reductions in serum folate, or vitamin B12; nor consistent rises in homocysteine over ~32 weeks of follow-up.61 However, these apparently null findings are artefacts of the post-fortification environment: after the 1998 US mandate, median serum folate concentrations in women of reproductive age rose sharply and the prevalence of low folate fell to <1% by 1999–2000.62 Under these conditions, serum folate largely reflects UMFA rather than functional folate status, masking antagonistic effects.
In contrast, Huang et al. (2016) observed significant reductions in serum folate among Chinese patients treated with anti-seizure medications, including lamotrigine, where no national folic acid fortification policy was in place.63 This divergence highlights how post-fortification serum folate assays in the U.S. may obscure lamotrigine-related folate depletion, inflating biomarker values through circulating unmetabolised folic acid (UMFA).
Recent pregnancy-focused studies further confirm this metabolic distortion: women with epilepsy using lamotrigine show lower concentrations of active folate metabolites than untreated women.64-66 While higher antiseizure drug levels are associated with greater UMFA, a reduced ratio of active MTHF to inactive folate, and evidence of increased folate catabolism. These findings indicate that lamotrigine’s antagonism is hidden, not absent, and that the prevailing fortification environment produces misleading biomarker profiles with significant implications for risk assessment.
Together, these factors culminate into a biologically plausible triple hit – MTHFR variants, anti-seizure medication exposure (including lamotrigine), and concealed dual folate and B12 insufficiency. This could aid in explaining the recent paradoxical rise in neural tube defects reported in UK surveillance data. This pattern warrants further investigation, ideally through comparing the UK with regions where the ASM Levetiracetam is prescribed first-line over Lamotrigine.
The precautionary implication is clear: women of reproductive age should undergo pharmacogenomic and nutritional profiling before lamotrigine is prescribed, to minimise avoidable teratogenic risk.
Corporate Context
In 2001, Abbott Laboratories acquired Knoll Pharmaceuticals (the pharmaceutical arm of BASF) for $6.9 billion.67 BASF itself remains one of the world’s major industrial producers of synthetic folic acid, while the Knoll lineage – now within AbbVie – also included folate-antagonist teratogenic anticonvulsants that are now withdrawn in America. Though this may be controversial, the dynamic does reflect a problem–solution–profit cycle whereby the same industrial actors – or their corporate successors – are implicated in creating or exacerbating a public health risk and profiting from its proposed remedy.68
Conclusion
Folic acid fortification was introduced as a preventative measure for NTDs, and the research strongly indicates that its implementation has catalysed severe downstream consequences across multiple health domains. This includes rising rates of early onset cancers, and potentially irreversible epigenetic damage that also disproportionately affect the most genetically vulnerable populations.
The study by De Wals et al. was technically correct in reporting a temporal decline in neural tube defects after the introduction of folic acid fortification in Canada. However, the paper has been highly influential; universally cited as causal evidence, underpinning justification for global fortification policy. Correlation must not be misinterpreted as causation; the observed decline in neural tube defects independently reflects the withdrawal and restriction of several teratogenic drugs. This reflects the broader problem–solution–profit cycle, in which continued interventions sustain dependence, and an ongoing requirement for further solutions. Furthermore, cessation of the cycle would elucidate previously obscured patterns of harm, both historical and ongoing – and the structural interests that have profited from them.
Various peer reviewed studies exist on the risk-benefit analyses of folic acid and fortification, and show conflicting results; the majority demonstrating the potential for significant harm to the population. Geographical NTD data has previously been stratified by siloed teratogenic drug exposure versus non exposure, making fortification appear to be the mechanism of beneficial change. However, that data reflects an underlying – and unaccounted for – global pharmacological shift.
Future policy and clinical practice must therefore prioritise public health by moving beyond fortification-based frameworks. Strategies should incorporate pharmacogenomic and nutritional profiling, with routine assessment of functional B12 and folate in women prescribed any anti-seizure medications, including newer generations such as lamotrigine. Without such measures, surveillance will continue to misinterpret biomarker signals and avoidable teratogenic outcomes will further increase.
References
1.De Wals P, Tairou F, Van Allen MI, Uh SH, Lowry RB, Sibbald B, et al. Reduction in neural-tube defects after folic acid fortification in Canada. N Engl J Med. 2007;357(2):135-42. 10.1056/NEJMoa067103
2.Food and Drug Administration. FDA-approved drug products – NDA 006800, Paradione (paramethadione). AbbVie Inc. [cited 2025 Sep]. Available from: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=BasicSearch.process
3.Food and Drug Administration. FDA-approved drug products – NDA 005856, Tridione (trimethadione). AbbVie Inc. [cited 2025 Sep]. Available from: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=BasicSearch.process
4.Independent Medicines and Medical Devices Safety Review (IMMDSR). Sodium valproate timeline – key events (Annex C). In: First do no harm – The report of the Independent Medicines and Medical Devices Safety Review. London: IMMDSR; 2020. [cited 2025 Sep]. Available from: https://www.immdsreview.org.uk/downloads/Annexes/Annex-C-Valproate-timeline.pdf
5.Health Canada. Recall of two valproic acid drugs, Depakene 500 mg and ratio-VALPROIC 500 mg. Health Canada News Release. 2007 May 28. [cited 2025 Sep] Available from: https://www.canada.ca/en/news/archive/2007/05/recall-two-valproic-acid-drugs-depakene-500-mg-ratio-valproic-500-mg.html
6.King PB, Lie RT, Irgens LM. Spina bifida and cleft lip among newborns of Norwegian women with epilepsy: changes related to the use of anticonvulsants. Am J Public Health. 1996;86(10):1454-6. Doi: https://doi.org/10.2105/AJPH.86.10.1454
7.German J, Ehlers KH, Kowal A, De George FV, Engle MA, Passarge E. Possible teratogenicity of trimethadione and paramethadione. Lancet. 1970;2(7666):261-2. Doi: https://doi.org/10.1016/s0140-6736(70)92608-5
8.Zackai EH, Mellman WJ, Neiderer B, Hanson JW. The fetal trimethadione syndrome. J Pediatr. 1975;87(2):280-4. doi: 10.1016/s0022-3476(75)80603-2
9.Food and Drug Administration. Schering Corp, et al. Withdrawal of approval of 92 new drug applications and 49 abbreviated new drug applications. Fed Regist. 2004;69(87):25124-30. Available from: https://www.govinfo.gov/content/pkg/FR-2004-05-05/pdf/04-10194.pdf
10.Caplan A, Teagarden JR, Bacher HP, Jarvis MF. A patient-centric model for discontinuation of a single-sourced approved drug. Clin Pharmacol Ther. 2019;106(3):494-7. doi: https://doi.org/10.1002/cpt.1411
11.Goossens JF, Thuru X, Bailly C. Properties and reactivity of the folic acid and folate photoproduct 6-formylpterin. Free Radic Biol Med. 2021; 169:386-95. doi: 10.1016/j.freeradbiomed.2021.05.002
12.Menezo Y, Elder K, Clement A, Clement P. Folic acid, folinic acid, 5-methyltetrahydrofolate supplementation for mutations that affect epigenesis through the folate and one-carbon cycles. Biomolecules. 2022;12(2):197. doi: https://doi.org/10.3390/biom12020197
13.Steindal AH, Tam TT, Lu XY, Juzeniene A, Moan J. 5-Methyltetrahydrofolate is photosensitive in the presence of riboflavin. Photochem Photobiol Sci. 2008;7(7):814-8. doi: https://doi.org/10.1111/j.1751-1097.2006.tb09826.x
14.Mason, J.B., & Selhub, J.Folate-binding protein and the absorption of folic acid in the small intestine of the suckling rat. The American journal of clinical nutrition,1988 48 3, 620-5. doi: https://doi.org/10.1093/ajcn/48.3.620
15.Sweeney MR, McPartlin J, Weir DG, Scott JM. Folic acid fortification and public health: report of unmetabolised folic acid in cord blood. Br J Nutr. 2005;94(6):727-30. doi: 10.1079/bjn20051572
16.Lucock M, Yates Z. Folic acid fortification: a double-edged sword. Curr Opin Clin Nutr Metab Care. 2009;12(6):555-64. doi: 10.1097/MCO.0b013e32833192bc
17.Troen AM, et al. Unmetabolized folic acid in plasma is associated with reduced natural killer cell cytotoxicity among postmenopausal women. J Nutr. 2006;136(1):189-94. doi: 10.1093/jn/136.1.189
18.Pfeiffer CM, Sternberg MR, Fazili Z, Yetley EA, Lacher DA, Bailey RL, et al. Unmetabolized folic acid is detected in nearly all serum samples from US children, adolescents, and adults. J Nutr. 2015;145(3):520-31. doi: 10.3945/jn.114.201210
19.Ondičová M, Irwin RE, Thursby SJ, Hilman L, Caffrey A, Cassidy T, et al. Folic acid intervention during pregnancy alters DNA methylation, affecting neural target genes through two distinct mechanisms. Clin Epigenetics. 2022;14(1):53. doi: https://doi.org/10.1186/s13148-022-01282-y
20.Padmanabhan N, Menelaou K, Gao J, Anderson A, Blake GET, Li T, et al. Abnormal folate metabolism causes age-, sex- and parent-of-origin-specific haematological defects in mice. J Physiol. 2018;596(18):4341-60. doi: 10.1113/JP276419
21.Blake GET, Zhao X, Yung HW, et al. Defective folate metabolism causes germline epigenetic instability and distinguishes Hira as a phenotype inheritance biomarker. Nat Commun. 2021; 12:3714. doi: https://doi.org/10.1038/s41467-021-24036-5
22.Kok DE, Dhonukshe-Rutten RA, Lute C, Heil SG, Uitterlinden AG, van der Velde N, et al. The effects of long-term daily folic acid and vitamin B12 supplementation on genome-wide DNA methylation in elderly subjects. Clin Epigenetics. 2015; 7:121. doi: https://doi.org/10.1186/s13148-015-0154-5
23.Zsigrai S, Kalmár A, Barták BK, Nagy ZB, Szigeti KA, Valcz G, et al. Folic acid treatment directly influences the genetic and epigenetic regulation along with the associated cellular maintenance processes of HT-29 and SW480 colorectal cancer cell lines. Cancers (Basel). 2022;14(7):1820. doi: 10.3390/cancers14071820
24.Vuik FE, Nieuwenburg SA, Bardou M, Lansdorp-Vogelaar I, Dinis-Ribeiro M, Bento MJ, et al. Increasing incidence of colorectal cancer in young adults in Europe over the last 25 years. Gut. 2019;68(10):1820-6. doi: 10.1136/gutjnl-2018-317592
25.Siegel RL, Miller KD, Jemal A. Colorectal cancer statistics, 2019. CA Cancer J Clin. 2019;69(6):438-51. doi: 10.3322/caac.21551
26.Araghi M, Soerjomataram I, Bardot A, Ferlay J, Cabasag CJ, Morrison DS, et al. Changes in colorectal cancer incidence in seven high-income countries: a population-based study. Lancet Gastroenterol Hepatol. 2019;4(7):511-8. doi:10.1016/S2468-1253(19)30147-5. Erratum in: Lancet Gastroenterol Hepatol. 2019;4(8):e8. doi: 10.1016/S2468-1253(19)30147-5
27.Ahnen DJ, Wade SW, Jones WF, Sifri R, Mendoza Silveiras J, Greenamyer J, et al. The increasing incidence of young-onset colorectal cancer: a call to action. Mayo Clin Proc. 2014;89(2):216-24. doi: https://doi.org/10.1016/j.mayocp.2013.09.006
28.Tio M, Andrici J, Cox M, Eslick G. Folate intake and the risk of prostate cancer: a systematic review and meta-analysis. Prostate Cancer Prostatic Dis. 2014;17(3):213-9. doi: https://doi.org/10.1038/pcan.2014.16
29.Figueiredo JC, Grau MV, Haile RW, Sandler RS, Summers RW, Bresalier RS, et al. Folic acid and risk of prostate cancer: results from a randomized clinical trial. J Natl Cancer Inst. 2009;101(6):432-5. doi: 10.1093/jnci/djp019
30.Cancer Research UK. Prostate cancer statistics [Internet]. London: Cancer Research UK; 2023. Available from: https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/prostate-cancer/prostate-cancer-stats0
31.American Cancer Society. Cancer facts & figures 2025. Atlanta: American Cancer Society; 2025. Available from: https://www.cancer.org/cancer/types/prostate-cancer/about/key-statistics.html
32.Quinn E, et al. Global heterogeneity in folic acid fortification policies and implications for prevention of neural tube defects and stroke: a systematic review. Lancet Glob Health. 2023;11(9):e1410-20. doi: 10.1016/j.eclinm.2023.102366
33.Committee on Medical Aspects of Food and Nutrition Policy. Folic acid and the prevention of disease. Report on Health and Social Subjects No. 50. London: The Stationery Office; 2000. [cited 2025 Sep] Available from: https://www.gov.uk/government/publications/coma-reports
34.UK Government. Birth defects prevented by fortifying flour with folic acid. London: UK Government; 2024 Nov 14. Press release. [cited 2025 Sep]. Available from: https://www.gov.uk/government/news/birth-defects-prevented-by-fortifying-flour-with-folic-acid?utm
35.Broughan JM, Wreyford B, Martin D, Melis G, Randall K, Obaro E, et al. Prevalence of neural tube defects in England prior to the mandatory fortification of non-wholemeal wheat flour with folic acid: a population-based cohort study. Arch Dis Child. 2024;109(2):106-12. doi: 10.1136/archdischild-2023-325856
36.Kirolos A, Vieira R, Calvert C, Griffiths E, Wood R. Trends in neural tube defects in Scotland 2000-2021 prior to the introduction of mandatory folic acid fortification of non-wholemeal wheat flour: a population-based study. Arch Dis Child. 2025 Mar 17 [Epub ahead of print]. Available from: https://adc.bmj.com/content/early/2025/05/24/archdischild-2024-328295
37.Kirke PN, Molloy AM, Daly LE, Burke H, Weir DG, Scott JM. Maternal plasma folate and vitamin B12 are independent risk factors for neural tube defects. QJM. 1993;86(11):703-8. doi: https://doi.org/10.1093/oxfordjournals.qjmed.a068749
38.Molloy AM, Kirke PN, Troendle JF, Burke H, Sutton M, Brody LC, et al. Maternal vitamin B12 status and risk of neural tube defects in a population with high neural tube defect prevalence and no folic acid fortification. Pediatrics. 2009;123(3):917-23. doi: 10.1542/peds.2008-1173
39.Tang KF, Li YL, Wang HY. Quantitative assessment of maternal biomarkers related to one-carbon metabolism and neural tube defects. Sci Rep. 2015; 5:8510. doi: https://doi.org/10.1038/srep08510
40.Gupta R, Kumari P, Pandey S, Joshi D, Sharma S, Prasad S, et al. Homocysteine and vitamin B12: other causes of neural tube defects in Eastern Uttar Pradesh and Western Bihar. Neurol India. 2018;66(4):1016-9. doi: 10.4103/0028-3886.236968 Available at: https://journals.lww.com/neur/fulltext/2018/66040/homocysteine_and_vitamin_b12__other_causes_of.21.aspx
41.Miller JW, Smith A, Troen AM, Mason JB, Jacques PF, Selhub J. Excess folic acid and vitamin B12 deficiency: clinical implications? Food Nutr Bull. 2024;45(1 Suppl):S67-72. doi: 10.1177/03795721241229503
42.Nie L, Liu X, Li X, Ren Z, Cheng X, Wu Y, et al. Beyond folate: the emerging role of maternal vitamin B12 in neural tube defects. J Dev Orig Health Dis. 2025;16(2):187-95. doi: https://doi.org/10.3390/nu17122040
43.Li Y, Qiu S, Shi J, Guo Y, Li Z, Cheng Y, et al. Association between MTHFR C677T/A1298C and susceptibility to autism spectrum disorders: a meta-analysis. Sci Rep. 2020; 10:1264. doi: 10.1186/s12887-020-02330-3
44. Moll S, Varga EA. Homocysteine and MTHFR mutations. Circulation. 2015;132(1):e6-9. doi: https://doi.org/10.1161/CIRCULATIONAHA.114.013311
45.Tomita LY, D’Almeida V, Mann Prado JC. Polymorphisms in genes involved in folate metabolism modify the association of dietary and circulating folate and vitamin B6 with cervical neoplasia. J Nutr. 2013;143(12):2007-14. doi: 10.3945/jn.113.182212
46.Valera-Gran D, Navarrete-Muñoz EM, Garcia de la Hera M, Fernandez-Somoano A, Tardon A, et al. Effect of maternal high dosages of folic acid supplements on neurocognitive development in children at 4–5 y of age: the prospective birth cohort Infancia y Medio Ambiente (INMA) study. Am J Clin Nutr. 2017;106(3):878-87. doi: 10.3945/ajcn.117.152769
47.Morris MS, Jacques PF, Rosenberg IH, Selhub J. Circulating unmetabolized folic acid and 5-methyltetrahydrofolate in relation to anemia, macrocytosis, and cognitive test performance in American seniors. Am J Clin Nutr. 2010;91(6):1733-44. doi: 10.3945/ajcn.2009.28671 Erratum in: Am J Clin Nutr. 2010;92(4):1002
48.Wu YL, Yang HY, Ding XX, Zhao X, Chen J, Bi P, et al. Association between methylenetetrahydrofolate reductase C677T polymorphism and epilepsy susceptibility: a meta-analysis. Seizure. 2014;23(6):411-6. doi: 10.1016/j.pnpbp.2013.06.015
49.Sarecka-Hujar B. Is there a relation between 677C>T polymorphism in the MTHFR gene and the susceptibility to epilepsy in young patients? A meta-analysis. Brain Sci. 2021;11(10):1327. doi: https://doi.org/10.3390/brainsci11101327
50.Zou XH, Wu Y, Zhuang JJ, Fei GJ, Zhai L, Guo XY. Association between MTHFR gene polymorphisms and response to antiepileptic drugs in epilepsy patients: a meta-analysis. BMC Neurol. 2022;22(1):158. doi: 10.1684/epd.2022.1470
51.Al-Eitan LN, Al-Dalalah IM, Mustafa MM, Alghamdi MA, Elshammari AK, Khreisat WH, et al. Effects of MTHFR and ABCC2 gene polymorphisms on antiepileptic drug responsiveness in Jordanian epileptic patients. Pharmgenomics Pers Med. 2019; 12:87-95. doi: 10.2147/PGPM.S211490
52.Munisamy M, Al-Gahtany M, Tripathi M, Subbiah V. Impact of MTHFR (C677T) gene polymorphism on antiepileptic drug monotherapy in North Indian epileptic population. Ann Saudi Med. 2015;35(1):51-7. doi: 10.5144/0256-4947.2015.51
53.Coppola G, Ingrosso D, Operto FF, Signoriello G, Lattanzio F, Barone E, et al. Role of folic acid depletion on homocysteine serum level in children and adolescents with epilepsy and different MTHFR C677T genotypes. Seizure. 2012;21(5):340-3. doi: 10.1016/j.seizure.2012.02.011
54.Ansari R, Mahta A, Mallack E, Luo JJ. Hyperhomocysteinemia and neurologic disorders: a review. J Clin Neurol. 2014;10(4):281-8. doi: 10.3988/jcn.2014.10.4.281
55.Díaz-Arrastia R. Homocysteine and neurologic disease. Arch Neurol. 2000;57(10):1422-7. doi: 10.1001/archneur.57.10.1422
56.Cappuccio G, Cozzolino C, Frisso G, Romanelli R, Parenti G, D’Amico A, et al. Pearls & oy-sters: familial epileptic encephalopathy due to methylenetetrahydrofolate reductase deficiency. Neurology. 2014;83(3): e41-4. doi: https://doi.org/10.1212/wnl.0000000000000591
57.Graydon JS, Claudio K, Baker S, Kocherla M, Ferreira M, Roche-Lima A, et al. Ethnogeographic prevalence and implications of the 677C>T and 1298A>C MTHFR polymorphisms in US primary care populations. Biomark Med. 2019;13(8):649-61. Doi: 10.2217/bmm-2018-0392
58.Binia A, Contreras AV, Canizales-Quinteros S, Alonzo VA, Tejero ME, Silva-Zolezzi I. Geographical and ethnic distribution of single nucleotide polymorphisms within genes of the folate/homocysteine pathway metabolism. Genes Nutr. 2014;9(5):421. doi: https://doi.org/10.1007/s12263-014-0421-7
59.Williams J, Mai CT, Mulinare J, Isenburg J. Updated estimates of neural tube defects prevented by mandatory folic acid fortification — United States, 1999–2011. MMWR Morb Mortal Wkly Rep. 2015;64(1):1-5 Available from: https://pubmed.ncbi.nlm.nih.gov/25590678/
60.Avachat C, Barry JM, Lyu X, Sherwin CM, Birnbaum AK. Management of anti-seizure medications during pregnancy: advancements in the past decade. Pharmaceutics. 2022;14(12):2733. doi: https://doi.org/10.3390/pharmaceutics14122733
61.Gidal BE, Tamura T, Hammer A, Vuong A. Blood homocysteine, folate and vitamin B12 concentrations in patients with epilepsy receiving lamotrigine or sodium valproate for initial monotherapy. Epilepsy Res. 2005;64(3):161-6. doi: 10.1016/j.eplepsyres.2005.03.005
62.Pfeiffer CM, Caudill SP, Gunter EW, Osterloh J, Sampson EJ. Biochemical indicators of B vitamin status in the US population after folic acid fortification: results from the National Health and Nutrition Examination Survey 1999–2000. Am J Clin Nutr. 2005;82(2):442-50. doi: 10.1093/ajcn.82.2.442
63.Huang H.L., Zhou,H.,Wang, N., Yu, C-Y. Effects of antiepileptic drugs on serum folate and vitamin B12 levels: a meta-analysis. Biomedical Reports. 2016; 127:1-9. doi: https://doi.org/10.3892/br.2016.737
64.Bjørk MH, Vegrim H, Alvestad S, et al. Pregnancy, folic acid, and antiseizure medication. Clin Epileptol. 2023; 36:203-11. doi: https://doi.org/10.1007/s10309-023-00602-3
65.Husebye ESN, Gilhus NE, Riedel B, Spigset O, Daltveit AK, Bjørk MH. Plasma unmetabolized folic acid in pregnancy and risk of autistic traits and language impairment in antiseizure medication-exposed children of women with epilepsy. Am J Clin Nutr. 2021;114(1):296-305. doi: 10.1093/ajcn/nqab436
66.Walker DI, Perry-Walker K, Finnell RH, Pennell KD, Tran V, May RC, et al. Metabolome-wide association of maternal folate and vitamin B12 with neural tube defects. Transl Res. 2019; 210:12-25. doi: 10.1016/j.taap.2018.12.001
67.Abbott Laboratories. Form 10-K annual report for the fiscal year ending December 31, 2003. United States Securities and Exchange Commission; 2003. [cited 2025 Sep]. Available from: 4d474e86-4320-493c-ac9d-133860a506fa
68.Legg T, Hatchard J, Gilmore AB. The science for profit model: how and why corporations influence science and the use of science in policy and practice. PLoS One. 2021;16(6): e0253272. doi: 10.1371/journal.pone.0253272
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