Periconceptional Supplementation Research Articles

Association of the Maternal MTHFR C677T Polymorphism with Susceptibility to Neural Tube Defects in Offsprings: Evidence from 25 Case-Control Studies

BackgroundMethylenetetrahydrofolate reductase (MTHFR) is a critical enzyme in folate metabolism and is involved in DNA methylation, DNA synthesis, and DNA repair. In addition, it is a possible risk factor in neural tube defects (NTDs). The association of the C677T polymorphism in the MTHFR gene and NTD susceptibility has been widely demonstrated, but the results remain inconclusive. In this study, we performed a meta-analysis with 2429 cases and 3570 controls to investigate the effect of the MTHFR C677T polymorphism on NTDs.MethodsAn electronic search of PubMed and Embase database for papers on the MTHFR C677T polymorphism and NTD risk was performed. All data were analysed with STATA (version 11). Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the association. Sensitivity analysis, test of heterogeneity, cumulative meta-analysis, and assessment of bias were performed in our meta-analysis.ResultsA significant association between the MTHFR C677T polymorphism and NTD susceptibility was revealed in our meta-analysis ( TT versus CC: OR = 2.022, 95% CI: 1.508, 2.712; CT+TT versus CC: OR = 1.303, 95% CI: 1.089, 1.558; TT versus CC+CT: OR = 1.716, 95% CI: 1.448, 2.033; 2TT+CT versus 2CC+CT: OR = 1.330, 95% CI: 1.160, 1.525). Moreover, an increased NTD risk was found after stratification of the MTHFR C677T variant data by ethnicity and source of controls.ConclusionThe results suggested the maternal MTHFR C677T polymorphism is a genetic risk factor for NTDs. Further functional studies to investigate folate-related gene polymorphisms, periconceptional multivitamin supplements, complex interactions, and the development of NTDs are warranted.

Awareness of spina bifida and periconceptional use of folic acid among pregnant women in a developing economy

Folate deficiency in pregnant women is a recognized cause of spina bifida. We sought to establish the level of awareness of spina bifida as well as the use of folate supplementation among pregnant women in a developing economy. Interviewer-administered questionnaires were used to obtain information from 200 to 20 randomly selected pregnant women attending antenatal clinics at the authors' institution. Demographic information and information on parity, folic acid use and knowledge on spina bifida including its cause, prevention and treatment were obtained. Data analyses were done using Epi Info version 6. The mean age of the women was 30.3 years (range 17-52 years). Sixty-six of the women (30.0 %) were primigravida. Most of the respondents [208 (94.5 %)] have attained, at least, secondary level of education. The average gestational age at antenatal clinic booking was 20.7 weeks (range 4-38 weeks), while the average gestational age at commencement of folic acid use was 18.5 weeks (range 4-38 weeks). None of them used folic acid in the preconception period. Knowledge about spina bifida is poor and a significant number [103 (46.8 %)] have superstitious belief about its aetiology. Only 56 (25.5 %) of the respondents are aware that folic acid use prevents its occurrence; however, 194 (88.2 %) are willing to receive periconceptional folate supplementation. There is paucity of knowledge about spina bifida among Nigerian pregnant women despite their high level of formal education. We advocate an aggressive public health campaign to enlighten the women about spina bifida and encourage periconceptional folate supplementation.

Relation of Childhood Malnutrition to Adult Mental Disorders

Relation of Childhood Malnutrition to Adult Mental Disorders

Polymorphisms in folate‐metabolizing genes and risk of having an offspring with congenital anomalies in the West Siberian region of Russia: a case–control study

Periconceptional folate supplementation prevents a number of congenital anomalies (CA). The aim of our study was to investigate the association of 11 polymorphisms in the folate-metabolizing genes with the risk of having an offspring with CA in the Russian ethnic group. We genotyped 280 mothers having a CA-affected pregnancy and 390 control mothers. The most common malformations among the cases were CA of the nervous, urinary, and cardiovascular systems, and these groups were analyzed separately. In the whole group of CA, we revealed the associations of MTHFR C677T and MTR A2756G loci with increased risk of CA-affected pregnancy. In the group of CA of the cardiovascular system, we observed an association of MTHFR A1298C with decreased risk and an association of MTR A2756G with increased risk of CA. After the Bonferroni correction, only the association between the genotype MTR 2756GG and the risk of having a fetus with CA of the cardiovascular system remained statistically significant (OR = 4.99, P = 0.03). These findings indicate that locus A2756G in the MTR gene may play a role in susceptibility to CA of the cardiovascular system in West Siberia, but further research is necessary to confirm the association.

A comparison of folate status in women of child-bearing age in Korea and in the United States

Correspondence: Chandrika J Piyathilake Department of Nutrition Sciences, University of Alabama at Birmingham, 1675 University Blvd, Webb 326, Birmingham, AL 35294, USA Tel +1 205 975 5398 Email piyathic@uab.edu Background: Even though several studies have demonstrated that periconceptional supplementation with folic acid (FA) reduces the occurrence of neural tube defects, FA fortification has been a topic of intense debate due to the possible adverse effects of higher folate status on several health conditions. Several countries, including Korea, have been indecisive as to whether fortification is warranted or not. It is therefore helpful for these countries to compare folate concentrations in their populations with populations exposed to mandatory FA fortification. Purpose: To evaluate the differences in the distribution of circulating concentrations of folate in Korea and the United States (US) at different time points. Methods: The Korean study populations consisted of women of child-bearing age recruited in 1999 and in 2009. The US study populations consisted of women of child-bearing age recruited in the post FA fortification era (2005 and 2009). Plasma and red blood cell (RBC) folate concentrations were measured using the Lactobacillus casei microbiological assay. Results: The percentage of US women with neural tube defect-protective levels of RBC folate was significantly higher compared to Korean women in 1999 and 2009. However, in 2009, when FA supplements became readily available for Koreans, 50% of Korean women in the study achieved the neural tube defect-protective level of RBC folate; 11% of them demonstrating supraphysiologic concentrations of plasma folate. Even though FA fortification in the US resulted in more than 80% of women achieving .400 ng/mL of RBC folate by 2009, nearly 50% also demonstrated having supraphysiologic concentrations of plasma folate, which prompted some researchers to raise concerns about possible adverse effects of higher folate status on several health conditions. Conclusion: Encouraging Korean women of reproductive age to take FA supplements and evaluating the outcome of such efforts would be worthwhile prior to implementing a populationwide mandatory FA fortification in Korea.

Preconception Women’s Health and Pediatrics: An Opportunity to Address Infant Mortality and Family Health

THE U.S. INFANT mortality rate remains unacceptably high, with large disparities found by race. Increasingly, research has demonstrated that interventions must go beyond ensuring access to care and prenatal focus to address the preconception health of women. Critical fetal development occurs in the earliest weeks after conception, often before a woman is aware of her pregnancy. The Maternal Child Health Bureau’s life course initiatives and the Centers for Disease Control’s preconception health initiatives are placing infant mortality and child health in a life course context, that is, uniting the reproductive health and pediatric longitudinal perspectives. In the recent report “Clinical Preventive Services forWomen”, the Institute ofMedicine recommended annual well-women visits incorporating preconception care, and Healthy People 2020 includes a section of objectives on preconception health and behaviors. With growing scientific recognition that early antecedents of child and adult health start prenatally and even preconceptionally, women’s health is key. Pediatric clinicians have been leaders in the efforts to reduce infant mortality and in family-centered care, but how can pediatrics further contribute? A golden opportunity exists to serve as preconception care (PCC) clinicians for preconceptional adolescents and interconceptional mothers seen in practice.

Neural tube defects—disorders of neurulation and related embryonic processes

Neural tube defects (NTDs) are severe congenital malformations affecting 1 in every 1000 pregnancies. 'Open' NTDs result from failure of primary neurulation as seen in anencephaly, myelomeningocele (open spina bifida), and craniorachischisis. Degeneration of the persistently open neural tube in utero leads to loss of neurological function below the lesion level. 'Closed' NTDs are skin-covered disorders of spinal cord structure, ranging from asymptomatic spina bifida occulta to severe spinal cord tethering, and usually traceable to disruption of secondary neurulation. 'Herniation' NTDs are those in which meninges, with or without brain or spinal cord tissue, become exteriorized through a pathological opening in the skull or vertebral column (e.g., encephalocele and meningocele). NTDs have multifactorial etiology, with genes and environmental factors interacting to determine individual risk of malformation. While over 200 mutant genes cause open NTDs in mice, much less is known about the genetic causation of human NTDs. Recent evidence has implicated genes of the planar cell polarity signaling pathway in a proportion of cases. The embryonic development of NTDs is complex, with diverse cellular and molecular mechanisms operating at different levels of the body axis. Molecular regulatory events include the bone morphogenetic protein and Sonic hedgehog pathways which have been implicated in control of neural plate bending. Primary prevention of NTDs has been implemented clinically following the demonstration that folic acid (FA), when taken as a periconceptional supplement, can prevent many cases. Not all NTDs respond to FA, however, and adjunct therapies are required for prevention of this FA-resistant category.

Novel effects of folinic acid supplementation in embryonic zebrafish, danio rerio

Although periconceptional folate supplementation has lead to a decrease in the incidence of neural tube defects (Rosano et al., 1999), studies suggest that there is also a relationship with the increased incidence of autism spectrum disorders (Beard et al., 2011). The purpose of the current study was to examine the effect of folinic acid (FA) on embryonic development. Adult zebrafish, Danio rerio, were maintained using standard procedures and breed in house. After light onset, embryos were sorted into either FA (10 mM for 24 hrs) or Control. Assessments (time to hatch, gross morphology, startle response (SR), and development of swim behavior (ST)) were made at 2, 3, and 5 DPF. FA was found to alter the timing of development, with an increase in the percentage hatched prematurely to 2 DPF. Embryos were also found to be smaller at 3 DPF (M = 3.22, SD = 0.26) than the control (M = 3.37, SD = 0.19). However, by 5 DPF the FA group had larger overall body size (FA: M = 3.67, SD = 0.17 Control: M = 3.46, SD = 0.20). While both SR and ST behaviors were similar at 3 DPF, at 5 DPF the FA had lower swim time (higher anxiety). The obtained results indicate that FA exposure had an effect on both anatomical developmental and locomotor behavior. Embryos exposed to FA hatched approximately 24 hours before the control group and showed higher level of anxiety in both the startle response and swim behavior.

Periconceptional maternal micronutrient supplementation is associated with widespread gender related changes in the epigenome: a study of a unique resource in the Gambia.

In addition to the genetic constitution inherited by an organism, the developmental trajectory and resulting mature phenotype are also determined by mechanisms acting during critical windows in early life that influence and establish stable patterns of gene expression. This is the crux of the developmental origins of health and disease hypothesis that suggests undernutrition during gestation and infancy predisposes to ill health in later life. The hypothesis that periconceptional maternal micronutrient supplementation might affect fetal genome-wide methylation within gene promoters was explored in cord blood samples from offspring of Gambian women enrolled into a unique randomized, double blind controlled trial. Significant changes in the epigenome in cord blood DNA samples were further explored in a subset of offspring at 9 months. Gender-specific changes related to periconceptional nutritional supplementation were identified in cord blood DNA samples, some of which showed persistent changes in infant blood DNA samples. Significant effects of periconceptional micronutrient supplementation were also observed in postnatal samples which were not evident in cord blood. In this Gambian population, the increased death rate of individuals born in nutritionally poor seasons has been related to infection and it is of interest that we identified differential methylation at genes associated with defence against infection and immune response. Although the sample size was relatively small, these pilot data suggest that periconceptional nutrition in humans is an important determinant of newborn whole genome methylation patterns but may also influence postnatal developmental patterns of gene promoter methylation linking early with disease risk.

DNA methylation profiling at imprinted loci after periconceptional micronutrient supplementation in humans: results of a pilot randomized controlled trial

Intrauterine exposures mediated by maternal diet may affect risk of cardiovascular disease, obesity, and type 2 diabetes. Recent evidence, primarily from animal studies and observational data in humans, suggests that the epigenome can be altered by maternal diet during the periconceptional period and that these programming events may underlie later disease risk. A randomized controlled trial of periconceptional micronutrient supplementation in The Gambia, where seasonal nutritional variations affect fetal growth and postnatal outcomes, provided a unique opportunity to test this hypothesis. Specifically, we targeted imprinted genes, which play important roles in allocation of maternal resources while being epigenetically regulated. DNA methylation at 12 differentially methylated regions (DMRs) was analyzed in cord blood samples from 58 offspring of women participating in a double-blind randomized-controlled trial of pre- and periconceptional micronutrient supplementation (including folate, zinc, and vitamins A, B, C, and D). We observed sex-specific effects of micronutrient supplementation, reducing methylation levels at two of the DMRs analyzed, IGF2R in girls and GTL2-2 in boys. This pilot study is the first to analyze DNA methylation in the context of a randomized controlled trial, and it provides suggestive evidence that periconceptional maternal nutrition alters offspring methylation at imprinted loci.

Deep sequencing study of the MTHFR gene to identify variants associated with myelomeningocele

Neural tube defects (NTDs) are congenital anomalies caused by a combination of genetic and environmental influences. A defect below the head region resulting in protuberance of meninges and nervous tissue is termed myelomeningocele (MM). MM, the most common NTD compatible with survival, occurs in approximately 1 in 1000 births worldwide. Maternal preconceptional and periconceptional folate supplementation reduces the risk of NTDs by up to 70%. A key enzyme in folate metabolism is 5, 10-methylene-tetrahydrofolate reductase (MTHFR). Sequence the 12 exons of the MTHFR gene among 96 subjects with MM to identify variants potentially contributing to the disease trait. Exons were amplified by polymerase chain reaction, and the products were sequenced with the Sanger method to reveal sequence variants compared to MTHFR reference sequences. Association of variants was examined by Fisher's test. A novel variant c.171+3G>T was identified in intron 1 in one affected subject. The variant was not found in the subject's unaffected mother's DNA, and the unaffected father's DNA was unavailable. We found significant differences in allele frequencies for seven SNPs in MM subjects compared with ethnically matched reference populations reported in the single nucleotide polymorphism database. We identified a novel variant c.171+3G>T in the MTHFR gene that potentially affects splicing in an affected subject. In addition, we observed five SNPs (rs13306561, rs2274976, rs2066462, rs12121543, and rs1476413) in the MTHFR gene not previously shown to associate with MM. The current study provides additional evidence that multiple variations in the MTHFR gene are associated with MM.

One-Carbon Vitamins, Epigenetic/Genetic Integrity and Colon Cancer: Research is Needed to Understand the Effect on Tumorigenic Signaling Pathways

Copyright: © 2012 Liu Z. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Evidence has established the protective effect of folic acid fortification and periconceptional supplementation on neural tube defects. A large and growing body of compelling evidence from both epidemiological and pre-clinical studies also indicates that adequate folate status, and possibly in combination with other one-carbon nutrients, is associated with a decreased risk of colorectal carcinogenesis [1,2]. Evidence is still accumulating in support of these claims, but some recent studies raise warnings in regard to the safety for use folate as a chemopreventive component. Not to mention some null observations [3,4], it is important to point out that some studies suggest that overly abundant intake of folate may paradoxically promote tumor progression if administered in an inopportune time when an individual already has harbored foci of precancerous or cancerous cells [5-8]. To fully take advantage of this chemopreventive agent and avoid its cancer-promoting effect (though more studies are needed to confirm), research is urgently needed to understand specific molecular mechanisms by which these paradoxical effects are mediated.

Anemia and Iron Deficiency in Pregnancy

Iron deficiency is still the world's most common nutritional deficiency, and generally, iron deficiency anemia is the most prevalent form of anemia. The major risk groups for iron deficiency include women of childbearing age, pregnant women, and lactating postpartum women. There exist plenty of studies attending and reconfirming this important issue. To combat this problem, different food iron fortification programmes have been implemented in some regions, iron supplementation guidelines have been elaborated in some countries, and iron therapy schemes involving both oral and intravenous administration have been proposed. But despite these efforts and the recommendations by the World Health Organization, the problem concerning iron deficiency and anemia is still unsolved in most parts of the world. Even in many industrialized countries, the topic of iron and pregnancy often stays unattended and there is a lack of consensus concerning guidelines in different countries. Other disorders, such as hemoglobinopathies, also contribute to the high prevalence of anemia worldwide. The prevalence of anemia is influenced by a variety of deficiencies (e.g., folate, vitamin B12, vitamin A, vitamin D, and vitamin C), infectious diseases, parasitic infestations, inflammatory diseases as well as malnutrition. As data for iron are quite profound, these are often scarce if we look on other vitamins and micronutrients, except for folic acid. As we know, periconceptional supplementation with folic acid has the potential to reduce the incidence of neural tube defects (e.g., spina bifida) dramatically. Unfortunately, folic acid prophylaxis is not commonly used for several reasons. By this special issue, our intention was to broaden the perspective on anemia in pregnancy and propose ways to solve the problems. We have chosen three articles concerning the prevention/treatment of iron deficiency anemia in pregnancy/postpartum including papers from Australia, Nigeria, and Denmark. Another Danish study focuses on the prevention of postpartum anemia through hemostatic sealing of the placental bed at caesarean section, thereby reducing perioperative blood losses. A paper from France and Lebanon evaluates the relationship between periconceptional folate deficiency and neural tube defects. A Chinese study addresses the supposed relationship between iron deficiency and postpartum depression. Together, these papers illustrate some of the many facets of the complexity of the prevention and treatment of anemia in pregnant and postpartum women. Alexander Krafft Laura Murray-Kolb Nils Milman

Lack of periconceptional vitamins or supplements that contain folic acid and diabetes mellitus–associated birth defects

The purpose of this study was to examine the risk of birth defects in relation to diabetes mellitus and the lack of use of periconceptional vitamins or supplements that contain folic acid. The National Birth Defects Prevention Study (1997-2004) is a multicenter, population-based case-control study of birth defects (14,721 cases and 5437 control infants). Cases were categorized into 18 types of heart defects and 26 noncardiac birth defects. We estimated odds ratios for independent and joint effects of preexisting diabetes mellitus and a lack of periconceptional use of vitamins or supplements that contain folic acid. The pattern of odds ratios suggested an increased risk of defects that are associated with diabetes mellitus in the absence vs the presence of the periconceptional use of vitamins or supplements that contain folic acid. The lack of periconceptional use of vitamins or supplements that contain folic acid may be associated with an excess risk for birth defects due to diabetes mellitus.

Polymorphism of MTHFR A1298C, a Marker in Northern Indian Mothers with DS Babies and its Association with Biochemical Risk Factors and CHD

Background: Down syndrome occurs due to nondisjunction in maternal meiosis. Polymorphism of MTHFR due to low folate, high homocysteine are implicated as risk factors. Objective: To evaluate A1298C polymorphism as a risk factor in DS babies and association with biochemical parameters and CHD. Methods: 81 mothers(mean age 24.9±3.2yrs) with babies having free trisomy 21 and 99 mothers (mean age 26.9±4.6yrs) having no children with DS were evaluated. Fasting blood was collected for plasma homocysteine, folate (serum and RBC) and for PCR amplification. The MTHFR A1298C polymorphisms were done by allele specific polymerase reaction and enzyme digestion. Homocysteine quantified by liquid chromatography-TMS. Cardiovascular system examination and Echo was done to delineate CHD. Results: The prevalence of A1298C polymorphism in cases and controls were 66.7% vs. 39.4% respectively. The heterozygous and homozygous genotype frequencies at 1298(AC and CC) among case and control were (38.3% vs. 22.2% and 28.4% vs. 17.25% respectively,OR=3.10, 95% CI 1.6-5.79, P=0.002). Low serum folate in 33.3% % of cases vs.8.0%% in controls(OR= 5.68, CI 95% 2.41-13.4, P= 0.0001). Low RBC folate was found in 28.3% of cases vs.11.1% in controls,(OR= 3.172, CI 95% 1.43-6.99 P=0.005). High homocysteine was found in 9.8% of cases vs. 2.0% in controls. The median intraquartile rangeof homocysteine in cases was10.2(Q1-Q3, 8.2-12.0) vs.7.6(Q1-Q3, 5.7-10.1) in controls. No relationship was observed among A1298C polymorphism and CHD.(Pvalue=0.601). Conclusion: MTHFR A1298C polymorphism associated with 3 times more risk of developing DS. Low serum, RBC folate and high homocysteine association are significant. Periconceptional folate supplementation may lead to a decline in DS births and CHD. Table Table

Apparent prevention of neural tube defects by periconceptional vitamin supplementation*

An earlier preliminary paper is expanded. Women who had given birth to one or more infants with a neural tube defect were recruited into a trial of periconceptional vitamin supplementation. Two hundred mothers attending five centres were fully supplemented (FS), 50 were partially supplemented (PS), and 300 were unsupplemented (US). Neural tube defect recurrences in the study pregnancies were 1(0.5%), in FS, none in PS, and 13 (4%) in US mothers. The difference in outcome between FS and US mothers is significant. The most likely explanation is that supplementation has prevented some neural tube defects, but further studies are needed.

Commentary: A brief history of folic acid in the prevention of neural tube defects

Schorah CJ, Sheppard S. Maternal nutrition in early pregnancy. Br J Nutr 1977;38:497–506. 4 Smithells RW, Sheppard S, Schorah CJ. Vitamin deficiencies and neural tube defects. Arch Dis Child 1976;51: 944–50. 5 Hibbard ED, Smithells RW. Folic acid metabolism and human embryopathy. Lancet 1965;i:1254. 6 Pritchard JA, Scott DE, Whalley PJ, Haling RF, Jr. Infants of mothers with megaloblastic anemia due to folate deficiency. J Am Med Soc 1970;211:1982–4. 7 Laurence KM, James N, Miller M, Campbell H. Increased risk of recurrence of pregnancies complicated by fetal neural tube defects in mothers receiving poor diets, and possible benefit of dietary counselling. Br Med J 1980;281: 1592–4. 8 Smithells RW, Sheppard S, Schorah CJ et al. Possible prevention of neural tube defects by periconceptional vitamin supplementation. Lancet 1980;i:339–40. 9 Wynn V. Vitamins and oral contraceptive use. Lancet 1975;i:561–4. 10 Gal I, Sharman IM, Pryse-Davies J. Vitamin A in relation to human congenital malformations. Adv Terator 1972;5: 143–59. 11 Nevin NC. Letter: Recurrence risk of neural tube defects. Lancet 1980;i:1301–2. 12 Record RG, McKeown T. Congenital malformations of the central nervous system. II. Maternal reproductive history and familial incidence. Br J Soc Med 1950;4:26–50. 13 Clarke CA, Hobson D, McKendrick OM, Rogers SC, Sheppard PM. Spina bifida and anencephaly: miscarriage as possible cause. Br Med J 1975;iv:743–6. 14 James WH. Birth ranks of spontaneous abortions in sibships of children affected by anencephaly or spina bifida. Br Med J 1978;i:72–3. 15 Seller MJ, Embury S, Polani PE, Adinolfi M. Neural tube defects in curly-tail mice. II. Effect of maternal administration of vitamin A. Proc R Soc Lond[Biol] 1979;206: 95–107.

Folic acid and primary prevention of birth defects

Birth defects (BDs) are an important public health problem, due to their overall incidence, occurring in 2-3% of live births in European Union. Neural tube defects (NTDs) are among major NTDs, due to their severity and relatively high incidence; in the meanwhile NTDs are also the most effectively preventable BDs to date. In particular, an adequate folic acid (FA) intake reduces both the occurrence and the recurrence of NTDs; FA is the synthetic form of folates, naturally occurring vitamins in a number of foods, especially vegetables. The daily intake of 0.4 mg of FA should be recommended to all women of childbearing age who plan to become pregnant. The Italian Network for Primary Prevention of BDs through FA Promotion has achieved a significant improvement in FA awareness and use in the periconceptional period. Nevertheless, primary prevention of BDs needs to make further progress; the Italian National Centre for Rare Diseases participates in european sureveillance of congenital anomalies (EUROCAT) Joint Action as coordinator of activities on the effectiveness of BDs prevention. Mandatory food fortification with FA has not been introduced in any European country. The health benefits of FA in reducing the risk of NTDs are undisputed; however mechanistic and animal studies suggest a relationship between high FA intakes and increased cancer promotion, while human studies are still inconsistent and inconclusive. A Working Group organized by the European Food Safety Authority pointed out significant uncertainties about fortification safety and the need for more studies; currently, FA intake from fortified foods and supplements should not exceed 1 mg/day in adults. In conclusion, based on up-to-date scientific evidence, the Italian Network strategy pivots on periconceptional supplementation integrated with promotion of healthy eating habits, support to health education, enhancing the role of women in managing life choices about their health and pregnancy and increasing the scientific knowledge about BDs primary prevention.

Human neural tube defects: Genetic causes and prevention

Neural tube defects (NTDs) are severe congenital malformations affecting 1-2 in 1,000 live births, whose etiology is multifactorial, involving environmental and genetic factors. NTDs arise as consequence of the failure of fusion of the neural tube early during embryogenesis. NTDs' pathogenesis has been linked to genes involved in folate metabolism, consistent with an epidemiologic evidence that 70% of NTDs can be prevented by maternal periconceptional supplementation. However, polymorphisms in such genes are not linked in all populations, suggesting that other genetic factors and environmental factors could be involved. Animal models have provided crucial mechanistic information and possible candidate genes to explain susceptibility to NTDs. A crucial role has been assigned to the planar cell polarity (PCP) pathway, a highly conserved, non-canonical Wnt-frizzled-dishevelled signaling cascade that plays a key role in establishing and maintaining polarity in the plane of the epithelium and in the process of convergent extension during gastrulation and neurulation in vertebrates. The Loop-tail (Lp) mouse that develops craniorachischisis carry missense mutations in the PCP core gene Vangl2, that is the mammalian homolog of the Drosophila Strabismus/Van gogh (Stbm/Vang). The presence of mutations in human VANGL1 and VANGL2 genes encourages us to extend the investigation to other PCP genes that, with VANGL, play an essential role in neurulation during development.

Low maternal vitamin B12 is a risk factor for neural tube defects: a meta-analysis

Objective. The objective of this study was to assess whether low level of maternal vitamin B12 is associated with an increased risk of fetal neural tube defects (NTDs), in order to contribute to research on further reduction of NTDs under a background of mandatory folic acid (FA) fortification.Methods. A meta-analysis was conducted. We retrieved and evaluated the studies published on the risk of low level of maternal vitamin B12 for NTDs. The homogeneity of the studies was examined using the forest graph. Meta-analysis was applied to calculate the odds ratio (OR) of fetal NTDs in relation to low maternal B12 and its 95% confidence interval (CI).Results. We identified nine published articles including 567cases and 1566 controls in the meta-analysis. All the studies selected were homogeneous according to the forest graph (χ2 = 15.05, P < 0.1). The estimated OR value of fetal NTDs in relation to low maternal B12 was 2.41 (95% CI: 1.90–3.06).Conclusion. Low maternal B12 status could be an important risk factor for the development of fetal NTDs. The addition of synthetic B12 to current recommendations for periconceptional FA tablet supplements or FA-fortified foods should be considered.