We studied the association between multivitamin use during the periconceptional period and the occurrence of neural tube defects using data from the Atlanta Birth Defects Case-Control Study. There were 347 babies with neural tube defects who were live born or stillborn to residents of metropolitan Atlanta from 1968 through 1980. The 2829 control-babies born without birth defects were randomly selected through birth certificates. Periconceptional multivitamin use was defined as reported use for each of the three months before conception through the first three months of pregnancy. Mothers who reported not using multivitamins any time during the six-month period were defined as nonusers. Fourteen percent of mothers reported periconceptional multivitamin use and 40% reported nonuse. Multivitamin users were different from nonusers in a number of demographic, health-related, and life-style characteristics. We found an overall apparent protective effect of periconceptional multivitamin use on the occurrence of neural tube defects, with a crude estimated relative risk of 0.40 (95% confidence interval, 0.25 to 0.63). At this time, it is not possible to determine whether this apparently lower risk is the direct result of multivitamin use or the result of other characteristics of women who use multivitamins.

Periconceptional Use of Multivitamins and the Occurrence of Neural Tube Defects

Homozygosity for the T allele of the C677T polymorphism of the gene encoding the folate dependent enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) is a risk factor for neural tube defects.1 Both the homozygous (TT) and heterozygous (CT) genotypes are associated with lower tissue concentrations of folate, higher homocysteine concentrations, and lower enzyme activity than the wild type (CC) genotype; these effects are more marked in homozygotes. Low folate and raised homocysteine levels in early pregnancy are risk factors for neural tube defects.2 We investigated the possibility that the CT genotype would also increase the risk of these malformations.

We recruited 397 individuals with spina bifida aperta (380) or encephalocele (17) throughout Ireland. Participants were aged between 5 months and 52 years (mean 16.8 years). We drew blood for analysis of DNA. We derived the controls from a random sample of 1000 newborn screening cards collected on all Irish births. Of these 1000, DNA was …

Impact of the MTHFR C677T polymorphism on risk of neural tube defects: case-control study / Peadar N. Kirke ... [et al.]

Many studies indicate a crucial role for the vitamin B12 and folate-dependent enzyme methionine synthase (MS) in brain development and function, but vitamin B12 status in the brain across the lifespan has not been previously investigated. Vitamin B12 (cobalamin, Cbl) exists in multiple forms, including methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl), serving as cofactors for MS and methylmalonylCoA mutase, respectively. We measured levels of five Cbl species in postmortem human frontal cortex of 43 control subjects, from 19 weeks of fetal development through 80 years of age, and 12 autistic and 9 schizophrenic subjects. Total Cbl was significantly lower in older control subjects (> 60 yrs of age), primarily reflecting a >10-fold age-dependent decline in the level of MeCbl. Levels of inactive cyanocobalamin (CNCbl) were remarkably higher in fetal brain samples. In both autistic and schizophrenic subjects MeCbl and AdoCbl levels were more than 3-fold lower than age-matched controls. In autistic subjects lower MeCbl was associated with decreased MS activity and elevated levels of its substrate homocysteine (HCY). Low levels of the antioxidant glutathione (GSH) have been linked to both autism and schizophrenia, and both total Cbl and MeCbl levels were decreased in glutamate-cysteine ligase modulatory subunit knockout (GCLM-KO) mice, which exhibit low GSH levels. Thus our findings reveal a previously unrecognized decrease in brain vitamin B12 status across the lifespan that may reflect an adaptation to increasing antioxidant demand, while accelerated deficits due to GSH deficiency may contribute to neurodevelopmental and neuropsychiatric disorders.

https://serval.unil.ch/resource/serval:BIB_7704AA1A1D31.P001/REF.pdf

Decreased Brain Levels of Vitamin B12 in Aging, Autism and Schizophrenia.

Even if in the absence of clinical folate deficiency, providing supplemental folic acid in the periconceptional period lowers the risk that the infant will have a neural tube defect (NTD). Findings that antifolate receptor antiserum leads to resorption of embryos as well as malformations in rats suggested that autoantibodies against these receptors could dispose to defects. The study group included 12 women who were, or had been, pregnant with an affected fetus and 24 control women (20 with a normal current or prior pregnancy and 4 nulligravidas). Serum specimens were analyzed for antifolate receptor autoantibodies by incubating samples with purified human placental folate receptors radiolabeled with 3 H-folic acid. Serum and autoantibodies isolated from serum were incubated with placental membranes, ED27 human placental cells, and KB cells, a human epidermoid carcinoma cell line, which express folate receptors. No significant demographic or clinical differences were found between the index subjects and control subjects. Serum antibodies against folate receptors were identified in 9 of the 12 index women (75%). Two of them were currently pregnant with a fetus exhibiting a NTD, whereas 7 had a history of such a pregnancy. Two of 20 control women (10%) had a current or previous infant with a NTD. The mean value for folate receptors bound by antiantibody was significantly greater in the index subjects. Only sera testing positive for autoantibody-blocked folic acid binding to placental membrane receptors, ED27 cells, and KB cells incubated at 4°C. Autoantibodies also blocked the uptake of 3 H-folic acid by KB cells incubated at 37°C. No anticardiolipin, antisingle-stranded DNA, or antithyroid autoantibodies were identified in sera from index subjects. Autoantibodies against folate receptors are present in sera from women whose pregnancies are complicated by a NTD. It remains to be determined whether these autoantibodies are pathogenic.

Autoantibodies Against Folate Receptors in Women With a Pregnancy Complicated by a Neural Tube Defect

Maternal exposure to dietary factors during pregnancy can influence embryonic development and may modulate the phenotype of offspring through epigenetic programming. Folate is critical for nucleotide synthesis, and preconceptional intake of dietary folic acid (FA) is credited with reduced incidences of neural tube defects in infants. While fortification of grains with FA resulted in a positive public-health outcome, concern has been raised for the need for further investigation of unintended consequences and potential health hazards arising from excessive FA intakes, especially following reports that FA may exert epigenetic effects. The objective of this article is to discuss the role of FA in human health and to review the benefits, concerns and epigenetic effects of maternal FA on the basis of recent findings that are important to design future studies.

/pdf/folic-acid-supplementation-in-pregnancy-and-implications-in-2ebw5agflc.pdf

Folic acid supplementation in pregnancy and implications in health and disease

Neural tube defects (NTDs) are common complex congenital malformations resulting from failure of the neural tube closure during embryogenesis. It is established that folic acid supplementation decreases the prevalence of NTDs, which has led to national public health policies regarding folic acid. To date, animal studies have not provided sufficient information to establish the metabolic and/or genomic mechanism(s) underlying human folic acid responsiveness in NTDs. However, several lines of evidence suggest that not only folates but also choline, B12 and methylation metabolisms are involved in NTDs. Decreased B12 vitamin and increased total choline or homocysteine in maternal blood have been shown to be associated with increased NTDs risk. Several polymorphisms of genes involved in these pathways have also been implicated in risk of development of NTDs. This raises the question whether supplementation with B12 vitamin, betaine or other methylation donors in addition to folic acid periconceptional supplementation will further reduce NTD risk. The objective of this article is to review the role of methylation metabolism in the onset of neural tube defects.

/pdf/neural-tube-defects-folic-acid-and-methylation-11qhzz58ed.pdf

Jean-François Benoist

Papers

Neural tube defects, folic acid and methylation.