Vitamin Supplements and Neural Tube Defects

Smithells, R. W.; Sheppard, Sheila; Schorah, C. J.; Seller, MaryJ.; Nevin, N. C.; Harris, Rodney; Read, Andrew P.; Fielding, D W

doi:10.1016/s0140-6736(82)92251-6

Cited by 37 publications

(41 citation statements)

References 2 publications

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“…Foremost among these factors is the periconceptional use of supplements containing folic acid, which is associated with a reduction in the risk of women having NTD-affected pregnancies. More than 30 years ago, seminal work by Smithells et al 6 showed that the diets and postpartum blood of women who had given birth to a foetus with an NTD were deficient in several micronutrients, particularly folate. Subsequent small non-randomized trials in women who had previously had NTD-affected pregnancies showed that taking folic acid or multivitamins containing folate during the periconceptional period resulted in a ~fourfold reduction in the risk of recurrence [7][8][9][10][11][12] .…”

Section: Folic Acid Prevents Neural Tube Defectsmentioning

confidence: 99%

Neural tube defects and folate: case far from closed

Shaw²,

et al. 2006

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Neural tube closure takes place during early embryogenesis and requires interactions between genetic and environmental factors. Failure of neural tube closure is a common congenital malformation that results in morbidity and mortality. A major clinical achievement has been the use of periconceptional folic acid supplements, which prevents ~50-75% of cases of neural tube defects. However, the mechanism underlying the beneficial effects of folic acid is far from clear. Biochemical, genetic and epidemiological observations have led to the development of the methylation hypothesis, which suggests that folic acid prevents neural tube defects by stimulating cellular methylation reactions. Exploring the methylation hypothesis could direct us towards additional strategies to prevent neural tube defects.Neural tube defects (NTDs) are complex congenital malformations of the CNS. Anencephaly and spina bifida are the most common and severe forms of NTD, with a prevalence of about 1 in 1,000 births, although this varies throughout the world 1 . Infants with anencephaly are stillborn or die shortly after birth, whereas infants with spina bifida can survive but are likely to have severe lifelong disabilities and are at risk of psychosocial maladjustment. The estimated lifetime medical costs are high; for example, in California, USA, the costs for children born with spina bifida exceed US$81 million per year 2 .It has been known for more than 20 years that women can reduce their risk of having an NTDaffected pregnancy by taking folic acid supplements. However, the underlying mechanisms byCorrespondence to H.J.B. H.Blom@cukz.umcn.nl. Competing interests statementThe authors declare no competing financial interests. DATABASES NIH Public Access Author ManuscriptNat Rev Neurosci. Author manuscript; available in PMC 2010 November 2. Neurulation and neural tube defectsNeurulation has long fascinated scientists, as evidenced by a devoted literature that extends back hundreds of years. The process of neurulation occurs during early embryogenesis, starting with the formation of the neural plate from specialized ectodermal cells and culminating in the closure of the neural tube (FIG. 1), the precursor of both the CNS and most of the PNS. Considered most simply, the neural plate develops bilateral neural folds, which elevate and fuse at the midline to create the neural tube. Subsequent development, together with vesiculation within the tube, gives rise to the brain and spinal cord. Further details of this complex process are beyond the scope of this review (for reviews, see REFS 4,5 ).Neurulation seems to be highly complex and tightly regulated. The development and closure of the neural tube is usually completed by 28 days post-conception. This means that by the time a woman finds out that she is pregnant, the neural tube is almost completely closed. For the neural tube to close properly, genes that regulate various morphogenetic activities must function cooperatively. These activities include programmed cell death, neural crest...

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Section: Folic Acid Prevents Neural Tube Defectsmentioning

confidence: 99%

Neural tube defects and folate: case far from closed

Shaw²,

et al. 2006

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“…The importance of folate in the nervous system was initially demonstrated in studies that established a greatly increased risk of neurodevelopmental disorders in the offspring of folate-deficient pregnant women (Smithells et al, 1976;Laurence et al, 1981;Blom et al, 2006). In the adult, epidemiological studies have linked lack of folate to neurodegenerative and neuropsychiatric diseases, including stroke, Parkinson's disease, dementia, and depression (Reynolds, 2002;He et al, 2004;Irizarry et al, 2005;Lamberti et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Folate Deficiency Induces Neurodegeneration and Brain Dysfunction in Mice Lacking Uracil DNA Glycosylase

Kronenberg

Harms²,

Sobol³

et al. 2008

J. Neurosci.

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Folate deficiency and resultant increased homocysteine levels have been linked experimentally and epidemiologically with neurodegenerative conditions like stroke and dementia. Moreover, folate deficiency has been implicated in the pathogenesis of psychiatric disorders, most notably depression. We hypothesized that the pathogenic mechanisms include uracil misincorporation and, therefore, analyzed the effects of folate deficiency in mice lacking uracil DNA glycosylase (UngϪ/Ϫ) versus wild-type controls. Folate depletion increased nuclear mutation rates in UngϪ/Ϫ embryonic fibroblasts, and conferred death of cultured UngϪ/Ϫ hippocampal neurons. Feeding animals a folate-deficient diet (FD) for 3 months induced degeneration of CA3 pyramidal neurons in UngϪ/Ϫ but not Ung؉/؉ mice along with decreased hippocampal expression of brain-derived neurotrophic factor protein and decreased brain levels of antioxidant glutathione. Furthermore, FD induced cognitive deficits and mood alterations such as anxious and despair-like behaviors that were aggravated in UngϪ/Ϫ mice. Independent of Ung genotype, FD increased plasma homocysteine levels, altered brain monoamine metabolism, and inhibited adult hippocampal neurogenesis. These results indicate that impaired uracil repair is involved in neurodegeneration and neuropsychiatric dysfunction induced by experimental folate deficiency.

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“…The first reports on folate deficiency and NTD, published by Smithells et al (2,3) , showed the protective effect of folic acid on the recurrence of NTD. A randomised study by Czeizel and Dudas (4) showed a decrease in first NTD occurrence in women supplemented with twelve vitamins containing 0?8 mg of folic acid, but not in women supplemented with trace elements and a very low dose of vitamin C. A rigorous double-blind randomised controlled trial supported by the UK Medical Research Council showed that supplementing women who had a history of children with NTD with 4 mg of folic acid daily decreased recurrence by 72 % (5) .…”

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Impact of folic acid fortification of flour on neural tube defects: a systematic review

Castillo-Lancellotti

Tur

Uauy

2012

Public Health Nutr.

170

141

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Objective: To review the impact of folic acid fortification of flour on the prevalence of neural tube defects (NTD). Design: Systematic review of the literature on MEDLINE via PubMed, Scopus, OvidSP and LILACS (Latin American and Caribbean Health Sciences Literature) reporting the impact of folic acid fortification of flour on the prevalence of NTD in 2000-2011. Focusing on Santiago of Chile's birth defects registry (1999)(2000)(2001)(2002)(2003)(2004)(2005)(2006)(2007)(2008)(2009) and the monitoring of flour fortification, we analysed the prevalence (NTD cases/ 10 000 births) pre and post flour fortification and the percentile distribution of folic acid content in flour (2005)(2006)(2007)(2008)(2009). We explored the potential association between median folic acid in flour (mg/kg) and the prevalence of NTD. Setting: Chile, Argentina, Brazil, Canada, Costa Rica, Iran, Jordan, South Africa and the USA. Subjects: Live births and stillbirths. Results: Twenty-seven studies that met inclusion criteria were evaluated. Costa Rica showed a significant reduction in NTD ( , 60 %). Prevalence in Chile decreased from 18?6 to 7?3/10 000 births from 1999 to 2007 and showed a slight increase to 8?5 in 2008-2009, possibly due to changes in fortification limits. When we related the prevalence of NTD with levels of flour fortification, the lowest prevalence was observed at a folic acid level of 1?5 mg/kg. Conclusions: Fortification of flour with folic acid has had a major impact on NTD in all countries where this has been reported. Chile showed a 55 % reduction in NTD prevalence between 1999 and 2009. There is a need to constantly monitor the levels of flour fortification to maximize benefits and prevent the potential risk of folic acid excess, moreover to be vigilant for any new adverse effects associated with excess. Keywords Folic acid Neural tube defects Spinal dysraphism Food fortification Systematic reviewThe importance of nutrition in the aetiology of neural tube defects (NTD) was suggested by Hibbard and Smithells, who found that women deficient in folate had an increased number of abortions, placental abruptions and fetal malformations and intra-uterine growth retardation (1) . The first reports on folate deficiency and NTD, published by Smithells et al. (2,3) , showed the protective effect of folic acid on the recurrence of NTD. A randomised study by Czeizel and Dudas (4) showed a decrease in first NTD occurrence in women supplemented with twelve vitamins containing 0?8 mg of folic acid, but not in women supplemented with trace elements and a very low dose of vitamin C. A rigorous double-blind randomised controlled trial supported by the UK Medical Research Council showed that supplementing women who had a history of children with NTD with 4 mg of folic acid daily decreased recurrence by 72 % (5) . Although some studies were retrospective, their results revealed an inverse relationship between NTD and folic acid consumption of 100-400 mg/d (6,7) . Based on this information, in 1992 the US Public Health Service r...

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Vitamin Supplements and Neural Tube Defects

Cited by 37 publications

References 2 publications

Neural tube defects and folate: case far from closed

Neural tube defects and folate: case far from closed

Folate Deficiency Induces Neurodegeneration and Brain Dysfunction in Mice Lacking Uracil DNA Glycosylase

Impact of folic acid fortification of flour on neural tube defects: a systematic review

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