Rate Of Neural Tube Defects Research Articles

Fortification of corn masa flour with folic acid in the United States.

Food fortification is an effective public health tool for addressing micronutrient deficiencies. The mandatory fortification of enriched cereal grains (e.g., wheat flour) with folic acid, which began in the United States in 1998, is an example of a successful intervention that significantly reduced the rate of neural tube defects (NTDs). However, despite the drop in NTD rates across all racial/ethnic groups after fortification, Hispanics continue to have the highest rates of this condition. One possible way to reduce this disparity is to fortify corn masa flour to increase the overall intake of folic acid in Hispanic women. We present the available evidence in favor of this approach, address possible safety issues, and outline next steps in the fortification of corn masa flour with folic acid in the United States.

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).

Spatial analysis of neural tube defects in a rural coal mining area

Shanxi province in northern China has one of the highest reported prevalence rates of neural tube defects (NTDs) in the world. The current study selected Heshun, the county with the highest rate of NTDs in Shanxi, as a study area and tested whether residence in a coal mining area was a contributing factor. A NTD cluster was detected in an area within 6 km of the coal mines for almost every year during 1998–2005. Poisson regression analysis revealed that there may be an association between production in coal mines and prevalence of NTDs in coal mine areas. Future work identifying factors independently correlated with NTDs in coal mining regions may provide further insights into the health effects of coal mines on NTDs.

Biochemistry and genetics of folate metabolism

Folates serve in many critical one-carbon transfer reactions including nucleotide synthesis, amino acid synthesis and methylation. Methylation is important for gene expression (through methylation of DNA), neurotransmitter synthesis and maintenance of homocysteine (a potentially toxic amino acid) at low levels. Genetic and nutritional deficiencies in folate metabolism may modulate risk for several complex traits including neural tube defects (NTD) and other birth defects, cardiovascular disease, pregnancy complications and some cancers. Inadequate dietary folate has been recognized as a risk factor in approximately 2/3 of NTD although metabolic disturbances in folate metabolism have emerged more recently as contributors to this common multifactorial disorder. Fortification of food with folate has been established in many countries to reduce the incidence of NTD; although NTD rates have in fact decreased in those countries, there are controversies regarding the impact of food fortification on other folate-related disorders. The first genetic risk factor identified for NTD is a common variant in methylenetetrahydrofolate reductase (MTHFR), the enzyme that synthesizes the primary circulatory form of folate, 5-methyltetrahydrofolate, which is utilized in the remethylation of homocysteine to methionine. This variant, present in the homozygous state in approx. 10% of many European and North American populations, is responsible for a fraction of the folate-responsive NTDs. Other variants in the pathway have been identified and may contribute although additional studies are required. A mouse model for MTHFR deficiency has been useful in studying the biochemical disturbances and mechanisms that could contribute to NTD and other complex traits. The presentation will focus on the impact of genetic polymorphisms/relevant enzymes on NTD risk, the use of mouse models to study mechanisms, and some aspects of the controversy surrounding high folate intake post-fortification.

A comparison of methods for spatial relative risk mapping of human neural tube defects

Birth defects are a major cause of infant mortality and disability in many parts of the world. Yet the etiology of neural tube defects (NTDs), the most common types of birth defects, is still unknown. The construction and analysis of maps of disease incidence data can help explain the geographical distribution of NTDs and can point to possible environmental causes of these birth defects. We compared two methods of mapping spatial relative risk of NTDs: (1) hierarchical Bayesian model, and (2) Spatial filtering method. Heshun county, which has the highest rate of NTDs in China, was selected as the region of interest. Both methods were used to produce a risk map of NTDs for rural Heshun for 1998–2001. Hierarchical Bayesian model estimated the relative risk for any given village in Heshun by “borrowing” strength from other villages in the study region. It did not remove all the random spatial noise in the rude disease rate. There were several areas of high incidence scattered around its risk map with no readily apparent pattern. The spatial filtering method calculated the relative risk for all villages based on a series of circulars. The risk map from the spatial filtering method revealed some spatial clusters of NTDs in Heshun. These two methods differed in their ability to map the spatial relative risk of NTDs. Distributional assumption of relative risk and the target of the risk assessment should be taken into consideration when choosing which method to use.

Maternal diet modulates the risk for neural tube defects in a mouse model of diabetic pregnancy

Pregnancies complicated by maternal diabetes have long been known to carry a higher risk for congenital malformations, such as neural tube defects. Using the FVB inbred mouse strain and the Streptozotocin-induced diabetes model, we tested whether the incidence of neural tube defects in diabetic pregnancies can be modulated by maternal diet. In a comparison of two commercial mouse diets, which are considered nutritionally replete, we found that maternal consumption of the unfavorable diet was associated with a more than 3-fold higher rate of neural tube defects. Our results demonstrate that maternal diet can act as a modifier of the risk for abnormal development in high-risk pregnancies, and provide support for the possibility that neural tube defects in human diabetic pregnancies might be preventable by optimized maternal nutrition.

Role of folic acid supplementation in prevention of neural tube defects: physicians yet unaware!

Folic acid supplementation is important in the prevention of Neural Tube Defects (NTD). The study was conducted to assess the awareness amongst physicians regarding the role of Folic Acid (FA) in the prevention of NTD. Physicians were interviewed regarding the awareness of FA dose, timing of supplementation and knowledge about its role in prevention of neural tube defects using a semistructured questionnaire. Among 202 physicians interviewed (48 pediatricians, 54 obstetricians, 100 recently qualified medical graduates) overall awareness about FA was present in 92.07%, similar in three groups (P > 0.05). Only 47.52% were aware of preconception administration, 61.38% about dose of supplementation and 11.88% about recurrence rate of NTD. Only 15 (7.4%) knew all these. Regarding the etiology of NTDs only 26.7% said both FA and genetic factors are involved. Though majority were aware that folic acid has a role in prevention of NTDs, their knowledge about timing and dose of supplementation was lacking. Hence attempts should be made to increase the awareness regarding prevention of NTD's by FA supplementation at a proper time.

Effect of folic acid fortification on the incidence of neural tube defects

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.

Spina bifida and birth outcome before and after fortification of flour with iron and folic acid in Oman

This paper presents the trend of spina bifida and other neural tube defects in Oman after the nationwide implementation of folate supplementation of pregnant women in 1990 and the fortification of wheat flour with iron and folate in 1996. The annual incidence of spina bifida fluctuated from 2.34 to 4.03 per 1000 deliveries between 1991 and 1996, but fell sharply to 2.11 per 1000 deliveries in 1997, after which the downward trend continued, reaching 0.29 per 1000 deliveries by 2006. The rate of other neural tube defects remained almost constant. The reduction in spina bifida rates in Oman could be linked to the start of flour fortification but not the supplementation programme.

Malformations in a Chornobyl-Impacted Region

One of the populations most exposed to chronic low-dose radiation from Chornobyl (Chernobyl in Russian) lives in Polissia, the region representing the northern half of Rivne Province (Oblast) in Ukraine. Here the patterns and population rates of malformations are reported and possible etiologic factors and regional contrasts are explored. Malformations, as defined by international standards, noted among all 96 438 births in Rivne between 2000 and 2006, were analyzed statistically. Contrasts of rates in Polissia compared with the rest of Rivne also were investigated. The overall rate of neural tube defects in Rivne is among the highest in Europe (22.2 per 10,000 live births). The rates of conjoined twins and teratomas also seem to be elevated. In Polissia, the overall rates of neural tube defects are even higher (27.0 vs 18.3, respectively; odds ratio: 1.46 [95% confidence interval: 1.13-1.93]), and the rates of microcephaly and microphthalmia may also be elevated. The malformation patterns observed suggest early disruptions of blastogenesis, manifesting as alterations of body axes, twinning, duplications, laterality, and midline formation. The results are sufficiently compelling to justify continuing and expanding this investigation of malformations in chronic low-dose radiation-impacted regions of Ukraine.

Exposure to folic acid antagonists during the first trimester of pregnancy and the risk of major malformations

* Previous studies have suggested a tendency of antifolate drugs to be associated with higher rates of neural tube defects. * This study makes use of the data on abortuses, which is missed in many other studies. In this case, the abortion data were critical. * The study documents that clinicians should avoid, as much as possible, the use of folic acid antagonists during the first trimester of pregnancy, when embryogenesis takes place. To investigate the safety of folic acid antagonists during the first trimester of pregnancy in a large cohort. Computerized databases for medications dispensed from 1998 to 2007 to women registered in 'Clalit' HMO, Israel southern district, was linked with maternal and infant hospitalization records, and to therapeutics abortions data. The risk for adverse pregnancy outcomes of folic acid antagonists exposure was assessed by adjusting for known confounders. Eighty-four thousand, eight hundred and twenty-three infants were born and 998 therapeutic abortions took place; 571 fetuses and infants were exposed to one or more folic acid antagonists in the first trimester of pregnancy. Exposure was associated with an overall increased risk of congenital malformations [odds ratio (OR) 2.43, 95% confidence interval (CI) 1.92, 3.08], due mainly to increased risk for neural tube (adjusted OR 6.5, 95% CI 4.34, 9.15) and cardiovascular defects (OR 1.76, CI 1.05, 2.95). First-trimester exposure to folic acid antagonists is associated with increased risk of congenital malformations.

Willingness-to-accept and purchase genetically modified rice with high folate content in Shanxi Province, China

Neural-tube defects (NTDs) are considered to be the most common congenital malformations. As Shanxi Province, a poor region in the North of China, has one of the highest reported prevalence rates of NTDs in the world, folate fortification of rice is an excellent alternative to low intake of folate acid pills in this region. This paper investigates the relations between socio-demographic indicators, consumer characteristics (knowledge, consumer perceptions on benefits, risks, safety and price), willingness-to-accept and willingness-to-pay genetically modified (GM) rice. The consumer survey compromises 944 face-to-face interviews with rice consumers in Shanxi Province, China. Multivariate analyses consist of multinomial logistic regression and multiple regression. The results indicate that consumers generally are willing-to-accept GM rice, with an acceptance rate of 62.2%. Acceptance is influenced by objective knowledge and consumers’ perceptions on benefits and risks. Willingness-to-pay GM rice is influenced by objective knowledge, risk perception and acceptance. Communication towards the use of GM rice should target mainly improving knowledge and consumers’ perceptions on high-risk groups within Shanxi Province, in particular low educated women.

Cost-effectiveness of mandatory folate fortification v. other options for the prevention of neural tube defects: results from Australia and New Zealand

To provide input to Australian and New Zealand government decision making regarding an optimal strategy to reduce the rate of neural tube defects (NTD). Standard comparative health economic evaluation techniques were employed for a set of intervention options for promoting folate/folic acid consumption in women capable of or planning a pregnancy. Evidence of effectiveness was informed by the international literature and costs were derived for Australia and New Zealand. Population-wide campaigns to promote supplement use and mandatory fortification were the most effective at reducing NTD, at an estimated 36 and 31 fewer cases per annum respectively for Australia and New Zealand, representing an 8 % reduction in the current annual NTD rate. Population-wide and targeted approaches to increase supplement use were cost-effective, at less than $AU 12,500 per disability-adjusted life year (DALY) averted ($US 9893, pound 5074), as was extending voluntary fortification. Mandatory fortification was not cost-effective for New Zealand at $AU 138,500 per DALY ($US 109 609, pound 56,216), with results uncertain for Australia, given widely varying cost estimates. Promoting a folate-rich diet was least cost-effective, with benefits restricted to impact on NTD. Several options for reducing NTD appear to fall well within accepted societal cost-effectiveness norms. All estimates are subject to considerable uncertainty, exacerbated by possible interactions between interventions, including impacts on currently effective strategies. The Australian and New Zealand governments have decided to proceed with mandatory fortification; it is hoped they will support a rigorous evaluation which will contribute to the evidence base.

Reaching Women and Health Care Providers with Women’s Wellness Messages: The North Carolina Folic Acid Campaign as a Model

olic acid supplementation is at the top of the list of many preconception health counseling recommendations intended to improve birth outcomes and women’s health before pregnancy. Folic acid deficiency is one of the preconception risk factors identified by the US Centers for Disease Control and Prevention’s seminal recommendations to improve preconception health and health care. 1 Women are encouraged to start taking a multivitamin or folic acid supplement several months before attempting pregnancy. Health care providers are advised to counsel all women of childbearing age to consume 400 mcg of folic acid daily as nearly half of all pregnancies are unintended. 2 Because of the strong evidence to support its use and benefits, folic acid supplementation is often cited as a prime example of how improved women’s wellness before conception can positively impact birth outcomes. 3 Entire public health campaigns have been devoted to the promotion of folic acid, and these campaigns offer important lessons about how to reach women and health care providers to promote women’s health and wellness. The North Carolina Folic Acid Campaign has been working for a decade to make sure both consumers and health care providers are aware of the benefits of folic acid. Our state has historically high rates of neural tube defects (NTDs), up to 70% of which can be prevented if women of childbearing age take adequate amounts of folic acid prior to pregnancy. 4

Folate and vitamin B12status of women of reproductive age living in Hanoi City and Hai Duong Province of Vietnam

To assess the folate and vitamin B12 status of a group of Vietnamese women of reproductive age and to estimate the rate of neural tube defects (NTD) based on red blood cell (RBC) folate concentrations. A representative sample of non-pregnant women (15-49 years) living in Hanoi City (n 244) and Hai Duong Province (n 245). RBC folate, plasma vitamin B12 and plasma holo-transcobalamin (holoTC), a sensitive indicator of vitamin B12 status. Mean (95% CI) concentrations of RBC folate, plasma B12 and plasma holoTC were 856 (837, 876) nmol/l, 494 (475, 513) pmol/l and 78 (74, 82) pmol/l, respectively. Only 3% and 4% of women had plasma B12 and holoTC concentrations indicative of deficiency. No woman had an RBC folate concentration indicative of deficiency (<317 nmol/l). Only 47% of women had an RBC folate concentration > or = 905 nmol/l. Accordingly, we predict the NTD rate in these regions of Vietnam to be 14.7 (14.2, 15.1) per 10,000 pregnancies. There was no evidence of folate and vitamin B12 deficiency among this population of Vietnamese women. However, suboptimal folate status may be placing three out of five women at increased risk of NTD. Reductions in NTD rates are still possible and women would benefit from additional folic acid during the periconceptional period from either supplements or fortified foods.

Arsenate-induced maternal glucose intolerance and neural tube defects in a mouse model

Background Epidemiological studies have linked environmental arsenic (As) exposure to increased type 2 diabetes risk. Periconceptional hyperglycemia is a significant risk factor for neural tube defects (NTDs), the second most common structural birth defect. A suspected teratogen, arsenic (As) induces NTDs in laboratory animals. Objectives We investigated whether maternal glucose homeostasis disruption was responsible for arsenate-induced NTDs in a well-established dosing regimen used in studies of arsenic's teratogenicity in early neurodevelopment. Methods We evaluated maternal intraperitoneal (IP) exposure to As 9.6 mg/kg (as sodium arsenate) in LM/Bc/Fnn mice for teratogenicity and disruption of maternal plasma glucose and insulin levels. Selected compounds (insulin pellet, sodium selenate (SS), N-acetyl cysteine (NAC), l-methionine (L-Met), N-tert-Butyl-α-phenylnitrone (PBN)) were investigated for their potential to mitigate arsenate's effects. Results Arsenate caused significant glucose elevation during an IP glucose tolerance test (IPGTT). Insulin levels were not different between arsenate and control dams before (arsenate, 0.55 ng/dl; control, 0.48 ng/dl) or after glucose challenge (arsenate, 1.09 ng/dl; control, 0.81 ng/dl). HOMA-IR index was higher for arsenate (3.9) vs control (2.5) dams ( p = 0.0260). Arsenate caused NTDs (100%, p < 0.0001). Insulin pellet and NAC were the most successful rescue agents, reducing NTD rates to 45% and 35%. Conclusions IPGTT, insulin assay, and HOMA-IR results suggest a modest failure of glucose stimulated insulin secretion and insulin resistance characteristic of glucose intolerance. Insulin's success in preventing arsenate-induced NTDs provides evidence that these arsenate-induced NTDs are secondary to elevated maternal glucose. The NAC rescue, which did not restore maternal glucose or insulin levels, suggests oxidative disruption plays a role.

Possible association between symptomatic cholelithiasis-complicated cholecystitis in pregnant women and congenital abnormalities in their offspring—A population-based case–control study

Objective To estimate the risk of congenital abnormalities in the offspring of pregnant women with symptomatic cholelithiasis and complicated cholecystitis. Study design Comparison of the occurrence of medically recorded symptomatic cholelithiasis and complicated cholecystitis occurred any time of pregnancy (particularly in the second and/or third gestational month) of pregnant women who had malformed foetuses/newborns (cases) and who delivered healthy babies (controls) in the population-based Hungarian Case–Control Surveillance System of Congenital Abnormalities. Results Of 22,843 cases with CA, 62 (0.27%) had mothers with symptomatic cholelithiasis, while 119 (0.31%) mothers of 38,151 controls were recorded with symptomatic cholelithiasis. In addition, the mothers of 109 cases (0.48%) were affected by complicated cholecystitis during pregnancy compared with 145 controls (0.38%). Regarding the frequency, these two biliary diseases did not show any significant differences in the maternal variables, therefore case mothers were combined. The analysis of specific groups of congenital abnormalities showed an association between symptomatic cholelithiasis-complicated cholecystitis in the second and/or third gestation months, and neural tube defects (adjusted OR with 95% CI: 4.1, 1.3–13.4). Conclusion A higher rate of neural tube defects was found in the offspring of mothers with severe diseases of the biliary system during pregnancy. This finding needs to be confirmed by further studies and/or explanations to determine whether it is causal or a chance event.

Multivitamins, Folic Acid and Birth Defects

Background: Consumption of folic acid prior to conception can prevent up to 70% of neural tube defect (NTD)- affected pregnancies. In 1992, the U.S. Public Health Service (USPHS) issued a recommendation that all women of childbearing age capable of becoming pregnant consume 400 μg of folic acid daily to reduce their risk for a NTD-affected pregnancy. A 26% decrease in the overall NTD rate in the United States was observed between 1995 and 2000, after the fortification of cereal grain products. However, the NTD prevalence for Hispanics remains almost twice that of the general population, both nationally and in North Carolina. Purpose: To measure the baseline knowledge, beliefs and behaviors about multivitamins, folic acid and birth defects of Spanish-speaking Hispanic women ages 18-35 in North Carolina. Methods: Face-to-face oral interviews with Spanish-speaking Hispanic women were conducted by native Spanish-speaking data collectors using a culturally appropriate survey instrument in 12 North Carolina counties. Results: Thirty-three percent of the total respondents (n = 896) reported taking a daily multivitamin. Of those who reported currently planning a pregnancy or trying to become pregnant (n = 134), 22% reported taking a daily multivitamin. Knowledge was highest about birth defects (79%), followed by multivitamins (64%), and then folic acid (54%). Ninety-nine percent of respondents who did not take a daily multivitamin reported they would do so upon the recommendation of their health care provider. Discussion: Multivitamin consumption is low among this group at increased risk, and even lower among those actively attempting or contemplating pregnancy. Health care professionals play a critical role in increasing the knowledge and influencing the behaviors of this population. Translation to Health Education Practice: Folic acid education in all preconception encounters with Hispanic women is critical to address this health disparity and help prevent NTD-affected pregnancies.

Plasma folate status and dietary folate intake among Chinese women of childbearing age

Maternal folic acid deficiency is an underlying risk for neural tube defects (NTDs). China has one of the highest prevalences of NTDs, and the prevalence rates of NTDs vary by region. We characterized plasma folate level and dietary folate intake among Chinese women of childbearing age by region (North and South, East and West, urban and rural) to provide evidence for establishing policy to prevent NTDs. A total of 1003 women of childbearing age from five provinces in China were interviewed. Fasting blood samples were collected. Plasma folate concentrations were determined by a microbiological assay. Dietary intake data were collected using a 24-h recall. Both the plasma folate concentrations and dietary folate intake of women in the South (25.9 nmol L(-1) and 211.0 microg day(-1)) were higher than those of women in the North (13.3 nmol L(-1) and 189.2 microg day(-1)). In the North, plasma folate concentrations and dietary folate intake of women in rural areas were lower than those of women in urban areas, whereas, in the South, an opposite pattern was observed. No difference was found between women in the East and West, in either the North or South regions. Plasma folate and dietary folate intake among Chinese women of childbearing age were suboptimal and varied by region. Different folic acid supplementation approaches and dosage should be undertaken to improve folate status of women in different areas. Particular attention should be paid to women in the North, especially in northern rural areas.

Risk assessment of human neural tube defects using a Bayesian belief network

Neural tube defects (NTDs) constitute the most common type of birth defects. How much risk of NTDs could an area take? The answer to this question will help people understand the geographical distribution of NTDs and explore its environmental causes. Most existing methods usually take the spatial correlation of cases into account and rarely consider the effect of environmental factors. However, especially in rural areas, the NTDs cases have a little effect on each other across space, whereas the role of environmental factors is significant. To demonstrate these points, Heshun, a county with the highest rate of NTDs in China, was selected as the region of interest in the study. Bayesian belief network was used to quantify the probability of NTDs occurred at villages with no births. The study indicated that the proposed method was easy to apply and high accuracy was achieved at a 95% confidence level.