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PubMed1981

Combined analysis of acetylcholinesterase and alpha-fetoprotein improves the accuracy of antenatal diagnosis of neural-tube defects.

Acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and alpha-fetoprotein (AFP) were measured in 293 amniotic fluids from the second and third trimesters of pregnancy in a prospective study of their diagnostic value in the detection of neural-tube defects (NTD). In normal samples, the mean AChE and BChE concentrations were 3.0 u/L (SEM = 9.1 u/L) and 15.2 u/L (SEM = 1.2 u/L) in the second trimester, and 1.6 u/L (SEM = 0.1 u/L) and 7.8 u/L (SEM = 0.6 u/L) in the third trimester. AFP levels fell throughout the second trimester to unmeasurable levels in the third. AChE levels were markedly elevated in samples from NTD pregnancies at all gestational ages, and a cut-off level of the mean + 3 SD optimally separated normal from abnormal samples. This cut-off correctly predicted 10 of 11 fetuses with neural lesions; there were three false positive results. A similar cut-off for AFP predicted nine of 11 cases of neural lesion with two false positive results. For BChE, a cut off of 50 u/L predicted eight of 11 neural lesions with two false positive results. The specificity, sensitivity, and predictive value positive (PVP) were calculated for each test. The assays of AFP and AChE were useful when used individually (PVP congruent to 80%), but a Bayesian combination of these two tests produced a superior PVP (98%). Because the cost of AChE assay is low, and the test is so simple, it is suggested that an AChE analysis should be performed whenever an amniocentesis is requested for the diagnosis of NTD.

Acetylcholinesterase↗
PubMed1987

Neural tube defects. Some remarks on the possible role of glycosaminoglycans in the genesis of the dysraphic state, the anomaly in the configuration of the posterior cranial fossa, and hydrocephalus.

Recent developments in the field of experimentally induced neural tube defects (NTD) indicate that specific substances, namely the glycosaminoglycans (GAGs) may play a role in the genesis of spinal malformations. The authors report the results obtained by evaluating the GAGs in rat fetuses with NTD, secondary to the administration of Trypan Blue during pregnancy. A characteristic decrease in GAGs formation in the spinal and cranial structures as well as in the subependymal regions of the brain was found in the malformed fetuses. The authors hypothesize that this anomaly in GAGs formation is responsible for both the NTD and the associated malformations, namely hydrocephalus and hypoplasia of the posterior cranial fossa.

Animals↗
PubMed1997

Screening of the C677T mutation on the methylenetetrahydrofolate reductase gene in French patients with neural tube defects.

We report the analysis of the distribution of the C677T mutation on the methylenetetrahydrofolate reductase (MTHFR) gene in prenatally diagnosed neural tube defects (NTD) cases and controls. In contrast to previous reports, we found the same distribution in fetuses with NTD and controls, which suggests that the MTHFR C677T mutation cannot be regarded as a genetic risk factor for NTD.

Anencephaly↗
PubMed1983

Empiric recurrence risk for neural tube defects (NTD) in Krakow region.

A sample of 347 families in the Krakow region of Southern Poland with at least one child with anencephaly and/or myelomeningocele or encephalomeningocele were ascertained by multiple selection. The birth prevalence of neural tube defects in this population was 75/80, 584 (0.93/1000). The risk of affected individuals among the probands' sibs was 3.3% (+/- 1.6), about 38 times the population prevalence at birth. The empiric risk was higher for female than for male sibs of the proband. Also, the probability of occurrence was higher for sibs of male probands. The differences were nonsignificant. The heritability calculated on the regression of siblings on propositi was 76% (+/- 7).

Genetic Counseling↗
PubMed1980

The potential of multivariate discriminant analysis in the antenatal detection of neural tube defects.

A method is described which improves the ability to distinguish between normal and neural tube-defective fetuses in utero. Early second trimester amniotic fluid is classified by stepwise discriminant analysis based upon biochemical analysis for alpha-fetoprotein and eight other easily assayed variables; classification is more reliable than using alpha-fetoprotein and gestational age alone.

Amniotic Fluid↗
PubMed1992

Folic acid and neural tube defect: can't we come to closure?

In a series of nonrandomized and randomized intervention trials and case-control and cohort studies, women using multivitamins or folic acid supplements during the first 6 weeks of pregnancy experienced a three- to fourfold reduction in neural tube defects among their offspring. Viewed collectively, these data provide strong evidence that an important subset of US women do not receive sufficient folic acid to minimize their risk of a defective pregnancy. Further, the amounts of folic acid contained in multivitamins (usually 200-400 micrograms per day) appear adequate to greatly reduce, and probably eliminate, the excess risk.

Female↗
PubMed2006

Homocysteine metabolism in families from southern Italy with neural tube defects: role of genetic and nutritional determinants.

OBJECTIVE: To evaluate the role of different polymorphic gene variants involved in homocysteine metabolism and plasma levels of homocysteine, folate and vitamin B12 in families from southern Italy with neural tube defects (NTDs). METHODS: Eighteen fathers, 15 NTD children and 60 women who had conceived NTD foetuses were investigated. A group of 100 adults and 43 apparently healthy children was used as control. At the time of blood draw, none were taking vitamin pills or nutritional supplements. RESULTS: Among controls, 79 (55.2%) were heterozygous for C677T MTHFR variant and 26 (18.2%) were TT homozygous. Among the cases, 35 (61.4%) out of 57 mothers and 7 (38.9%) out of 18 fathers carried the T allele; 12 (21.1%) mothers and 2 (11.1%) fathers had the TT genotype. Four (26.7%) out of 15 probands were TT homozygous and 11 (73.3%) were heterozygous (Fisher exact test p = 0.025). No significant difference between groups was observed for the 1298C MTHFR variant and CBS haplotypes. Median homocysteine in NTD children was significantly higher (10.0 micromol/L) than that of controls (median 4.5 micromol/L, Mann-Whitney p < 0.05). Folate and B12 were not different among groups. CONCLUSIONS: The T677 MTHFR allele is significantly associated with the occurrence of NTDs; no significant association has been observed with other genetic determinants analysed. Homocysteine levels in children with NTDs are significantly higher than those of the paediatric population from the same geographical area.

Adolescent↗
PubMed1992

A randomised trial of low dose folic acid to prevent neural tube defects. The Irish Vitamin Study Group.

A randomised trial was initiated in Ireland in 1981 to determine if periconceptional supplementation with either folic acid alone or a multivitamin preparation alone could reduce the recurrence risk of neural tube defects (NTDs) in women with a previously affected pregnancy from 5.0% to 1.0% or less. The trial was concluded before the initial target number of study subjects was reached and without a clear treatment effect being observed. A total of 354 women were randomised to receive one of three treatments: folic acid, multivitamins without folic acid, and folic acid plus multivitamins. At the end of the trial 257 women had had a first trial pregnancy outcome (261 infants/fetuses) where the presence or absence of NTDs was ascertainable. There was one NTD recurrence in the 89 infants/fetuses of women in the multivitamin group and no recurrence in the 172 infants/fetuses of women in the folic acid groups, a non-significant difference. Otherwise eligible women who were pregnant when first contacted constituted a non-randomised control group; there were three recurrences among the 103 infants in this group. The difference in the recurrence rate between the folic acid groups and the non-randomised controls was statistically significant but we have reservations about the validity of this comparison. Although our findings do not provide clear evidence of a protective effect of folic acid supplementation they are consistent with those of the Medical Research Council (MRC) trial which demonstrated the efficacy of folic acid in preventing recurrence of NTDs and they raise the possibility that folic acid may be protective at a much lower dosage than that used in the MRC trial.

Adult↗
PubMedDate not supplied

Assessing combined chemical exposures as risk factors for neural tube defects.

Many studies have investigated whether chemical exposures early in pregnancy increase risks to women of delivering offspring with congenital anomalies. We investigated whether periconceptional exposures to chemicals in combination increased risks to women of having neural tube defect (NTD)-affected pregnancies. Women were asked about occupational tasks performed during the periconceptional period. These tasks were assigned by an industrial hygienist to a priori defined exposure categories. The exposure categories included 74 chemical groups. Two population-based case control studies were analyzed. Information on tasks was obtained from mothers of 538 NTD cases and their 539 controls in one study, and mothers of 265 NTD cases and 481 controls from another study. We used data from the first study to identify clues. Specifically, we estimated NTD risks for maternal occupational exposures to all possible pairs, triplets, and quadruplets of 74 chemical groups. Chemical combinations revealing elevated NTD risks in these "clue generation" analyses were then investigated in the second population-based case-control study for their contribution to risk of NTDs. We computed odds ratios for each of the total 192,374 possible comparisons and identified all combinations that produced odds ratios of 5 or more. A 5-fold elevated risk criterion revealed 53 combinations. These 53 reflected various combinations of exposures exclusive to 12 of 74 chemical groups. Analyses of data from the second study did not identify odds ratios of 2.0 or greater for maternal exposures to the 12 chemical groups that resulted in 5-fold elevated risks in the first study. Despite the use of a labor-intensive method to categorize exposures, we were unable to substantiate clues associated with combined chemical exposures identified in one large case-control study as NTD risk factors in a second case-control study.

Adult↗
PubMed1986

Effect of mitomycin C on the neural tube defects of the curly-tail mouse.

Around 60% of the mouse mutants called curly-tail, have tail aberrations in the form of a coil or a kink, with or without lumbosacral spina bifida, and rarely, exencephaly. These neural tube defects (NTD) are the result of an incompletely penetrant recessive gene. A single injection of various doses (1-6 mg/kg) of the DNA inhibitor mitomycin C was given to pregnant curly-tail mice on day 7, 8, or 9 of gestation, and its effect on the NTD of the embryos was noted. No dose used was lethal to the embryo. When given on day 7 or day 8, mitomycin C markedly increased the number of exencephalics, and additionally, on day 8, it reduced the number of posterior abnormalities. However, on day 9, no exencephaly was produced, and there was a drastic reduction in the number of tail and spinal defects, the overall incidence of NTD being as low as 15% with 2 mg/kg. A twofold effect of mitomycin C on the curly-tail embryos was thus observed--according to the time in development it was administered, firstly, a teratogenic effect, and later, a "remedial" or preventive effect.

Animals↗
PubMed1983

Second trimester amniotic fluid acetylcholinesterase quantitation in the prenatal diagnosis of neural tube defects.

Amniotic fluid acetylcholinesterase (AChe) activity was assayed in second trimester amniotic fluids by inhibition of non-specific cholinesterase using lysivane. Of the 196 samples analysed, 146 were from normal pregnancies; 11 (5.6%) from severe open neural tube defects; two from small open spina bifidas; seven from fetal chromosome abnormalities and two from severe skeletal dysplasias. In addition nine amniotic fluids were meconium stained and 19 (9.7%) had varying degrees of blood staining. Acetylcholinesterase values remained relatively constant from 13-21 weeks gestation in normal pregnancies and a cut-off limit of 3.2 U/l was set (mean + 2 SD). Heavily blood stained amniotic fluids were associated with AChe levels on or above the normal cut-off limit. Meconium staining caused a non-significant elevation of AChe. No significant elevation of AChe was demonstrated for fetal chromosome abnormalities, or severe skeletal dysplasias. Anencephaly and severe open spina bifida had significantly elevated AChe levels.

Acetylcholinesterase↗
PubMed1979

Contrasting effects of maternal fertility and birth rank on the occurrence of neural tube defects.

The relationships between the occurrence of anencephalus and spina bifida, sibship size and birth rank were examined, using linked records for births in British Columbia. Comparison of 414 sibships in which at least one infant had a neural tube defect with 1362 randomly chosen unaffected sibships showed that the affected sibships were larger. There were both more births than expected after the affected birth, and shorter intervals between births before the affected birth. Within sibships, the risk of anencephalus or spina bifida decreased strongly with increasing birth rank. No associations were seen with maternal age at first birth.

Anencephaly↗
PubMed2003

Polymorphisms within the vitamin B12 dependent methylmalonyl-coA mutase are not risk factors for neural tube defects.

Methionine synthase and methylmalonyl-CoA mutase (mutase) are the only two known vitamin B(12) (B(12)) dependent enzymes in humans. A lower level of B(12) has been shown to be an independent maternal risk factor for neural tube defects (NTDs) prompting an investigation of common genetic variants within B(12) dependent enzymes. To investigate the role of methylmalonyl-CoA mutase variants we studied 279 complete NTD triads (NTD affected case and both parents) and 256 controls. Based on case-control and family based (transmission disequilibrium test) analyses we did not find an association between the mutase single nucleotide polymorphisms (SNPs) K212K (636A-->G), H532R (1595A-->G) and V671I (2011G-->A) and NTDs. However, there was a significant difference in the frequencies of these polymorphisms between a group of African Americans and American Caucasians (K212K, P=0.002; H532R, P</=0.001; V671I, P=0.006). In conclusion, common variants in the mutase gene do not appear to be risk factors for NTDs but their allele frequencies are significantly different between ethnic groups.

Case-Control Studies↗
PubMed2004

[Morphological study on the neural tube defects caused by passive smoking].

OBJECTIVE: To investigate the possible mechanisms of teratogenesis caused by passive smoking. METHODS: The stereomicroscope and electron microscope were used to observe the effects of passive smoking on the development of golden hamsters' neural tube and alternations of neuroepithelial ultrastructures. RESULTS: Passive smoking could induce teratogenesis during neurulation (chi 2 = 51.28, P < 0.01). The main forms of neural tube defects were spina bifida, exencephaly, and so on. In embryos of every passive smoking group, neuroepithelial cells arranged irregularly. The intercellular spaces became wide. The apical portion of many neuroepithelial cells bulged out into the lumen and many microvilli were shorted and swollen. A lot of vacuolation appeared in the cytoplasm. The cristae of mitochondria reduced even disappeared, and some mitochondria became elongate. Irregular nuclear, increased heterochromatin and karyopycnosis/karyorrhexis were observed easily. Perinuclear cisternae partially swollen and embraced tangible material. Some death cell's decomposed a lot of apoptotic bodies. Most of the apoptotic bodies were found within the cytoplasm of otherwise healthy-looking or healthy cells. CONCLUSION: These data prove that passive smoking can cause dymorphogenesis of the neural tube. And tobacco smoking might induce excess degeneration, death, and cells loss in the neural tube and mesenchyme, thereby resulting in failure of formation and differentiation of neural tube.

Abnormalities, Drug-Induced↗
PubMed1979

Cut-off levels for maternal plasma alpha-fetoprotein in the diagnosis of neural tube defects: validation of the use of multiples of the normal median.

A retrospective study was made of measurement of maternal plasma alpha-feto-protein (AFP) by a standard radioimmunoassay technique, as a method of screening for neural tube defects (NTDs) between 15 and 20 weeks gestation. There was a good fit of a log-normal distribution to the data at each week and multiples of the normal median were equivalent to constant centiles over weeks 15 to 20 and possibly at later weeks also. There were 700 plasma samples from women with normal prenancies and 60 from women with pregnancies complicated by fetal NTDs (30 with anencephaly and 30 with spina bifida). At 15 to 20 weeks of pregnancy, 90 per cent of women with fetuses affected by anencephaly, 70 per cent of those with fetuses affected by open spina bifida and 3 per cent ofthose with normal pregnancies had plasma AFP levels at or above 2.4 times the normal median for each gestational week. It was estimated that 2.1, 2.4 and 3.1 times the normal median maternal plasma AFP levels were equivalent to the 95th, 97th and 99th centiles respectively. The interassay coefficients of variation estimated on control sera throughout the entire study were 4 to 6 per cent.

Female↗
PubMed1999

Achieving a public health recommendation for preventing neural tube defects with folic acid.

OBJECTIVES: This study examined 3 approaches to achieving the public health recommendation that all women of child-bearing age ingest 0.40 mg of folic acid per day to reduce the occurrence of neural tube defects (NTDs). METHODS: A total of 1136 mothers of infants with major malformations from the Boston and Philadelphia areas, whose pregnancies began from 1993 to 1995, were interviewed within 6 months of delivery about vitamin supplementation, dietary intakes, and other factors. RESULTS: Seventy-one percent of the 1136 women in the study did not take folic acid--containing supplements daily before conception, but the proportion decreased over the years of the study. Women not taking supplements consumed an average of 0.25 mg of naturally occurring folates daily. On the basis of dietary intakes reported by women not taking folic acid supplements, a simulation of cereal grain fortification with folic acid at the level required by the US Food and Drug Administration showed that an average of only 0.13 mg of folic acid would be ingested daily. CONCLUSIONS: With consumption of folic acid only through dietary intake, sizeable portions of the childbearing population would receive less than the level of folic acid recommended for preventing NTDs. Even with food fortification, women of childbearing age should be advised to take folic acid--containing supplements on a daily basis.

Adult↗
PubMed1994

Developmental basis of severe neural tube defects in the loop-tail (Lp) mutant mouse: use of microsatellite DNA markers to identify embryonic genotype.

Mouse embryos homozygous for the mutation loop-tail (Lp) develop lethal defects in which the neural tube remains open from the hindbrain to the caudal extremity, a condition that closely resembles the human malformation craniorachischisis. Heterozygotes develop tail defects and occasional spina bifida, but are generally viable. In order to study the early development of these defects, it is necessary to determine the genotype of embryos at stages prior to the first appearance of the morphological abnormalities. We used a microsatellite DNA sequence, Crp, that is closely linked to the Lp locus and which segregates polymorphic variants in matings between Lp/+ mice, thus permitting identification of embryos of Lp/Lp, Lp/+ and +/+ genotypes. We found that the severe phenotype craniorachischisis is present at 9.5 and 10.5 days of gestation only in Lp/Lp embryos in utero, whereas Lp/+ and +/+ littermates show neural tube closure throughout most of the body axis. The open neural tube phenotype also develops in Lp/Lp embryos growing in whole embryo culture. A small proportion of Lp/+ embryos were found to develop this phenotype in vitro, but only when culture conditions were suboptimal. Analysis of 8.5-day embryos revealed that the initial defect in Lp/Lp embryos is failure to initiate neural tube closure at the cervical/hindbrain boundary when the embryo has 6-7 somites. Thereafter, the neural tube remains open throughout the body axis, with the exception of the midbrain and forebrain where neural tube closure is initiated independently. Closure at the midbrain/forebrain boundary does not appear to be defective in Lp/Lp embryos. Heterozygous Lp/+ embryos initiate neural tube closure at the cervical/hindbrain boundary with a slight delay compared with +/+ littermates. Moreover, at 10.5 days of gestation, Lp/+ embryos undergo delayed closure of the posterior neuropore. Thus, Lp/+ embryos are defective in several aspects of the neurulation process. The pattern of delayed neuropore closure in Lp/+ embryos resembles that caused by the ct and Sp mutations and is likely to be responsible for the development of tail defects (i.e., looped tails) and spina bifida in Lp/+ mice. The use of microsatellite markers to determine the genotype of mutant embryos has general application: microsatellites are widespread throughout the mouse genome, so that informative sequences are likely to be available with close linkage to the majority of mutant genes. Moreover, polymorphisms can be detected using the polymerase chain reaction, making it possible to determine the genotype of very early embryos when only small amounts of material are available.

Animals↗
PubMed2005

Challenges in translating scientific evidence into mandatory food fortification policy: an antipodean case study of the folate-neural tube defect relationship.

OBJECTIVE: To identify challenges in translating scientific evidence of a nutrient and health relationship into mandatory food fortification policy. DESIGN: A case study approach was used in which available evidence associated with the folate-neural tube defect relationship was reviewed against the Australia New Zealand Food Regulation Ministerial Council's Policy Guideline for mandatory food fortification. RESULTS: Three particular challenges were identified. The first is knowing when and how to act in the face of scientific uncertainty. The second is knowing how to address the special needs of at-risk individuals without compromising the health and safety of the population as a whole. The third is to ensure that a policy is sufficiently monitored and evaluated. CONCLUSIONS: Despite the availability of compelling evidence of a relationship between a particular nutrient and a health outcome, a definitive policy response may not be apparent. Judgement and interpretation inevitably play significant roles in influencing whether and how authorities translate scientific evidence into mandatory food fortification policy. In relation to the case study, it would be prudent to undertake a risk-benefit analysis of policy alternatives and to implement nutrition education activities to promote folic acid supplement use among the target group. Should mandatory folate fortification be implemented, comprehensive monitoring and evaluation of this policy will be essential to know that it is implemented as planned and does more good than harm. In relation to mandatory food fortification policy-making around the world, ongoing national nutrition surveys are required to complement national policy guidelines.

Australia↗