Occurrence Of Neural Tube Defects Research Articles

Folic acid supplementation can adversely affect murine neural tube closure and embryonic survival

Neural tube defects (NTDs), a common birth defect in humans, result from the failure of the embryonic neural tube (NT) to close properly. NT closure is a complex, poorly understood morphogenetic process influenced by genes and environment. The most effective environmental influence in decreasing the risk for NTDs is folic acid (FA) fortification and supplementation, and these findings led to the recommendation of periconceptual FA intake and mandatory fortification of the US grain supply in 1998. To explore the relationship between genetics and responsiveness to FA supplementation, we used five mouse NTDs models-Zic2, Shroom3, Frem2, Grhl2 (Grainyhead-like 2) and L3P (Line3P)-and a long-term generational FA supplementation scheme. Contrary to expectations, we find that three genetic mutants respond adversely to FA supplementation with increased incidence of NTDs in homozygous mutants, occurrence of NTDs in heterozygous embryos and embryonic lethality prior to NT closure. Because of these unexpected responses, we examined NTD risk after short-term FA supplementation. Our results indicate that, for the same genetic allele, NTD risk can depend on the length of FA exposure. Our data indicate that, depending on the gene mutation, FA supplementation may adversely influence embryonic development and NT closure.

More folic acid, the five questions: Why, who, when, how much, and how

In recent years, a number of studies have been performed to evaluate the possible health benefits of an increased intake of folic acid (FA) on human health. However, the only well-documented benefit emerging from randomized controlled trials, nonrandomized interventions trials, and observational studies is the risk reduction of neural tube defects (NTDs). NTDs are congenital malformations that include anencephaly, encephalocele, and spina bifida caused by the failure of fusion of the neural tube that normally closes between 22nd and 28th day since conception (on an average 40-42th day after the first day of last menstrual period). The occurrence of NTDs varies among population between 0.8 and 3 per 1,000, and it is estimated that 324,000 pregnancies are affected every year worldwide. More FA can decrease the NTDs risk up to 0.6 per 1,000 births. Other malformations as congenital heart defects, cleft lip, and limb deficiencies can be most probably also reduced. To decrease the NTDs risk, it is recommended that all women capable of becoming pregnant should have more FA. The goal is that every woman could start her pregnancy with an optimal folate status, estimated today to be as more than 906 nmol/L of red blood cell folate concentration. More FA can be obtained through a strict Mediterranean pattern of nutrition and healthy life style, fortified food, supplements. Women and health authorities can choose the most appropriate strategy. Monitoring folate status of women during the periconceptional period is an essential way to evaluate the success of the preferred strategy.

Dieting to Lose Weight and Occurrence of Neural Tube Defects in Offspring of Mexican–American Women

Lowered maternal weight gain and reduction in early pregnancy have been associated with risk of neural tube defects (NTDs) in offspring. We examined the association of self-reported maternal dieting behaviors on the occurrence of NTDs. We conducted a population based case-control study among Mexican-American women who were residents of the 14 Texas counties bordering Mexico. Case women had an NTD-affected pregnancy identified at birth or prenatally and had deliveries during the years 1995-2000. Control women were those who delivered live born infants without an apparent congenital malformation, randomly selected and frequency-matched to cases by year and facility. One hundred eighty-four case women and 225 control women were asked in person about the use of nutritional supplements, dieting to lose weight, and type of weight reduction supplements used during the 3 months before conception. Women who reported being on a diet to lose weight during the 3 months before conception had an NTD odds ratio (OR) of 1.9 (95% confidence interval (CI) = 1.1, 3.3) compared with those not reporting being on a diet. Neither consuming vitamin drinks (OR = 1.2) nor using diet pills (OR = 1.6) during the 3 months before conception had ORs that were different from the null, when compared to women not reporting those behaviors. The risk effect for dieting did not differ markedly among normal or underweight (OR = 2.0, 95% CI = 0.7, 5.6), overweight (OR = 1.9, 95% CI = 0.7, 5.0), or obese women (OR = 1.5, 95% CI = 0.6, 4.0). No effect was seen among dieting women who were consuming at least 1.0 mg/day of folate (OR = 1.1, CI = 0.3, 4.5). Maternal dieting prior to conception may increase the risk of NTDs in offspring.

Long Term Maintenance of Neural Tube Defects Prevention in a High Prevalence State

To assess the efficacy of folic acid (FA) supplementation and fortification in preventing neural tube defects (NTDs) in a high prevalence region of the United States. Active and passive surveillance methods were used to identify all fetuses/infants affected with an NTD in South Carolina. Prevalence rates were compared with FA intake to determine the effects of increased intake on NTD occurrence and recurrence. From 1992 to 2009, 916 NTD cases occurred in South Carolina, with isolated defects comprising 79% of cases. The NTD rate decreased 58% during this period. There was one NTD-affected pregnancy in 418 subsequent pregnancies (0.2%) in mothers with earlier NTD-affected pregnancies who consumed periconceptional FA supplements, and there were 4 NTDs in 66 pregnancies (6.1%) in which the mother did not take FA supplements. FA supplementation increased from 8% to 35% from 1992 to 2007, and knowledge of the protective benefits of FA increased from 8% to 65% in women of childbearing age. Increased periconceptional intake of FA appeared to reduce NTDs in a high-prevalence region. The rate of spina bifida and anencephaly in South Carolina is now essentially the same (0.69 cases per 1000 live births and fetal deaths) as the 1998 to 2005 US rate (0.69).

Folate metabolism pathway and Plasmodium falciparum malaria infection in pregnancy

Malaria induced by Plasmodium falciparum is a major cause of mortality. P. falciparum has the ability to use host plasma folate as its primary folate source. Folate is a cofactor needed for both malaria parasite growth and host erythrocyte production. This review examines the possible impairment of the folate-mediated one-carbon metabolism pathway as a result of P. falciparum malaria infection during pregnancy. Folate deficiency during malaria infection is presented, with an emphasis on the controversy regarding the decrease of plasma or erythrocyte folate secondary to malaria. Maternal folate deficiency increases the risk of adverse pregnancy outcomes. Functional folate deficiency and/or increased plasma homocysteine levels during pregnancy of infected women in areas endemic for malaria is a probable scenario accentuating the impairment of placenta function leading to the occurrence of neural tube defects, low birth weights, and intrauterine growth retardations. Potential questions that may be answered in future investigations using an appropriate protocol to study pregnant women with malaria are also addressed.

Birth Cohort Studies Conducted by Peking University, China

S-31C2-3 Background/Aims: Large birth cohort study with long-term follow-up is a powerful and feasible way to assess the impact of environment, genetics, and environment-genetics interaction on different health outcomes of both pregnant women and their offspring, by prospectively collecting extensive data and specimen during various periods from preconception to childhood or even later life. Methods: Peking University Institute of Reproductive and Child Health have conducted 3 large birth cohort studies. Results: First cohort study includes about 230,000 children, whose mother had participated in a previous folic acid intervention study to prevent the occurrence of neural tube defects in China. Women entered the program either at premarital health assessment or at any stage of pregnancy. Second cohort includes 17,000 children, whose mother had participated in a 3-armed randomized controlled trial to assess the impact of iron-folic acid and multi-micronutrient supplementations on mortality, morbidity, and complications during pregnancy, labor, and delivery in China. Women were enrolled before 20 weeks of gestational age, women's venous blood and baby's cord blood were collected, and children born to the enrolled women are being followed up. Third cohort study is now enrolling women, and is planned to enroll 10,000 women before or during early pregnancy, to collect women's venous blood, and follow these enrolled women up to 42 days postpartum. For all 3 cohort studies, maternal and children's data about demographic, relevant obstetric and pregnancy outcomes, folic acid supplements taking, and body growth were collected at the time of entry, subsequent prenatal visits, delivery, or at the follow-up. Conclusion: These cohort studies provide exciting opportunities to explore the cause and prevention measures for various interested health outcomes including the adverse health effects of environmental contaminants.

The role of folic acid in prevention of neural tube defects caused by high dose progesterone.

To describe the effect of high dose progesterone (HDP) alone, or in combination with folic acid (FA), on occurrence of neural tube defects (NTDs) in chick embryo. 60 Fertile, specific eggs of Fyoumi species of chick were selected at zero hr of incubation. They were incubated at 37.5 °C and 75% relative humidity until the embryos reached stage eight of development. At this stage the eggs were divided into four groups consisting of 15 eggs/group. The 1st group was incubated without any operation. The 2nd group was injected with physiological saline. The 3rd and 4th groups were injected with HDP (20x physiologic dose of progesterone) and HDP with supplement of 5 micrograms/embryo of FA, respectively. After 48 hrs of incubation, all embryos were reviewed for the presence of NTDs under light microscopy. None of the eggs in the control, and saline injection groups showed NTDs, whereas 75 % (9/12) of the embryos in the 3rd group, and 58.3 % (7/12) of the chick embryos in 4th group showed NTDs. Exogenous progesterone at levels twenty times above its physiologic range in chick embryos causes NTDs. FA supplementation decreases the frequency of NTDs but does not abolish them.

Maternal smoking, passive tobacco smoke, and neural tube defects

Although cigarette smoke is a well-established toxin and harmful to the developing embryo, the evidence for an independent effect on the occurrence of neural tube defects (NTDs) is mixed. In this study, we examined the relation between NTDs and maternal exposures to cigarette smoke, including passive smoke exposure. We used cases and controls from the large, multistate, population-based National Birth Defects Prevention Study. A total of 1041 NTD cases and 5862 live birth controls, delivered during 1997 to 2004, were available for analyses. Mothers were interviewed by telephone between 6 weeks and 24 months after delivery. Participation rates were 71% for NTD case mothers and 69% for control mothers. Compared with nonsmokers (and also not exposed to passive cigarette smoke), mothers exposed only to passive smoke had an increased NTD odds ratio (OR, 1.7; 95% confidence interval [CI], 1.4-2.0), adjusted for race-ethnicity, and study center. There was no increased OR for mothers who actively smoked 24 or fewer cigarettes per day. Mothers who smoked 25 or more cigarettes per day had an elevated OR (OR, 1.6; 95% CI, 0.9-3.0), but the OR adjusted for race-ethnicity, and center was compatible with the null. Results suggest that maternal exposure to passive smoke is associated with NTDs. Women who plan on becoming pregnant should minimize their exposure to passive smoke and refrain from smoking.

Gene–environment interactions, folate metabolism and the embryonic nervous system

Formation of brain and spinal cord requires the successful closure of neural ectoderm into an embryonic neural tube. Defects in this process result in anencephaly or spina bifida, which together constitute a leading cause of mortality and morbidity in children, affecting all ethnic and socioeconomic groups. The subject of intensive research for decades, neural tube defects (NTDs), are understood to arise from complex interactions of genes and environmental conditions, though systems-level details are still elusive. Despite the variety of underlying causes, a single intervention, folic acid supplementation given in the first gestational month, can measurably reduce the occurrence of NTDs in a population. Evidence for and the scope of gene-environment interactions in the genesis of NTDs is discussed. A systems-based approach is now possible toward studies of genetic and environmental influences underlying NTDs that will enable the assessment of individual risk and personalized optimization of prevention.

Effects of Folic acid on stem cell proliferation and differentiation derived from posterior neural tube of Pax3 mutant (Splotch) mouse

Periconceptional maternal folic acid (FA) supplementation has been shown to be extremely effective in reducing the occurrence of neural tube defects (NTDs). However, little is known about the anti‐teratogenic mechanism of FA in neural tube anomalies. The proliferation or differentiation of neural stem cells (NSCs) can be influenced by various maternal factors, leading to alteration of the cell‐fate of the neural crest. Here we try to elucidate how folic acid can influence on stem cell proliferation and differentiation in Pax3 mutant (Splotch) mouse embryo. By using neurosphere culture derived from posterior neural tube of E10.5 mouse embryos, wild type (WT) and Splotch homozygote (Sp−/−), we observed colony forming ability that could be extremely increased by folic acid treatment on Sp−/− that caused neural tube defect in 100% whereas only few colonies could be seen without treatment. Those rescued sphere colonies showed definite immunoreactivity to stem cell, e.g. Oct3/4, Sox2, CD133, nestin and alkaline phosphatase suggesting they were pluripotent progenitor‐like cell. After plating those spheres on Matrigel, cells that migrated out from spheres and differentiated could express GFAP, Brn3a, β‐‡V‐tubulin, O4 and synaptogenesis markers, e.g. Snap25 or synaptotagmin. Thus this study suggested that folic acid could play an important role on stem cell proliferation and differentiation.

Use of Oral Contraceptives in Pregnancy and Major Structural Birth Defects in Offspring

Oral contraceptives (OCs) are the most commonly used reversible contraceptive method among US women. Although the majority of previous studies have reported no association between OC use during pregnancy and birth defects, some studies have reported increased occurrence of neural tube defects, limb reduction defects, and urinary tract anomalies. We assessed OC use among mothers who participated in the multisite, case-control, National Birth Defects Prevention Study. Mothers of 9986 infants with 32 types of birth defects and 4000 infants without birth defects were included. Maternal OC use during the first 3 months of pregnancy was associated with an increased odds ratio for 2 of 32 birth defects: hypoplastic left heart syndrome (adjusted odds ratio = 2.3 [95% confidence interval = 1.3-4.3) and gastroschisis (1.8 [1.3-2.7]). Previous reports of associations between OC use and specific types of anomalies were not corroborated. Given that associations were assessed for 32 types of birth defects, our findings of 2 increased associations between OC use and gastroschisis and hypoplastic left heart syndrome should be interpreted as hypotheses until they can be evaluated further. Overall, our findings are consistent with the majority of previous studies that found women who use OCs during early pregnancy have no increased risk for most types of major congenital malformations.

Genetic background influences embryonic lethality and the occurrence of neural tube defects in Men1 null mice: relevance to genetic modifiers

Germline mutations of the multiple endocrine neoplasia type 1 (MEN1) gene cause parathyroid, pancreatic and pituitary tumours in man. MEN1 mutations also cause familial isolated primary hyperparathyroidism (FIHP) and the same MEN1 mutations, in different families, can cause either FIHP or MEN1. This suggests a role for genetic background and modifier genes in altering the expression of a mutation. We investigated the effects of genetic background on the phenotype of embryonic lethality that occurs in a mouse model for MEN1. Men1(+/-) mice were backcrossed to generate C57BL/6 and 129S6/SvEv incipient congenic strains, and used to obtain homozygous Men1(-/-) mice. No viable Men1(-/-) mice were obtained. The analysis of 411 live embryos obtained at 9.5-16.5 days post-coitum (dpc) revealed that significant deviations from the expected Mendelian 1:2:1 genotype ratio were first observed at 12.5 and 14.5 dpc in the 129S6/SvEv and C57BL/6 strains respectively (P<0.05). Moreover, live Men1(-/-) embryos were absent by 13.5 and 15.5 dpc in the 129S6/SvEv and C57BL/6 strains respectively thereby indicating an earlier lethality by 2 days in the 129S6/SvEv strain (P<0.01). Men1(-/-) embryos had macroscopic haemorrhages, and histology and optical projection tomography revealed them to have internal haemorrhages, myocardial hypotrophy, pericardial effusion, hepatic abnormalities and neural tube defects. The neural tube defects occurred exclusively in 129S6/SvEv embryos (21 vs 0%, P<0.01). Thus, our findings demonstrate the importance of genetic background in influencing the phenotypes of embryonic lethality and neural tube defects in Men1(-/-) mice, and implicate a role for genetic modifiers.

Cobalamin, folic acid, and homocysteine

Cobalamin deficiency can lead to several adverse health consequences: folate trapping in the methylation cycle and subsequent impaired DNA biosynthesis; pernicious anemia hematologically, similar to that caused by folate deficiency; elevated blood homocysteine (tHcy) (risk factor for cardiovascular disease and adverse pregnancy outcomes); and neural tube defects (NTDs). Population-wide folate status is expected to improve where folic acid fortification policies for reducing NTD occurrence are established. However, there is concern that cobalamin deficiency and its characteristic neuropathy could be masked when hematological abnormalities in risk groups such as the elderly and vegetarians are reversed through folic acid supplementation. Folate-cobalamin interactions and their impact on health are reviewed here.

Folic acid, methylation and neural tube closure in humans

This review provides a brief description of folate use and folic acid metabolism in relation to neural tube defect (NTD) risk. First, a meta-analysis of reduction in NTD recurrence and occurrence risk with periconceptional folic acid supplementation is presented. Second, an overview of the complex folate metabolism is given. Third, SNPs for genes involved in folate and homocysteine metabolism that have been studied in relation to NTD riskare discussed. Fourth, the questions whether folate receptor autoantibodies or hampered methylation are mechanisms underlying NTDs are briefly discussed.

Urban–rural residence and the occurrence of neural tube defects in Texas, 1999–2003

Neural tube birth defects (NTDs) affect more than 4000 pregnancies in the US annually. The etiology of NTDs is believed to be multifactorial, but much remains unknown. We examined the pattern and magnitude of urban–rural variation in anencephaly, spina bifida without anencephaly, and encephalocele in Texas in relation with urban–rural residence for the period 1999–2003. There was no evidence that urban–rural residence was associated with changes in the rate of anencephaly or spina bifida without anencephaly in unadjusted or adjusted analyses. In contrast, rates of encephalocele were statistically significantly higher in areas classified as suburban or more rural compared to urban areas using four different urban–rural residence indicators.

Periconceptional folic acid and multivitamin supplementation for the prevention of neural tube defects and other congenital abnormalities

The pioneering studies of Smithells et al. showed the reduction of recurrent neural-tube defects (NTD) after periconceptional folic acid-containing multivitamin supplementation. The Hungarian Periconceptional Service was established in 1984, and this primary health care system offered a chance to organize a randomized controlled trial to check whether the supplementation of a multivitamin containing 0.8 mg of folic acid during the periconceptional period is appropriate for the reduction of a first occurrence of NTD in the family. This found a reduction of approximately 90% of primary NTD. An unexpected finding was a significant reduction in the rate of congenital abnormalities overall: 20.6 per 1000 in the 'multivitamin' group, and 40.6 per 1000 in the 'trace-element-like' placebo group (RR = 0.53, 95% CI: 0.35-0.70). When the 6 cases of NTD were excluded, this difference in the rates of major congenital abnormalities between the two study-groups remained very highly significant (p < 0.0001). Cardiovascular malformations and urinary tract defects were particularly affected. These findings were confirmed in the Hungarian cohort-controlled trial and by observational studies in other countries. Two questions remain to be answered. Is folic acid better alone or with multivitamins? What is the optimal dose of folic acid? Overall, the Hungarian experiences of periconceptional care have shown not only primary prevention of several severe congenital abnormalities but also a good cost-benefit balance.

575: Results of a genetic association study of genes in folate metabolism and spina bifida

Neural tube defects (NTDs) are one of the most common birth defects in the United States. Epidemiologic studies have shown that maternal folate status is foremost in the prevention of occurrence and recurrence of many NTDs. Our objective was to test single nucleotide polymorphisms (SNPs) of 11 candidate genes known to regulate the folate/homocysteine metabolism pathway for their contribution to spina bifida (SB) susceptibility.

Autoantibodies to folate receptor during pregnancy and neural tube defect risk

Periconceptional folic acid can reduce the occurrence of neural tube defects (NTDs) by up to 70%, and autoantibodies for folate receptors (FRs) have been observed in serum from women with a pregnancy complicated by an NTD. This population-based cohort study has examined serum from pregnant mothers for autoantibodies to FRs, antibodies to bovine folate binding protein (FBP), and inhibition of folic acid binding to FR and FBP in association with NTD risk. The mid-gestational maternal serum specimens used for this study were collected during the 15–18th week of pregnancy. Samples were obtained from the California Birth Defects Monitoring Program; 29 mothers had a pregnancy complicated by spina bifida and 76 mothers had unaffected children. The presence of IgG and IgM antibodies to human FR, bovine FBP, and inhibition of folic acid binding to FR and FBP was determined. Higher activity of IgM to FBP in cases verses controls was observed ( P = 0.04). Higher activity of IgM and IgG autoantibodies to FR was observed ( P < 0.001 and P = 0.04, respectively). Risk estimates at two standard deviations above average control antibody concentrations were OR = 2.07 (CI = 1.02, 4.06) for anti-FBP IgM, OR = 2.15 (CI = 1.02, 4.69) for anti-FR IgG and OR = 3.19 (CI = 1.47, 6.92) for anti-FR IgM. These data support the hypothesis that high titers of antibodies and blocking of folic acid binding to FRs by maternal serum should be regarded as risk factors for NTDs.

Valproic acid increases expression of methylenetetrahydrofolate reductase (MTHFR) and induces lower teratogenicity in MTHFR deficiency

Valproate (VPA) treatment in pregnancy leads to congenital anomalies, possibly by disrupting folate or homocysteine metabolism. Since methylenetetrahydrofolate reductase (MTHFR) is a key enzyme of folate interconversion and homocysteine metabolism, we addressed the possibility that VPA might have different teratogenicity in Mthfr(+/+) and Mthfr(+/-) mice and that VPA might interfere with folate metabolism through MTHFR modulation. Mthfr(+/+) and Mthfr(+/-) pregnant mice were injected with VPA on gestational day 8.5; resorption rates and occurrence of neural tube defects (NTDs) were examined on gestational day 14.5. We also examined the effects of VPA on MTHFR expression in HepG2 cells and on MTHFR activity and homocysteine levels in mice. Mthfr(+/+) mice had increased resorption rates (36%) after VPA treatment, compared to saline treatment (10%), whereas resorption rates were similar in Mthfr(+/-) mice with the two treatments (25-27%). NTDs were only observed in one group (VPA-treated Mthfr(+/+)). In HepG2 cells, VPA increased MTHFR promoter activity and MTHFR mRNA and protein (2.5- and 3.7-fold, respectively). Consistent with cellular MTHFR upregulation by VPA, brain MTHFR enzyme activity was increased and plasma homocysteine was decreased in VPA-treated pregnant mice compared to saline-treated animals. These results underscore the importance of folate interconversion in VPA-induced teratogenicity, since VPA increases MTHFR expression and has lower teratogenic potential in MTHFR deficiency.

Folate intake, markers of folate status and oral clefts: is the evidence converging?

The ability of folic acid in the periconceptional period to prevent the occurrence of neural tube defects has stimulated tremendous interest in its effects on other health outcomes. Its possible effect on oral clefts has generated considerable debate. The purpose of this systematic review and meta-analysis was to assemble evidence on the role of folate in the aetiology of cleft lip with or without cleft palate (CL/P) and cleft palate only (CPO). Medline, PubMed, Embase, Science Citation Index and the HuGE Published Literature Database were searched to February 2007 for articles related to oral clefts and multivitamin use, dietary folate, folic acid fortification, biochemical markers of folate status and polymorphisms in 5,10-methylenetetrahydrofolate reductase (MTHFR) and other genes involved in folate metabolism. Random effects meta-analysis was conducted when appropriate. Maternal multivitamin use was inversely associated with CL/P [odds ratio (OR) 0.75, 95% CI 0.65-0.88, based on 5717 cases and 59 784 controls] but to a lesser extent CPO (OR 0.88, 95% CI 0.76-1.01, 2586 cases and 59 684 controls). The volume of evidence on dietary folate, fortification and biochemical and genetic measures of folate status is substantially less; in aggregate, the evidence suggests that no association exists but there is substantial heterogeneity between studies. The evidence is not converging and there is no strong evidence for an association between oral clefts and folic acid intake alone. Multivitamin use in early pregnancy, however, may protect against oral clefts, especially CL/P although this association may be confounded by other lifestyle factors associated with multivitamin use.