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PubMed2003

Folic acid supplements and fortification affect the risk for neural tube defects, vascular disease and cancer: evolving science.

Folic acid supplements reduce the risk of neural tube defects and may be associated with reduced risk for vascular disease and cancer. Research data from both observational and controlled intervention studies provide strong support for the existing public health policies related to folic acid and neural tube defects. However, educational efforts to promote daily intake of folic acid supplements by women of reproductive age have not, in most cases, resulted in increased supplement use. In contrast, food fortification appears to be associated with a reduction in neural tube defects in the United States and Canada but is not practiced universally. The potential for folic acid supplements to reduce the incidence and severity of vascular disease and cancer is the focus of major research efforts including ongoing intervention studies.

Dietary Supplements↗
PubMed1979

Amniotic-fluid acetylcholinesterase as a possible diagnostic test for neural-tube defects in early pregnancy.

Raised levels (greater than or equal to 4.5 munits/ml) of acetylcholinesterase (AChE) activity in amniotic fluid at 14--23 weeks of pregnancy were significantly associated with open fetal neural-tube defects. Out of 72 pregnancies correctly classified by the amniotic-fluid alpha-fetoprotein (A.F.P.) test, 2 of 56 without neural-tube defects and all 16 with open neural-tube defects (8 with anencephaly and 8awith open spina bifida) had raised levels of AChE. Out of 5 pregnancies misclassified by the A.F.P. test (4 without neural-tube defects and 1 with open spina bifida), only 1 was misclassified by the AChE test--namely, one of those without a neural-tube defect. Thus, only 3 of the 77 pregnancies tested were misclassified by the quantitative AChE test. A qualitative test for an isoenzyme of AChE found in cerebrospinal fluid correctly classified these 3 pregnancies. These findings suggest that the analysis of AChE in amniotic fluid may be a useful test in the diagnosis of open neural-tube defects.

Acetylcholinesterase↗
PubMed2005

Epidemiology of neural tube defects.

The epidemiological investigation of the common open neural tube defects (NTDs), anencephaly, and spina bifida, has a long history. The most significant finding from these past studies of NTDs was the identification of the protective effect of maternal, periconceptional supplementation with folic acid. Fortuitously, the association between folic acid and NTDs became widely accepted in the early 1990s, at a time when genetic association studies of complex traits were becoming increasingly feasible. The confluence of these events has had a major impact on the direction of epidemiological, NTD research. Association studies to evaluate genes that may influence the risk of NTDs through their role in folate-related processes, or through other metabolic or developmental pathways are now commonplace. Moreover, the study of genetic as well as non-genetic, factors that may influence NTD risk through effects on the nutrient status of the mother or embryo has emerged as a major research focus. Research efforts over the past decade indicate that gene-gene, gene-environment, and higher-order interactions, as well as maternal genetic effects influence NTD risk, highlighting the complexity of the factors that underlie these conditions. The challenge for the future is to design studies that address these complexities, and are adequately powered to detect the factors or combination of factors that influence the development of NTDs.

Humans↗
PubMed1995

Periconceptional vitamin supplementation to prevent neural tube defects: how can we do it?

The discovery that folic acid can reduce neural tube defect rates offers a great opportunity for primary prevention. Unfortunately, women must receive the folic acid before or immediately after conception, before many know that they are pregnant. Thus, we are faced with a difficult choice: (1) ask all women at risk of getting pregnant to take supplements, or (2) fortify the food supply to ensure that all women at risk receive additional folic acid. Neither approach is ideal. Many women will not take vitamin supplements. Fortification at sufficiently high levels to provide all women with 400 micrograms of folic acid will expose other segments of the population to unacceptably high levels. Because many women of child-bearing age are unaware of the benefits of folic acid, a vigorous education campaign should begin immediately to encourage women at risk to take supplements. Adding 70 micrograms of folic acid per 100 g of grain could be justified easily because this amount is removed from grain in processing. If it is technically feasible, adding up to 140 micrograms is likely to be safe, and could prevent more NTDs. A major educational campaign and modest fortification of grain with folic acid may be the best practical solution.

Adolescent↗
PubMed2002

Does prenatal screening for 5,10-methylenetetrahydrofolate reductase (MTHFR) mutations in high-risk neural tube defect pregnancies make sense?

Despite the fact that neural tube defects (NTDs) are the most common congenital malformations of the central nervous system, investigators have yet to identify responsible gene(s). Research efforts have been productive in the identification of environmental factors, such as periconceptional folic acid supplementation, that modulate risk for the development of NTDs. Studies of the folic acid biosynthetic pathway led to the discovery of an association between elevated levels of homocysteine and NTD risk. Researchers subsequently identified single nucleotide polymorphisms in the gene coding for the enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR). Association studies suggested it was a potential risk factor for NTDs, because the thermolabile form of the enzyme led to elevated homocysteine concentrations when folic acid intake is low. Numerous studies analyzing MTHFR variants have resulted in positive associations with increased NTD risk only in certain populations, suggesting that these variants are not large contributors to the etiology of NTDs. With our limited understanding of the genes involved in regulating NTD susceptibility, the paucity of data on how folic acid protects the developing embryo, as well as the observed decrease in birth prevalence of NTDs following folic acid supplementation and food fortification, it makes little sense for prospective parents to be tested for MTHFR variants, or for variants of other known folate pathway genes.

Animals↗
PubMedDate not supplied

Patterns of inheritance in Irish and Italian families with neural tube defects: comparison between high and low rate areas.

Neural tube defects (NTDs) may result from a genetic susceptibility interacting with environmental exposures occurring early in pregnancy. Current research is concerned with enlarging our understanding of the action of folic acid, a B group vitamin, which has been shown to prevent the occurrence of NTDs in clinical trials. Despite the epidemic waves in the incidence of NTDs and the existence of areas with very high rates, there have been few studies that explored the genetic contribution to NTDs in high rates versus low rate areas. We investigated the genetic epidemiologic factors that occur in NTD families and compared their frequency in a high rate area-Ireland-with a low rate area-Italy. We explored the existence of three features indicative of hereditary factors and found that all three factors were higher in Ireland than in Italy. These factors were (i) sibling recurrence risk (3.3% vs 1.6%; p = 0.2), (ii), other malformations in siblings (11.5% vs 3.3%; p < 0.001) and (iii) average number of children in mothers' families vs fathers' families (average difference in Ireland 1.0 vs 0.4 in Italy; p < 0.1). These results support the motion that geographic differences in occurrence of NTDs are due at least in part to differing prevalences of genetic susceptibility factors. Further epidemiological and molecular studies are needed to confirm this observation. In addition, studies of the interactions between environmental agents and genetic susceptibility will be important in determining their relative contributions.

Child↗
PubMed2006

Confirmation of the R653Q polymorphism of the trifunctional C1-synthase enzyme as a maternal risk for neural tube defects in the Irish population.

The risk of neural tube defects (NTDs) is known to have a significant genetic component that could act through either the NTD patient and/or maternal genotype. The success of folic acid supplementation in NTD prevention has focused attention on polymorphisms within folate-related genes. We previously identified the 1958G>A (R653Q) polymorphism of the trifunctional enzyme MTHFD1 (methylenetetrahydrofolate-dehydrogenase, methenyltetrahydrofolate-cyclohydrolase, formyltetrahydrofolate synthetase; often referred to as 'C1 synthase') as a maternal risk for NTDs, but this association remains to be verified in a separate study to rule out a chance finding. To exclude this possibility, we genotyped an independent sample of mothers with a history of an NTD-affected pregnancy derived from the same Irish population. In this sample there was a significant excess of 1958AA homozygote mothers of NTD cases (n=245) compared to controls (n=770). The direction and magnitude of risk (odds ratio 1.49 (1.07-2.09), P=0.019) is consistent with our earlier finding. Sequencing of the MTHFD1 gene revealed that this association is not being driven by another common variant within the coding region. We have established that the MTHFD1 1958G>A polymorphism has a significant role in influencing a mother's risk of having an NTD-affected pregnancy in the Irish population.

Amino Acid Substitution↗
PubMed2002

D-chiro-inositol is more effective than myo-inositol in preventing folate-resistant mouse neural tube defects.

BACKGROUND: Among mouse genetic mutants that develop neural tube defects (NTDs), some respond to folic acid administration during early pregnancy, whereas NTDs in other mutants are not prevented. This parallels human NTDs, in which up to 30% of cases may be resistant to folic acid. Most spina bifida cases in the folic acid-resistant 'curly tail' mouse can be prevented by treatment with inositol early in embryonic development. Here, the effectiveness and safety during pregnancy of two isomers, myo- and D-chiro-inositol, in preventing mouse NTDs was compared. METHODS AND RESULTS: Inositol was administered either directly to embryos in vitro, or to pregnant females by s.c. or oral routes. Although D-chiro- and myo-inositol both reduced the frequency of spina bifida in curly tail mice by all routes of administration, D-chiro-inositol consistently exhibited the more potent effect, reducing spina bifida by 73-86% in utero compared with a 53-56% reduction with myo-inositol. Pathological analysis revealed no association of either myo- or D-chiro-inositol with reduced litter size or fetal malformation. CONCLUSIONS: D-chiro-inositol offers a safe and effective method for preventing folic acid-resistant NTDs in the curly tail mouse. This raises the possibility of using inositol as an adjunct therapy to folic acid for prevention of NTDs in humans.

Administration, Oral↗
PubMed1999

Awareness of folic acid for neural tube defect prevention among Israeli women.

The failure of neural tube closure during early embryogenesis results in a range of neural tube defects (NTD), the most common of which is spina bifida. The role of folic acid in reducing the rate of NTD has been well-established. Three recent cases of infants with NTD inspired this investigative study into the level of awareness and knowledge of folic acid and its function in the prevention of NTD among Israeli women. Of 920 women interviewed, only 51 (5.5%) had heard of folic acid, and 27 (2.8%) were reported to have taken it. The source of information and the motivation for self-medication were also explored with regard to socioeconomic and health profile. Awareness of folic acid was significant among women aged 17-29 years (P = 0.005) and those aged 30-39 years (P = 0.009), and among semireligious and nonreligious women (P = 0.008 and 0.01, respectively). Among women who were aware of folic acid, only nonreligious women tended to take it. No correlation was found between folic acid intake and age, religiosity, nationality, number of pregnancies, and health status among women who were aware of folic acid intake. The poor level of awareness, evident in our study, demands that the medical community broadcast the benefit of folic acid. Furthermore, government health initiatives, such as the addition of folic acid to flour preparations, may effectively ensure its appropriate daily intake. These improved education and prevention programs may forcibly reduce the rate of NTD-affected pregnancies.

Adolescent↗
PubMed2006

Impact of methylenetetrahydrofolate reductase deficiency and low dietary folate on the development of neural tube defects in splotch mice.

BACKGROUND: The etiology of neural tube defects (NTDs) is multifactorial, with environmental and genetic determinants. Folate supplementation prevents the majority of NTDs, and a polymorphism in methylenetetrahydrofolate reductase (MTHFR) has become recognized as a genetic risk factor. The mechanisms by which folate affects NTD development are unclear. The Splotch (Sp) mouse is a well-characterized mouse model for studying spontaneous NTDs. To assess the potential interaction between folate metabolism and the Sp mutant in NTD development, we studied mice with both Sp and Mthfr mutations, as well as the interaction between Sp and low dietary folate. METHODS: Wild-type, single Mthfr+/-mutant, single Sp/+mutant, and double mutant (Mthfr+/-, Sp/+) female mice were mated with males of the same genotype. Embryos were examined for NTDs on gestational day (GD) 13.5. To investigate the effects of folate deficiency on Sp mice, Sp/+female mice were fed a control diet (CD), a moderately folic acid-deficient diet (MFADD), or a severely folic acid-deficient diet (SFADD). They were mated with Sp/+males and the embryos were examined. RESULTS: There were no differences in the incidence or severity of NTDs in embryos from double-mutant mating pairs compared to those from single Sp mutants. Embryos from Mthfr+/-dams did not exhibit NTDs. Diets deficient in folate did not influence the incidence or severity of NTDs in embryos from Sp/+mice. CONCLUSIONS: We did not observe an interaction between Sp and Mthfr mutations, or between the Sp mutation and low dietary folate, in NTD development in Splotch mice.

Animals↗
PubMed2002

Single nucleotide polymorphisms in the transcobalamin gene: relationship with transcobalamin concentrations and risk for neural tube defects.

Homocysteine levels are elevated in mothers of neural tube defect (NTD) children, which may be due to a disturbed folate or vitamin B12 metabolism. Vitamin B12 is transported to the tissues by transcobalamin (TC). We previously showed that a low holo-TC/total-TC ratio is a risk factor for NTD, possibly due to an impaired binding of vitamin B12 to TC. The coding region of the TC gene of 12 individuals was analysed for genetic variations responsible for a disturbed vitamin B12 binding. The influence of the genetic variations observed on total-TC, holo-TC, holo-TC/total-TC, erythrocyte vitamin B12, plasma homocysteine concentrations and risk for NTD was explored in 42 mothers of a child with NTD and in 73 female controls. Direct sequencing analyses revealed five single nucleotide polymorphisms (SNPs). Three SNPs affected total-TC concentrations, whereas two SNPs seem to affect the binding of vitamin B12. None of the genotypes defined by the SNPs had a significant effect on homocysteine levels, or was associated with an increased NTD risk. Among the five SNPs observed only P259R could partly explain the reduced proportion of vitamin B12 bound to TC, which has been associated with an increased risk for having a child with NTD. Some of the variants studied affected total-TC and holo-TC/total-TC ratio but a larger study population is required to elucidate whether these SNPs influence delivery of vitamin B12 to the tissue, influence homocysteine levels and whether they are associated with an increased NTD risk.

Adult↗
PubMedDate not supplied

Early pregnancy screening for neural tube defects in Israel.

A pilot project to detect neural tube defects (NTD) of the fetus by maternal serum alpha-fetoprotein (MSAFP) screening of women in early pregnancy was initiated in Tel Aviv in 1982 at the instigation of the Israel Ministry of Health. The program was designed to be an extension of routine pregnancy care, which in this city is provided in municipal family clinics that are attended by about 50% of pregnant women before the 20th week of pregnancy. Of these women, 89% complied with the program. Women with a MSAFP level above a cutoff point of 2.4 multiples of the median (MOM) were invited for an ultrasound examination of the fetus, without having to repeat the MSAFP test, thereby reducing maternal anxiety. This deviation from the usual test system protocol did not impair sensitivity (87%), or specificity of the test on its own (95.6%), or in combination with ultrasound examination of the fetus and alpha-fetoprotein and acetylcholinesterase testing of the amniotic fluid (99.9%). The program detected 13 fetuses with an NTD; there were two false-negative results and one false-positive. The predictive value of a positive test was 93%. Its effectiveness as a preventive measure was impaired by the fact that 50% of pregnant women did not attend the family clinic before the 20th gestational week. An educational program for professionals and for the public is contemplated in order to reduce this proportion. Only 50% of normal twin pregnancies had an elevated MSAFP. A check on compliance with other screening systems during the interview for MSAFP screening led to the detection and elective abortion of two fetuses with Tay-Sachs disease. MSAFP screening in Israel is cost-effective rather than cost-beneficial.

Amniocentesis↗
PubMed1977

Amniography for the early detection of neural tube defects.

Among the methods available for the midtrimester diagnosis of neural tube defects, it has been suggested that amniography be used to determine the presence of meningomyelocele. Twelve studies are reported in which the procedure was utilized. In 3 cases, a neural tube defect was present but was not detected by this method. The experience reported here challenges the value of this procedure and suggests that it should be evaluated further by utilizing it in cases where a positive diagnosis has been made by other methods and pregnancy termination is to be performed.

Adolescent↗
PubMed1995

Nutritional patterns of mothers of children with neural tube defects in Newfoundland.

In an exploratory study of the genetic epidemiology of neural tube defects in Newfoundland, we studied mothers who had given birth to a child with a neural tube defect (NTD) with respect to their nutrition, as well as various other factors. The frequency of NTD in the area studied was 3.5/1,000 births and has not decreased recently, as it has in some other parts of the world. Twenty-five mothers of children with NTD and a comparison group (CG), matched for age and neighbourhood, completed 3 day dietary records. The NTD group consisted of all mothers who had given birth to an NTD child within the previous 3.5 years in the chosen area. The CG mothers were ascertained through the local public health nurse who chose the nearest unaffected child born in the same time period as the NTD probands. NTD mothers were younger, heavier, and of lower socioeconomic status than were CG mothers. CG group women consumed more vitamin supplements during the periconceptional period (P < 0.05) and consumed more dairy and cereal products, fruits and vegetables (other than potatoes), and fewer sweets than did NTD mothers. Sixty-four percent of NTD mothers had folacin intakes below the recommended level (168 mg) compared to 27% of CG mothers (P < 0.01). These findings support previous evidence that poor maternal nutrition, and low dietary folate in particular, increase the chance of having a child with an NTD, and emphasize the need for supplementary folate in the diet of women of childbearing age in areas where the frequency of NTDs is high.

Adult↗
PubMed1993

A comparison of amniotic fluid alpha-fetoprotein and acetylcholinesterase in the prenatal diagnosis of open neural tube defects and anterior abdominal wall defects.

Amniotic fluid samples received for routine prenatal diagnosis of open neural tube defects were used for a study to compare amniotic fluid acetylcholinesterase (AChE) determination using a monoclonal antibody (4F19) enzyme antigen immunoassay and amniotic fluid alpha-fetoprotein (AFP) measurement as diagnostic tests for open neural tube defects. The study was based on 9964 women with singleton pregnancies and known outcome (including 6 with anencephaly and 18 with open spina bifida) having an amniocentesis at 14-23 weeks of gestation. The AChE immunoassay yielded detection rates for anencephaly of 100 per cent (95 per cent confidence interval (CI) 54.07-100 per cent), for open spina bifida of 100 per cent (95 per cent CI 81.47-100 per cent), for anterior abdominal wall defects of 20 per cent (95 per cent CI 0.51-71.64 per cent), and a false-positive rate of 0.22 per cent (95 per cent CI 0.14-0.34 per cent) excluding anencephaly, open spina bifida, and anterior abdominal wall defects. For similar detection rates the false-positive rate of the AFP test was significantly higher, 0.74 per cent (95 per cent CI 0.58-0.94 per cent). On the basis of these findings, it is recommended that the technically simple AChE immunoassay should be used on all samples; the AFP test should only be used on the 0.5 per cent of the samples with concentrations of AChE activity > or = 8.5 nkat/l for clear samples and blood-stained samples becoming clear after centrifugation, and > or = 25.0 nkat/l for blood-stained samples that are discoloured after centrifugation; an AFP cut-off level of 2.0 MOM is recommended for this policy. Thereby, the detection rates for anencephaly, open spina bifida, and anterior abdominal wall defects would be 100, 100, and 20 per cent, respectively (95 per cent CIs 54.07-100, 81.47-100, and 0.51-71.64 per cent, respectively), and the false-positive rate would be 0.08 per cent (95 per cent CI 0.03-0.16 per cent) (excluding anencephaly, open spina bifida, and anterior abdominal wall defects).

Abdominal Muscles↗
PubMed1996

Growth hormone treatment of children with neural tube defects: results from 6 months to 6 years.

OBJECTIVE: Patients with neural tube defects (myelomeningocele) have severe growth retardation, and treatment with recombinant human growth hormone (rHGH) for 6 months accelerates growth velocity. We examined patients treated for longer periods to determine whether accelerated growth persists, and whether patients demonstrated to be growth hormone deficient have a greater response to rHGH therapy. METHODS: We retrospectively evaluated the growth rate and length standard deviation score (SDS) of 22 patients in response to treatment with 0.3 mg/kg per week of rHGH for 7 to 72 months. Nine of 22 patients were growth hormone deficient (nocturnal and provocative growth hormone responses < 7 ng/ml). Treatment success was defined as an increase of length SDS of > 0.2 SD per year. RESULTS: Fourteen patients (64%) had treatment successes, and eight had treatment failures. Length SDS improved from a pretreatment value of -2.9 (+/- 1.2) to the most recent length SDS of -1.9 (+/- 1.4) (p < 0.001). The growth rate was significantly increased through year 4 of treatment. The annualized growth rate after 6 months of rHGH treatment was significantly different for the success and failure groups (11.0 +/- 2.6 cm/yr vs 5.1 +/- 3 cm/yr, p < 0.001). The annualized 6-month growth rate during treatment was related to the probability of treatment success. CONCLUSION: Treatment with rHGH significantly improves the growth rate and length SDS of children with neural tube defects. The 6-month annualized growth velocity during treatment was predictive of long-term treatment response. The effect on adult stature is unknown.

Adolescent↗
PubMedDate not supplied

Severity of abnormality influences decision to terminate pregnancies affected with fetal neural tube defects.

We examined parental decision concerning pregnancy management in women having fetuses with neural tube defects (NTDs) to determine whether severity of defect or method of detection has an impact on the decision making process. Analysis of decisions by 50 women, whose pregnancies were affected by an isolated neural tube defect (NTD) and characterized by a singleton gestation at 24 gestational weeks or less with normal chromosomal complement (46,XX or 46,XY), were assessed. All 23 women carrying fetuses with anencephaly elected to terminate their pregnancies. Of the 27 women carrying fetuses with spina bifida, 21 (77.8%) elected to terminate their pregnancies and 6 (22.2%) elected to continue their pregnancies. Of the 6 pregnancies that were continued, 4 were initially detected by ultrasonography and 2 were ascertained by maternal serum alpha-fetoprotein screening; defects ranged from 2 to 14 vertebral bodies, and none of the defects were craniad to the T9 level. This is in comparison to 5 of the 21 spina bifida cases that were elective pregnancy terminations, which were characterized by fetal lesions craniad to the T9 level. Severity of NTD thus appears to influence the decision to continue or terminate an affected pregnancy.

Abortion, Induced↗
PubMed2000

[A clinico-epidemiological study of neural tube defects in newborn infants].

This is a retrospective study on the rate of inborn defects of neural tube in University Hospital of Obstetrics and Gynaecology--Sofia for two 5-years-long periods of time: from 1986 to 1990 and from 1993 to 1997. The results show an increasing rate of inborn NTD during the second period of time which can be partly explained by the fact that the hospital is National Perinatal Centre where high risk pregnancies and deliveries are concentrated. Most disturbing is the fact that more than half of life-born and still-born infants with NTD are at an age of gestation higher than 34 g.w. This is a result of late perinatal diagnosis of these defects and brings up serious psychological, social and economical problems.

Bulgaria↗