Folate, DNA methylation, and mouse models of breast tumorigenesis

The history of folic acid.

Objective: The study aimed to assess the folic acid status of lactating women in China and to analyze factors related to folic acid deficiency in these subjects. Methods: The data on lactating women were extracted from the Chinese National Nutrition and Health Surveillance in 2013. By a multi-stage stratified cluster random sampling method, 10 331 lactating women were selected for the study. The lactating women, 0-24 months postpartum, were from 55 sites in 30 provinces of China, excluding the Tibet Autonomous Region. A standard questionnaire was used to obtain general information and dietary intake during the previous one month period was collected using a food frequency questionnaire. A total of 20% of the total number of lactating women were randomly selected to analyze serum folic acid. Finally, 1 894 lactating women, with questionnaire results and serum folic acid data, were included in the study. Serum folic acid concentrations were analyzed using an electro-chemiluminescence immunoassay method. Folic acid deficiency was defined as a serum folic acid level <2 ng/ml. A multiple logistic regression analysis was used to analyze the factors associated with folic acid deficiency in these women. Results: After excluding abnormal values, 1 894 lactating women were included in the study. Based on our findings, the prevalence of folate deficiency was 3.0% (56/1 894) in lactating women in China. The prevalence of folic acid deficiency was 0.3% (1/388), 1.3% (7/550), 6.0% (38/639) and 3.2% (10/317) in larger, medium or small cities, general rural counties and poor rural counties, respectively. The prevalence of folic acid deficiency was 6.3% (17/269) and 2.4% (39/1 623) for minority and Han ethnic groups, respectively, and was 6.3% (52/823) and 0.4% (4/1 071) for subjects in northern and southern areas of China, respectively. Binary unconditionally logistic regression was used to analyze the factors associated with folic acid deficiency in the lactating women. The results showed that, compared with those living in the south and those in the Han ethnic group, those living in the north and belonging to the minority ethnic group had a greater risk of folic acid deficiency, with (OR=3.63, 95% CI: 1.64-8.05) and (OR=5.42, 95% CI: 1.75-16.74), respectively. With each month of age during childhood, the prevalence of folic acid deficiency decreased by 10% (OR=0.90, 95%CI: 0.85-0.96). Compared with low income subjects, those with middle incomes had OR (95%CI) of 0.25 (0.10-0.60) for folic acid deficiency. A lesser intake of cereal was associated with a greater risk of folic acid deficiency in lactating women (OR=3.04, 95%CI: 1.18-7.79). A lesser intake of tubers was a protective factor for folic acid deficiency in lactating women (OR=0.29, 95% CI:0.12-0.70). Conclusion: The folic acid status of Chinese lactating women has, in general, recently improved. However, living in northern areas, during early lactating periods, belonging to an ethnic minority, living in rural areas, having a low income, lower intake of cereal and excessive intake of tubers were risk factors for folic acid deficiency in lactating women. In these women, folic acid intervention should be considered a priority.

Prevalence of Folic Acid Deficiency and Cost Effectiveness of Folic Acid Testing: A Single Center Experience

Mandatory food fortification with folic acid

The prevalence of folic acid deficiency among adolescent girls living in Edirne, Turkey

In a few countries enriched cereal grains have been fortified with folic acid to reduce the incidence of neural tube defects. The objective of this study was to analyse the effect of folic acid fortified foods on the incidence of neural tube defects in live newborns at Princess Badea Teaching Hospital, in the north of Jordan, before and after the national food fortification with folic acid was implemented. For the 7-year period from 1 January 2000 to 31 December 2006, we retrospectively extracted the total number of births at Princess Badea Hospital, as well as the number of pregnancies affected by spina bifida and anencephaly, per 1000 births during the periods before (2000-01), during (2002-04) and after (2005-06) folic acid fortification of grain products, was implemented. Neural tube defects were defined in accordance with the International Classification of Diseases, 10th revision (ICD-10): anencephaly, encephalocele and spina bifida. A total of 78 subjects with neural tube defects were recorded among 61 447 births during the study period. The incidence of neural tube defects decreased from 1.85 per 1000 births before fortification [95% confidence interval (CI) 1.2, 2.4] to 1.07 per 1000 births during the fortification period [95% CI 0.7, 1.5], and 0.95 after full fortification [95% CI 0.5, 1.5], a 49% reduction. The difference between incidence of neural tube defects in the periods before and after food fortification with folic acid was statistically significant. We conclude that food fortification with folic acid was associated with a significant reduction in the rate of neural tube defects in north Jordan.

To investigate the prevalence of folic acid deficiency in Queensland-wide data of routine laboratory measurements, especially in high-risk sub-populations. Secondary health data analysis. Analysis of routine folic acid tests conducted by Pathology Queensland (AUSLAB). Female and male persons aged 0-117 years with routine folic acid testing between 1 January 2004 and 31 December 2015. If repeat tests on the same person were conducted, only the initial test was analysed (n 291 908). Overall the prevalence of folic acid deficiency declined from 7·5 % before (2004-2008) to 1·1 % after mandatory folic acid fortification (2010-2015; P < 0·001) reflecting a relative reduction of 85 %. Levels of erythrocyte folate increased significantly from a median (interquartile range) of 820 (580-1180) nmol/l in 2008 before fortification to 1020 (780-1350) nmol/l in 2010 (P < 0·001) after fortification. The prevalence of folic acid deficiency in the Indigenous population (14 792 samples) declined by 93 % (17·4 v. 1·3 %; P < 0·001); and by 84 % in non-Indigenous residents (7·0 v. 1·1 %; P < 0·001). In a logistic regression model the observed decrease of folic acid deficiency between 2008 and 2010 was found independent of gender, age and ethnicity (ORcrude = 0·20; 95 % CI 0·18, 0·23; P < 0·001; ORadjusted = 0·21; 95 % CI 0·18, 0·23; P < 0·001). While voluntary folic acid fortification, introduced in 1995, failed especially in high-risk subgroups, the 2009 mandatory folic acid fortification programme coincided with a substantial decrease of folic acid deficiency in the entire population.

Nutrition and epigenetic changes is the emerging topic of interest in the present scenario to understand the effects of increased supplementation of micronutrients like Folic Acid (FA). The study is taken up in the public health interest, to evaluate the importance of balancing the different micronutrients in the diet to avoid unbalanced nutritional disorders and other health complications later in life. It has been hypothesized that disease risks after birth or later in life can be determined by paternal or maternal diet. This raised an interest to study in-utero effects of environmental exposures like air pollution, toxins, nutrition, etc. It had been assumed that during embryonic period most of the dividing tissues get exposed to the environmental insults and that change results in predisposition of cancer or other health outcomes. There could be the possibility of maternal exposures like nutrition may alter the intrauterine one-carbon metabolism or the precursor milieu and may be involved in the disruption of one-carbon metabolism in developing offspring. Modification in methyl me of offspring with subsequent changes in phenotypes has been noted in the preliminary studies with increased folic acid (FA) supplementation during pregnancy. Maternal folate deficiency has been implicated as a cause of prematurity and both folate deficiency and cobalamin deficiency have been implicated in recurrent fetal loss and neural tube defects. Folic acid supplementation at the time of conception and in the first 12 weeks of pregnancy is expected to reduce by 70% the incidence of neural tube defects (NTDs) (meningomyelocele, encephalocele and spina bifida) in the fetus. Most of the protective effect can be achieved by taking folic acid, 0.4 mg daily at the time of conception. However there is no clear relationship between maternal folatestatus and the fetal abnormalities. It has been observed that, the lower the maternal folate, the greater the risk to the fetus. On the other hand maternal cobalamin status is a strong predictor of vitamin B12 in breastfed infants up to at least 6 months of age. Because of the transfer from mother to offspring during pregnancy and lactation, maternal requirements during this period are increased and deficiency may occur. The influence of low vitamin B12 during pregnancy may have cognitive ability of children later in life. Hypothyroidism is caused by insufficient production of thyroid hormones by the thyroid gland. In females, hypothyroidism is associated mainly with oligomenorrhea.

Curly tail mouse mutant embryos (ct/ct) develop spinal neural tube defects (NTD) in 54% of cases, comprising isolated tail flexion defects and spinal bifida with tail flexion defects. Both types of spinal NTD result from delayed closure of the posterior neuropore (PNP). Previous studies (Seller et al. [1979] Proc. R. Soc. Lond. Biol. 206:95-107; Seller and Perkins [1982] Prenat. Diagn. 2:297-300) described a paradoxical effect of retinoic acid (RA) on the phenotypic expression of the ct mutation: Treatment with low doses of RA on day 8 of gestation increased the incidence of total NTD, whereas low doses of RA administered on day 9 resulted in reduced incidence of total NTD. In order to investigate further the reported preventive effect of RA, we have carried out detailed analyses of the effects of maternal treatment with 5 mg/kg RA on the incidence of NTD at different developmental stages, and on the development and growth of ct/ct embryos. We found that 5 mg/kg RA reduces the incidence of spinal NTD in a stage-specific manner, without increasing the incidence of cranial NTD. The effect of RA is specific: There were no other alterations in morphogenesis, growth, development, resorption rate, or litter size. RA was more effective in the prevention of isolated tail flexion defects than of spina bifida. Prevention of isolated tail flexion defects was maximal (50% reduction) when RA was administered between 10 days 4 hours and 10 days 8 hours post coitum (p.c.) inclusive (24 to 34 somite stage).(ABSTRACT TRUNCATED AT 250 WORDS)

Some, but not complete, reassurance on the safety of folic acid fortification

BackgroundThe incidence of neural tube defects (NTDs) declined by about 40 % in Canada with the introduction of a national folic acid (FA) fortification program. Despite the fact that few Canadians currently exhibit folate deficiency, NTDs are still the second most common congenital abnormality. FA fortification may have aided in reducing the incidence of NTDs by overcoming abnormal one carbon metabolism cycling, the process which provides one carbon units for methylation of DNA. We considered that NTDs persisting in a folate-replete population may also occur in the context of FA-independent compromised one carbon metabolism, and that this might manifest as abnormal DNA methylation (DNAm). Second trimester human placental chorionic villi, kidney, spinal cord, brain, and muscle were collected from 19 control, 22 spina bifida, and 15 anencephalic fetuses in British Columbia, Canada. DNA was extracted, assessed for methylenetetrahydrofolate reductase (MTHFR) genotype and for genome-wide DNAm using repetitive elements, in addition to the Illumina Infinium HumanMethylation450 (450k) array.ResultsNo difference in repetitive element DNAm was noted between NTD status groups. Using a false discovery rate <0.05 and average group difference in DNAm ≥0.05, differentially methylated array sites were identified only in (1) the comparison of anencephaly to controls in chorionic villi (n = 4 sites) and (2) the comparison of spina bifida to controls in kidney (n = 3342 sites).ConclusionsWe suggest that the distinctive DNAm of spina bifida kidneys may be consequent to the neural tube defect or reflective of a common etiology for abnormal neural tube and renal development. Though there were some small shifts in DNAm in the other tested tissues, our data do not support the long-standing hypothesis of generalized altered genome-wide DNAm in NTDs. This finding may be related to the fact that most Canadians are not folate deficient, but it importantly opens the field to the investigation of other epigenetic and non-epigenetic mechanisms in the etiology of NTDs.Electronic supplementary materialThe online version of this article (doi:10.1186/s13072-016-0054-8) contains supplementary material, which is available to authorized users.

After completing this article, readers should be able to:Birth defects are the leading cause of infant mortality and a major contributor to heightened morbidity in the United states. The basic definition of a birth defect is a structural abnormality present at birth. Infant mortality attributable to birth defects has not declined as rapidly as overall infant mortality; from 1968 to 1995, the proportion of infant mortality due to birth defects increased from 14.5% to 22.2%. It has been estimated that approximately 20% to 25% of all birth defects are due to gene mutations, 5% to 10% to chromosomal abnormalities, and another 5% to 10% to exposure to a known teratogenic agent (such as prescription drugs, chemicals, or radiation)or a maternal factor. Together, these percentages account for only 30% to 40% of birth defects, leaving the etiology of more than 50%unexplained. It has been speculated that environmental factors account for no more than 10% of all congenital anomalies. Genetic factors are responsible for 30% of pediatric hospital admissions.Birth defects rank somewhere between second and fifth among causes of death in children younger than 1 year of age; 3% to 4% of infants in their first year of life are diagnosed as having major birth defects. Of the 120,000 to 150,000 infants born with serious birth defects each year, approximately 6,000 die during their first 28 days of life and another 2,000 die before reaching their first birthdays.In an aggregate analysis of the expense of illness in the United States, congenital abnormalities as a group was estimated to cost$6.3 billion in 1980 or 1.4% of the total cost of illness. This estimate did not include nonmedical direct costs, such as special education and developmental services. Although recent advances in medical technology have increased the chances of survival for children who have birth defects and disabilities, the quality of life for most of these children remains compromised. The economic cost of medical conditions such as birth defects often is discussed without a full understanding of how these conditions affect the lives of infants and families.Because estimates of the cost per new case of birth defects represent the savings from preventing a case,an incidence-based approach enables assessment of the value of prevention strategies. This type of approach was used to estimate the cost of illness for some of the major, most clinically important structural birth defects in the United States. This report used data from a California birth defect monitoring program (adjusted to provide national estimates) and national data to estimate the costs of major structural birth defects occurring in the United States during 1992 (Table 1). The birth defects were selected based on their clinical significance and broad representation of the organ systemThese findings are subject to at least four limitations. First,California data used to estimate incidence rates and treatment costs may not be representative of the United States;total costs per case may vary from state to state. Second, the contribution of time and effort by family members to the provision of care were not estimated and may be substantial for some cases. Third, the psychological costs of these types of illness, which may exceed traditional human capital costs, were not included. For these and other reasons, the use of the human capital approach underestimates what the public is willing to pay to prevent these conditions. Finally, excess medical and educational costs probably were underestimated for some conditions because they could not be ascertained completely. If all of the approximately 120,000 to 150,000 infants born each year in the United States who have serious birth defects had been included in this analysis, the economic costs would have been higher.NTDs are among the most serious and common birth defects to cause infant mortality, morbidity, and disability in the United States. Each year, approximately 4,000 births that involve NTDs as well as other defects result in miscarriage or stillbirth. There are several forms of NTDs, and they vary widely in severity. The birth prevalence of these conditions has declined substantially over the past 60 years due to better medical care. NTDs are reported in 3.6 to 4.6/10,000 live births in the United States. These rates underestimate true incidence,however, because affected pregnancies may be spontaneously or electively aborted and because not all cases are detected and reported at birth. Population-based active surveillance programs that include prenatal diagnosis have reported NTD rates of 7.2 to 15.6/10,000 liveborn and stillborn infants. Women in the United States who have had a pregnancy resulting in an infant or fetus who has an NTD have a 2% to 3% risk for having another pregnancy resulting in a similarly affected infant or fetus.Spina bifida is an inclusive name for various conditions characterized by incomplete fusion of the vertebral arches with a protruding sac that contains meninges, spinal cord, or nerve roots that cause permanent damage to the spinal cord and spinal nerves. It is a complicated and common birth defect that can affect pregnancy without warning. Results of prenatal examinations suggest that affected fetuses exhibit leg movement until the third trimester but become paralyzed later in pregnancy, several months after the initial spinal cord defect occurs. The Centers for Disease Control and Prevention (CDC) estimates that 300,000 to 400,000 infants are born each year with spina bifida worldwide. In the United States,approximately 2,500 infants are born annually with spina bifida and anencephaly, and an estimated 1,500 fetuses affected by these birth defects are aborted.Based on 1992 cohort data, the estimated lifetime cost of spinal bifida is $294,000 per case. Spina bifida can range from mild (spina bifida occulta) to severe(myelomeningocele). Depending on the pattern and level of spinal cord involvement, the resultant deficit can include a lifelong handicap due to infectious complications, motor and sensory paraplegia, bladder and bowel incontinence, Arnold-Chiari malformations, and hydrocephalous.Unlike spina bifada, in which 80%to 90% of infants survive into adulthood, anencephaly is a lethal malformation characterized by the absence of the cranial vault and the cerebral hemisphere that usually results in stillbirth or death within hours or days. Fifty percent of anencephalic fetuses are aborted spontaneously, but if pregnancy goes to term, the infants quickly succumb,showing only slow, stereotyped movements and frequent decerebrate posturing. The incidence of anencephaly is 1/1,000 live births and is responsible for about 50% of all NTDs.Encephalocele is a rare congenital defect of the skull that results in herniation of meninges and brain tissue. It is seen most commonly in the occipital region, where it may be associated with other anomalies,such as brainstem and skull base deformities and hydrocephalous. The incidence of occipital encephalocele is 1/10,000 live births. Most encephaloceles are detected in children shortly after birth, and the outcome relates to the position of the defect and to the associated anomalies. The primitive nervous system begins as a flat neural plate 2 weeks after conception, which becomes indented by a longitudinal groove at 20 days,with neural folds on the flanks. These folds begin to fuse in the midline, forming a cylinder in the middle of the plate. In a zipper fashion, this dorsal closure is promulgated rostally and caudally, resulting in a tubular structure with an open anterior and posterior aperture. At 26 days, the anterior aperture closes,followed at 29 days by the posterior aperture. Factors necessary for formation of the neural tube are intrinsic in the neural ectoderm and adjacent mesoderm. A teratologic insult in embryogenesis timed to interfere with the closure of the anterior aperture will result in anencephalus. Failure of the posterior aperture to close results in an exposed spinal cord, which is recognized later as spina bifida. In broad terms, NTDs result from incomplete neurulation and refer to a wide spectrum of congenital malformations in which separations of the midline vertebral and cranial elements are the common feature,but they usually are taken to mean anencephalus, spina bifida, and encephalocele.Despite considerable progress having been made in understanding NTDs, they remain the most common serious birth defect, and the etiology of most cases still is unknown. It is accepted that there is a genetic-environmental interaction in the causation of NTDs. Genetic and epidemiologic studies have suggested high-risk groups: those who have a past history of NTDs; a maternal age of less than 20 or more than 35 years; parity (primipara and grand multipara); and low socioeconomic status with gross nutritional deficiency and inadequate antenatal care.Several clinical and epidemiologic studies have reported various teratogens that produce NTDs in offspring, including radiation;maternal hyperthermia such as prolonged high fever; exposure to heat and hot-tub use; hypo- and hypervitaminosis A; maternal viral infections such as rubella, toxoplasma, and cytomegalovirus; and drugs such as aminopterin, pyrimethamine,trimethoprim, triamterane,sulfasalazine, methotrexate, anticonvulsants(eg, valproic acid and carbamazepine),aliphatic nitrites, phenothiazines, cyclophosphamide,and cyanide. Teratogens cause NTDs by acting as folic acid antagonists or by being associated with inadequate folic acid availability to the embryo.A number of environmental agents also have been hypothesized as etiologic, particularly dietary agents such as soft water, blighted potatoes, nitrite-cured corn beef,canned peas treated with magnesium salts, effluent from factories, and zinc deficiency. However, none of these factors has been proved scientifically to be linked with NTDs.Certain occupations such as male painters, female agricultural workers, and male welders have been associated with an increased risk of NTDs in offspring. Also, several studies suggested that compared with women of normal weight,women who are extremely obese before pregnancy have a significantly increased risk of having an infant who has NTDs and several other malformations, such as central nervous system, great vessel, ventral wall, or other intestinal defects.Mildly elevated maternal plasma homocysteine (Hcy) levels recently have been observed in some pregnancies that resulted in NTDs and other birth defects. In the past 2 decades, research has shown mild hyperhomocysteinemia to be linked to an increased risk of premature atherosclerosis, pregnancies complicated by NTDs, early pregnancy loss, and venous thrombosis. Plasma Hcy is governed by both genetic and nutritional factors. A lack of B vitamins (folic acid), mutation of the 5,10-methylenetetrahydrofolate reductase genes, or a combination of the two can explain elevated Hcy levels in blood plasma. Genetic mutations were found on the first chromosome (677 C T and 1298 A–C) and can explain up to 50% of the protective effect of folic acid against NTDs. A personal or family history of a pregnancy affected by an NTD is associated with an increased risk of having an affected pregnancy, as is maternal type 1 diabetes, but about 90% to 95% of cases occur in the absence of any positive history. Infants of women who have type 1 diabetes have a 1% to 2% risk of NTDs. NTDs are seen more frequently in certain racial/ethnic groups, particularly Hispanics and Caucasians of European extraction,and are less common among Ashkenazi Jews, most Asians, and African-Americans. NTDs also appear to occur more frequently in association with fetal alcohol syndrome. Folic acid supplementation is not known to prevent NTDs or other teratogenic effects of alcohol on the embryo and fetuses of alcoholic women. The primary goal for such women is to avoid excessive alcohol ingestion during pregnancy. Women who have a folic acid deficiency because of intestinal disorders (such as celiac disease,small intestine malabsorption, or intestinal bypass) and those who have epilepsy and are using certain anticonvulsants may be at greater risk for having offspring who have NTDs. Infants of women treated with valproic acid and carbamazepine during pregnancy have an estimated 1% to 2% and 1% risk for spina bifida in offspring,respectively. It seems prudent to determine whether women who have epilepsy and are planning a pregnancy have a folic acid deficiency. It is not known, however, whether folic acid supplementation would decrease the risk of NTDs in the offspring of these women.Thirty years ago, it was suggested that maternal intake of certain vitamins during pregnancy affected the incidence of serious fetal malformations. Subsequent research has revealed that folate (folic acid), a B vitamin, plays a crucial role in the development of the central nervous system during the early weeks of gestation, which generally is before pregnancy is confirmed. In a significant number of embryos, an inadequate supply of folate at this time leads to failure of the primitive neural tube to close and differentiate normally, resulting in NTDs. Numerous studies have confirmed the importance of an adequate intake of folate during the weeks just before and after conception. Randomized placebo-controlled trials and nonrandomized controlled trials in pregnant women who had a prior pregnancy affected by an NTD have demonstrated that folic acid supplements substantially reduce the risk of recurrent NTDs.It has been suspected that diet has a role in the causation of NTDs. The possibility that folic acid might be involved was raised in 1964 by Hibbard. In 1980 and 1981, the results of two other interventional studies were published in which vitamin supplementation was instituted around the time of conception among women who already had had a child who had an NTD. In the first study, which was not randomized,participating women were given a mixture of eight vitamins that included folic acid (0.36 mg/d), with women who already were pregnant or who had declined to take part in the study serving as controls. The risk of recurrence in the supplemented group was about one-seventh that of the group who received no supplements. The second study was a small randomized trial of folic acid supplementation alone (4 mg/d). It yielded inconclusive results when analyzed according to randomly allocated treatment group (so avoiding bias), but when analyzed after transferring to the control group those women in the folic acid group who did not take their capsules (ie, ignoring the randomization and so introducing the possibility of bias), the supplemented women had a significantly lower risk.To avoid bias, an international multicenter, double-blind,randomized British Medical Research Council (MRC) prevention trial was initiated in July 1983. Conducted at 33 centers (17 in the United Kingdom and 16 in six other countries), it was designed to determine whether supplementation with 4 mg folic acid(one of the vitamins in the B group)or a mixture of seven other vitamins(A, D, B1, B2, B6, C, and nicotinamide) around the time of conception could prevent NTDs. A total of 1,817 women who had previous pregnancies affected by an NTD that was not associated with the autosomal recessive disorder were eligible for the study if they were planning another pregnancy and were not already taking vitamin supplements. Women who had epilepsy were excluded in case the folic acid supplementation adversely affected their treatment. The effect of both forms of supplementation was investigated by use of a factorial study design.The women were allocated randomly to one of four groups—folic acid, other vitamins, both, or neither. The four groups were similar with respect to age and the occurrence of previous pregnancies. Women were asked to take a single capsule each day from the date of randomization until 12 weeks of pregnancy (estimated from the first day of the last menstrual period). Of 1,817 women, 1,195 had a completed pregnancy in which the fetus or infant was known to have or not have an NTD. A total of 27 infants had known NTDs, with 6 in the folic acid groups and 21 in the two other groups. Sequential analysis showed a 72% protective effect(relative risk, 0.28; 95% confidence interval [CI], 0.12 to 0.71). The other vitamins showed no significant protective effect (relative risk, 0.80;95% CI, 0.32 to 1.72). There was no demonstrable harm from the folic acid supplementation, although the ability of the study to detect rare or slight adverse effects was limited. The study result is unlikely to be due to chance, and the randomized double-blind design excluded bias as an explanation. The results also demonstrate that folic acid, rather than any other vitamins, is responsible for the preventive effect.Another significant study was a randomized, double-blind, controlled trial from Hungary that enrolled 4,753 women planning pregnancy. Results documented that the first occurrences of NTDs could be prevented significantly by administering periconceptional multivitamin supplements daily that included 0.8 mg of folic acid. This study was extended to examine the effect of supplementation on other congenital abnormalities. Periconceptional administration of multivitamin supplements reduced NTDs by 50% and the incidence of other major genetic congenital abnormalities, such as cardiovascular anomalies, defects of the urinary tract, congenital hypertrophic pyloric stenosis, and congenital limb defects.Six observational studies of dietary folate or the use of folic acid and other vitamin supplements and NTDs and one nonrandomized folic acid supplementation study have been published. All but one showed an association, but all may have suffered from selection bias, and none could identify folic acid specifically as the responsible vitamin.Results of the British MRC randomized, controlled trial proved that folic acid can prevent spina bifida and anencephaly and provided critical scientific data on which to base public health policy for preventing these birth defects. Within weeks of publication of this study, the CDC developed and issued guidelines for women who had had a pregnancy affected by spina bifida or anencephaly. In September 1992, the United States Public Health Service(USPHS) issued the recommendation that all women of child-bearing age who are capable of becoming pregnant should be offered treatment with 0.4 mg of folic acid daily to reduce their risk of having an NTD-affected pregnancy. For women who already have had an NTD-affected pregnancy, the USPHS also administration of of folic acid day 1 to months prior to the conception and the first months of during the past years it that who not take folic acid supplements are at increased risk for folate which has been to cause spina bifida and anencephaly and has been associated with an increased risk for cardiovascular The that of folic acid during the periconceptional can reduce the number of NTDs has been for several data are from randomized control nonrandomized interventional and observational studies (Table Research on adverse effects from folic acid supplementation is limited. that folic acid supplements in daily of 1 to mg can the of vitamin diagnosis and treatment and leading to permanent is to interventional studies and case in also has been reported in some folic acid of less than 1 but the is not particularly at lower this has been as one to avoid supplementation or with folic acid. However, it also has been that it is to and the deficiency diagnosis at the risk of an NTD. of folate and levels and high Hcy levels with NTDs, that a for these defects may be an abnormality in a and If these results are supplementation with both folic acid and may be to prevent NTDs. This could reduce the for adverse effects of folate supplementation in in of the trials of pregnant women reported serious adverse effects associated with folic acid In the infants born to women who received a with folic acid did not in mortality, and and total serious or disorders at to 21 of age from those born to women only The of and was significantly increased among those received but more affected infants in the supplemented group also had a family history of these This also may be a effect due to the number of A group of children born to women who had taken daily mg of folic acid to prevent NTD revealed no adverse effects on developmental status at age to years compared with the There were significant in but whether this was attributable to folic acid or to other causes to having had a affected is of the randomized and nonrandomized controlled trials showed that among women at high risk of having a child who had an who received 4 of folic acid had approximately cases of NTD-affected offspring than those who received no supplements. interventional and studies also this the of this is 30% of NTDs appear to folic acid with the a of The administration of to the can such defects, but this not occur in The by which this is is to be by the of the acid in the which a folate did not reduce NTDs, but The has been to determine the agents that prevent NTDs in Prevention has been found with acid, C, vitamin C, and vitamin prevention was seen with folic acid, acid, vitamin B6, vitamin or of of folic acid still is being suggested that there may be a rather than a deficiency have found that the Hcy level is significantly for of infants who have NTDs during pregnancy than for vitamin controls. is a and a defect in it would to increased levels of an abnormality in Hcy particularly an abnormality of by folic acid is is in to produce basic and for of which may be the responsible for incidence of NTDs is the the of and of maternal and The two are as and should not be as part of the of women at risk of NTDs. is used both as a and as a after positive results on All cases of anencephaly and approximately of cases of spinal bifida could be by of and in the rates of NTDs in the United States before the availability of prenatal the of a substantial environmental in the etiology of these defects data that folic acid can to NTDs when at of 4 to women who already have had an NTD-affected pregnancy. Results of the British MRC study suggest that the of other vitamins to the folic acid no in of NTDs. on the findings from several folic acid supplementation at a of 4 1 to months prior to conception and the first trimester is for women planning pregnancy who have had a pregnancy affected by an results of controlled trials that folic acid supplementation will not prevent all NTDs. The protective effect demonstrated in studies of folic by the of NTD from none to it is to estimate that administration of folic acid supplementation to all women capable of pregnancy would reduce the incidence of NTDs in the United use of periconceptional folic acid supplements not for the of such is to be reduced if there is a lower risk of The possibility of the number of cases of NTDs in the United States by with the of of folic acid per day an important in public should be made to that all women capable of becoming pregnant 0.4 mg of folic acid daily to this of this recommendation a because 50% of the pregnancies in the United States are it is if not to a daily intake of 0.4 mg of folate diet the protective of vitamin supplementation, women begin to take supplements before conception a less if pregnancy of is a health that can intake of folic acid during the critical of In the USPHS that folic acid of and corn would become as of is to the daily intake of folic acid among women of age by about would prevent about spina bifida and anencephaly birth defects each year and as as premature each year from most commonly risk of is the of that often is associated with vitamin might the diagnosis and treatment of this the for should be of this possibility and that vitamin although occurring most commonly in the can occur at any Also, care should be taken to total folate to less than 1 the of a intake of folate in the periconceptional may be by women who could become pregnant to a diet with a daily vitamin with folic or these should be to other health and the public about the value of folic acid supplementation in preventing NTDs. surveillance programs should the prevalence of NTDs in fetuses and and clinical research into the by which folic acid NTDs should be In more clinical trials are to determine the of folic acid in preventing the occurrence and recurrence of NTDs.

Type 2 diabetes (T2D) is associated with elevated frequencies of micronuclei (MNi) and other DNA damage biomarkers. Interestingly, individuals with T2D are more likely to be deficient in micronutrients (folic acid, pyridoxal-phosphate, cobalamin) that play key roles in one-carbon metabolism and maintaining genomic integrity. Furthermore, it has recently been shown that deficiencies in these nutrients, in particular folic acid leaves cells susceptible to glucose-induced DNA damage. Therefore, we sought to investigate if the B lymphoblastoid WIL2-NS cell line cultured under folic acid-deficient conditions was more sensitive to DNA damage induced by glucose, or the reactive glycolytic byproduct methylglyoxal (MGO) and subsequent advanced glycation endproduct formation. Here, we show that only WIL2-NS cultured under folic acid-deficient conditions (23 nmol/l) experience an increase in MNi frequency when exposed to high concentrations of glucose (45 mmol/l) or MGO (100 µmol/l). Furthermore, we showed aminoguanidine, a well-validated MGO and free radical scavenger was able to prevent further MNi formation in folic acid-deficient cells exposed to high glucose, which may be due to a reduction in MGO-induced oxidative stress. Interestingly, we also observed an increase in MGO and other dicarbonyl stress biomarkers in folic acid-deficient cells, irrespective of glucose concentrations. Overall, our evidence shows that folic acid-deficient WIL2-NS cells are more susceptible to glucose and/or MGO-induced MNi formation. These results suggest that individuals with T2D experiencing hyperglycemia and folic acid deficiency may be at higher risk of chromosomal instability.

In the past, northern China's Shanxi Province has reported the highest incidence of neural tube defects (NTDs) in the world. However, little is known about the epidemiology of NTDs in this area in recent years. Data were collected from a population-based birth defects surveillance system in 4 counties that captures information on all live births, stillbirths of at least 20 weeks' gestation, and pregnancy terminations at any gestational age resulting from prenatal diagnosis of a birth defect. We also surveyed mothers of NTD case patients to determine their use of folic acid before and during early pregnancy. During 2003, 160 NTD cases were identified among 11,534 births (NTD birth prevalence = 138.7/10,000 births). The rates of anencephaly, spina bifida and encephalocele were 65.9, 58.1, and 14.7 per 10,000, respectively, and a female predominance was observed among anencephaly cases (male-to-female relative risk [RR], 0.49; 95% confidence interval [CI], 0.30-0.79), but not among spina bifida (RR, 0.90; 95% CI, 0.55-1.45) and encephalocele (RR, 1.03; 95% CI, 0.40-2.69) cases. The percentages of pregnancy termination following prenatal diagnosis of anencephaly, spina bifida, and encephalocele were 50%, 41.8%, and 35.3%, respectively. NTD birth prevalence tended to be higher among mothers aged <20 or > or =30 years (P = .06) and was markedly associated with lower levels of maternal education (P < .001). Among 143 NTD mothers, only 6 (4.2%) used folic acid supplements during the periconceptional period. The NTD birth prevalence rate in the study area is among the highest worldwide. Folic acid deficiency may be one important risk factor.

There is increased worldwide concern about the consequences of folic acid and vitamin B12 deficiencies on health, which include megaloblastic anemia, neural tube defects and cardiovascular disease. This study intended to determine the prevalence of folic acid and vitamin B12 deficiencies in vulnerable groups in labor and poor socioeconomic strata of the Venezuelan population. A total of 5658 serum samples were processed to determine folic acid and vitamin B12 concentrations. The study involved three surveys performed during 2001-2002 and included infants, children, adolescents and pregnant women from labor and poor socioeconomic strata of the population. The method used was a radio immunoassay designed for the simultaneous measurement of serum folic acid and vitamin B12. The prevalence of folic acid deficiency was higher than 30% for all groups studied, reaching 81.79% in adolescents. Vitamin B12 deficiency was 11.4% in samples collected nationwide, but there was also a similar prevalence of high serum levels. The prevalence of folic acid and vitamin B12 deficiencies in pregnant women reached 36.32 and 61.34%, respectively. This work shows that there is a high prevalence of folic acid deficiency, especially in women of reproductive age, pregnant adolescents and in the whole population studied in Vargas state. This situation requires immediate intervention as supplementation or food fortification programs.