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PubMed1987

Differential staining techniques in amniotic fluid cytology diagnosis of neural tube defects: a prospective study of 129 pregnancies.

In order to assess the utility of amniotic fluid cytology in the diagnosis of neural tube defects (NTDs), we performed a prospective study of 129 pregnancies selected for maternal age or history of prior congenital defects or multiple stillbirths. Amniotic fluid obtained between the 16th and 22nd weeks of gestation was cytocentrifuged and stained with hematoxylineosin (H&E), Papanicolaou, and Diff-Quik. Chromosomal analysis, amniotic fluid alpha fetoprotein (AFP) level, and eventual pregnancy outcome were recorded for each case. The AFP levels were normal in 128 cases, including two closed NTDs (meningomyelocele and encephalocele). Three patients had abnormal chromosomal studies: two with 47,XXX and one with trisomy 21. Of these 128 cases, 16 had inadequate cytologic preparations; the remainder, including the five aforementioned patients, showed predominantly squamous cells, amnion cells, and minicells. Other cell types, including genito-urinary cells, umbilical cord cells, respiratory cells, and macrophages, were also present in smaller numbers. One case exhibited a large population of small, darkly staining neural cells and large macrophages. The AFP in this case was markedly elevated, and the fetus was noted to be anencephalic. We found the H&E to be the preferred stain for both cytologic detail and minicell preservation; however papanicolaou was better for bloody specimens. Amniotic fluid cytology may provide a rapid and inexpensive method of confirming the diagnosis of open NTDs.

Amniotic Fluid↗
PubMed1982

Neural tube defects in France: segregation analysis.

Segregation analysis was performed on a subset of a large body of French data comprising 298 nuclear families. Two models were used in this analysis: the transmission probability model [Elston and Stewart, 1971; Elston, 1981] and the mixed model [Morton and MacLean, 1974]. Both models are consistent with familial aggregation of neural tube defects, in this sample, being due to either the segregation of a recessive major gene or a sibling environmental effect, or both factors. In each case, other environmental factors are also involved. These results were compared to the findings of other studies and discussed in respect to the diversity of the epidemiological features displayed by different populations. Some observations of vertical transmission in a British study and the proportion of affected first cousins, in both France and Great Britain, lead us to reject a possible absence of transmission. We propose a monogenic component with a large influence of environmental factors, some of which may be common to sibs, to explain the occurrence of neural tube defects in this sample.

Environment↗
PubMed1980

Comparison of pregnancy outcome after amniocentesis for previous neural tube defect or raised maternal serum alphafetoprotein.

Amniocentesis was performed in 219 pregnancies because a previous pregnancy produced a fetus with neural tube defect (NTD) and in 212 pregnancies in which the indication for amniocentesis was a high maternal serum alphafetoprotein (AFP) level. The proportion of abnormal fetuses, the frequency of low birth weight infants, and the frequency of undesired fetal loss were significantly greater in the group with high maternal serum AFP, in which there was also a significant excess of male births. It is concluded that maternal serum AFP screening defines a group of high risk pregnancies. The greater fetal loss and low birth weight associated with high maternal serum AFP levels were not the result of amniocentesis but were an inherent feature of these pregnancies.

Adult↗
PubMed1982

Neural-tube defect risk assessment for individual pregnancies using alphafetoprotein and acetylcholinesterase test results.

Pregnancies at risk of being associated with (open) neural tube defects can be identified by maternal serum and amniotic-fluid alphafetoprotein (AFP) concentrations in excess of established screening cut-off valves in conjunction with the results of an amniotic fluid electrophoretic acetylcholinesterase screening test. The risk associated with the AFP cut-off values are formulated in terms of a population screening programme. These "population risks" are of little value in the assessment of test results from individual "at-risk" pregnancies, especially when the observed AFP concentrations are in proximity to the "cut-off" values. A complete risk assessment procedure for individual pregnancies is described and presented in graphical form to permit immediate access by clinical staff.

Acetylcholinesterase↗
PubMed2003

Disruption of scribble (Scrb1) causes severe neural tube defects in the circletail mouse.

Circletail is one of only two mouse mutants that exhibit the most severe form of neural tube defect (NTD), termed craniorachischisis. In this disorder, almost the entire brain and spinal cord is affected, owing to a failure to initiate neural tube closure. Craniorachischisis is a significant cause of lethality in humans, yet the molecular mechanisms involved remain poorly understood. Here, we report the identification of the gene mutated in circletail (Crc), using a positional cloning approach. This gene, Scrb1, encodes a member of the LAP protein family related to Drosophila scribble, with 16 leucine rich repeats and four PDZ domains. The Crc mutant contains a single base insertion that creates a frame shift and leads to premature termination of the Scrb1 protein. We report the expression pattern of Scrb1 during embryonic and fetal development, and show that Scrb1 expression closely mirrors the phenotypic defects observed in Crc/Crc mutants. In addition, circletail genetically interacts with the loop-tail mutant, and we reveal overlapping expression of Scrb1 with Vangl2, the gene mutated in loop-tail. The identification of the Crc gene further defines the nature of the genetic pathway required for the initiation of neural tube closure and provides an important new candidate that may be implicated in the aetiology of human NTDs.

Amino Acid Sequence↗
PubMed2005

Reduced folate carrier polymorphisms and neural tube defect risk.

The reduced folate carrier (RFCI) is essential for folate transport into cells. Low folate is an important cause of neural tube defects (NTDs), and a single-nucleotide polymorphism (H27R) (80G-->A) in the RFCI gene has been reported to be a NTD risk factor. We investigated H27R and a 61 bp tandem repeat polymorphism as potential risk factors for NTDs, using a large homogeneous Irish population by case/control comparison, log-linear analysis, and transmission disequilibrium testing. No association was found between NTDs and H27R in mothers [p = 0.23, odds ratio (OR) 0.87, 95% confidence interval (CI) 0.69-1.09], fathers (p = 0.11, OR 0.83, 95% CI 0.66-1.04), or cases (p = 0.36, OR 0.9, 95% CI 0.72-1.12) when compared to controls or through log-linear modeling for dominant or recessive effects or with the transmission disequilibrium test for preferential allele transmission. Using log-linear models, a significant protective case effect was seen for the 61 bp polymorphism (p = 0.0039, OR 0.21, 95% CI 0.05-0.85). When analyzed by genotype, individuals homozygous for a single copy of the 61 bp sequence were underrepresented in cases as compared to controls, although these results did not reach statistical significance (p = 0.081, OR 0.5, 95% CI 0.23-1.09, goodness of fit p = 0.42). We compared the frequencies of H27R and the 61 bp polymorphism in African-Americans and American-Caucasians. The frequencies of H27R polymorphism differed significantly between the two populations (p = 0.0001). This large study does not confirm previous reports that H27R is a risk factor for NTDs. The previously unstudied 61 bp tandem repeat, however, has a possible protective NTD effect in our Irish population. This requires confirmation in other studies.

Black or African American↗
PubMed1998

Prenatally diagnosed neural tube defects: ultrasound, chromosome, and autopsy or postnatal findings in 212 cases.

From January 1990 until December 1996, 212 cases of neural tube defect (NTD) were seen through the Prenatal Diagnosis Program of the University of Toronto. Of the 212 cases, 200 were karyotyped successfully and of these, 13 (6.5%) had chromosome abnormalities. When classified according to the site of the NTD, 2.3% (2/88) of anencephalics, 7.1% (1/14) of encephaloceles, and 10.2% (10/98) of meningomyeloceles had abnormal karyotypes. The absence of associated ultrasound abnormalities was not necessarily predictive of a chromosomally normal fetus; 4/167 (2.4%) of fetuses with isolated NTDs had chromosome abnormalities. Conversely, 24/33 (72%) of fetuses with additional findings on ultrasound had normal chromosomes. The diagnosis of a chromosome abnormality associated with NTD has important implications for recurrence risk and prenatal diagnosis, not only for the parents but potentially for other relatives. Based on our finding that 6.5% of prenatally detected NTDs are associated with chromosome abnormalities, we recommend karyotyping of all fetuses and/or newborns with NTD.

Adolescent↗
PubMedDate not supplied

Exposure to polychlorinated biphenyls and risk of neural-tube defects in a Mexican American population.

The authors examined the association between maternal polychlorinated biphenyl (PCB) levels and risk of neural tube defects (NTDs) in Mexican American women with NTD-affected pregnancies who resided in the 14 Texas-Mexico border counties during 1995-2000 (cases). Controls were randomly selected from study area women delivering normal live births. For PCB congeners with sufficient numbers of detectable values (PCB 99, 101, 110, 118, 138, 153, 180), there was little association between the proportions with detectable PCB levels in cases and controls. Odds ratios were <1 or compatible with the null, but power was low for some congeners. An index of seven PCB congeners (105, 118, 138, 153, 170, 180, 194) was also not associated with NTD risk. The maternal serum PCB levels in this study population (median PCB 153 level: 18 ng/g) were comparable to those with background exposure and do not appear to have contributed to the high prevalence of NTDs in this population.

Adult↗
PubMed1995

Clomiphene citrate and neural tube defects: a pooled analysis of controlled epidemiologic studies and recommendations for future studies.

OBJECTIVE: To estimate the degree to which neural tube defects (NTDs) are associated with periconceptional clomiphene citrate (CC) exposure in controlled epidemiologic studies, to investigate the consistency of study findings with respect to this association, and to identify key problems that future studies should address. DESIGN: Pooled analysis of 10 epidemiologic studies. SETTINGS: Hospitals and clinics. PATIENTS: Women undergoing treatment for infertility. INTERVENTIONS: Oral administration of CC. MAIN OUTCOME MEASURE: Prevalence ratio for NTDs. RESULTS: Ten controlled epidemiologic studies were identified that supplied sufficient data on CC and NTDs for inclusion. The estimated ratio of NTD prevalence among CC-exposed versus unexposed pregnancies ranged from 0.55 to 5.73 among the studies, but the variation was compatible with random fluctuation. The estimated summary prevalence ratio was 1.08, with 95% confidence limits of 0.76 and 1.51. CONCLUSION: This analysis indicates that an elevation in NTD risk due to CC cannot be ruled out, but any such elevation seems likely to be less than twofold, and there may be no elevation at all. Future studies should be designed to avoid several methodological problems not addressed in studies to date.

Administration, Oral↗
PubMed2002

Metabolic effects of C677T and A1298C mutations at the MTHFR gene in Brazilian children with neural tube defects.

BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) deficiency leads to impairment in folate metabolism and is implicated as a risk factor for neural tube defects (NTDs). Both C677T and A1298C MTHFR mutations are associated with NTDs, in some populations. METHODS: The frequencies of the C677T and A1298C MTHFR mutations were determined in 25 children with NTDs, case mothers and 75 healthy individuals from Sao Paulo City. Both C677T and A1298C mutations were analyzed by PCR-FLRP. The effects of MTHFR mutations on folate, vitamin B12 and homocysteine concentrations were also evaluated. RESULTS: C677T and A1298C allele frequencies in NTDs children and mothers were similar to that found in controls. Eleven in 23 NTDs patients and 10 in 21 NTDs mothers had folate or vitamin B12 concentrations in the lower end of the normal range. In NTDs children, C677T MTHFR genotypes did not affect vitamins and homocysteine concentrations, but plasma homocysteine was higher (p=0.028) in patients with 1298AA MTHFR genotype. Moreover, 677CT/1298AA haplotype was associated with lower vitamin B12 concentrations (p<0.05) in NTDs children. CONCLUSIONS: MTHFR gene mutations may affect vitamin B12 and homocysteine metabolism in Brazilian children with NTDs.

Adolescent↗
PubMed1993

[Neural tube defects at the Pedro García Clara Hospital, Zulia State, Venezuela].

The results of a retrospective analysis of newborn population with neural tube defects (NTD) occurred in the Hospital Pedro Garcia Clara at Zulia State for the period 1982-1988, sex, birth condition, maternal age, number of pregnancies and mother's mean permanency of time in the zone, were studied. The control sample were children who were born the same day and of the same sex as the malformed children. By that period, the NTDs occupied the first place as morbidity caused for congenital malformations. NTDs had an incidence rate of 2.28 out of thousand total of births and can be considered one of the highest reported in the country. The major rate, 5.5 per 1000 was observed in 1986. The frequency of NTDs was higher in stillbirths and females. There were no differences between NTDs and controls in relation with maternal age and number of pregnancies in the mother. There was a heterogeneous geographical distribution with high concentration of cases of NTDs in Bachaquero and Mene Grande. The permanency of the NTDs's mothers was greater than that the controls' mothers. According to this investigation, it is suggested a necessity for more profound studies in order to identify and clarify some possible environmental conditions that could explain the present findings.

Female↗
PubMed2003

[Prophylaxis of neural tube defects with folic acid in pregnant women from a health district].

OBJECTIVES: To evaluate the knowledge about the prophylaxis of neural tube defects (NTD) with supplements of folic acid and the correct therapeutic compliance. DESIGN: Observational, descriptive study. PARTICIPANTS: 346 pregnant women attending to deliver at the department of obstetrics and gynaecology, university hospital. MATERIAL AND METHODS: The following outcomes were gathered through a questionnaire: demographic variables, previous personal or family history of a pregnancy affected by a NTD, planning of pregnancy, knowledge about the value of the use of folic acid, health professional who prescribed it, and the beginning and duration of the prophylaxis. RESULTS: 95% of the participants used supplements of folic acid during their pregnancy. A 34% was able to describe folic acid as an efficacious method to diminish the incidence of NTD. The percentage of women who used correctly the prophylaxis was significantly greater when it was prescribed by a family physician (P=.003). CONCLUSIONS: A great proportion of women from our health district take folic acid during pregnancy, but just a small percent accomplishes the treatment correctly. The lack of awareness among women about the need for periconceptional folic acid supplements and how it should be taken following the recommendations to prevent NTD are the main reasons for not accomplishing a correct prophylaxis. Family physicians could play an important role as health educators.

Cross-Sectional Studies↗
PubMed2002

Incidence of neural tube defects in Ontario, 1986-1999.

BACKGROUND: Prenatal screening and the promotion of folic acid intake could affect the incidence of neural tube defects (NTDs). We examined trends in the total NTD incidence, as detected in live births, stillbirths and therapeutic abortions, from 1986 to 1999 in Ontario. METHODS: To capture cases of NTDs we used data from the Canadian Congenital Anomalies Surveillance System and hospital data on therapeutic abortions. We calculated the total incidence of NTDs by combining the numbers of NTDs occurring in live births, stillbirths and therapeutic abortions. RESULTS: The total NTD incidence rate increased from 11.7 per 10,000 pregnancies in 1986 to 16.2 per 10,000 in 1995, and it subsequently decreased to 8.6 per 10,000 by 1999. The NTD birth rate (live births and stillbirths) decreased from 10.6 per 10,000 births in 1986 to 5.3 per 10,000 in 1999. The rate of therapeutic abortions with an NTD or hydrocephalus rose from 17.5 per 10,000 abortions in 1986 to 50.7 per 10,000 in 1995 and fell to 28.7 per 10,000 abortions in 1999. INTERPRETATION: The total NTD incidence rate increased from 1986 to 1995, probably because of increased prenatal screening and better detection of NTDs. The decline from 1995 to 1999 may have been due to increased folic acid intake among women at the time of conception.

Abortion, Therapeutic↗
PubMed2004

[Effects of folic acid cooperated with soybean isoflavone on the neural tube defects pregnant rats].

OBJECTIVE: To study the effect of folic acid cooperating with soybean isoflavone on the oxidative status of neural tube defects (NTDs) pregnant rats induced by cyclophosphamide, to observe the relationship of the two factors, folic acid and the isoflavone and to look for the best co-intervention group. METHODS: The 100 pregnant rats of 2.5-3 months old were randomly divided into the control group, model group, co-intervention groups and solo-intervention groups. The animals were executed on the 20th day of gestation as to examining the levels of antioxidative indices (GSH, GSH-Px, Se, Mn, Fe) in blood. The incidence rates of NTDs were calculated. RESULTS: The interaction of folic acid and isoflavone had significant effect on the indices related with antioxidation (P < 0.05). Folic acid 0.7 mg/kg cooperated with isoflavone 160 mg/kg had the best intervention effects in our study. Compared with the solo-intervention by folic acid 1.4 mg/kg and isoflavone 320 mg/kg, the effect of co-intervention (folic acid 0.7 mg/kg cooperated with isoflavone 160 mg/kg) was significantly better (P < 0.05). CONCLUSION: Folic acid should be the main protective factor of NTDs, and isoflavone might reinforce the protective effects of folic the acid on NTDs by increasing the antioxidative ability, however, the effect is related with the ratio of the two factors.

Animals↗
PubMed2005

Candidate gene analysis in human neural tube defects.

Biochemical and developmental pathways, mouse models, and positional evidence have provided numerous candidate genes for the study of human neural tube defects. In a survey of 80 studies on 38 candidate genes, few found significant results in human populations through case-control or family-based association studies. While the folate pathway has been explored extensively, only the MTHFR 677C > T polymorphism was significant, and only in an Irish population. Developmental pathways such as the Wnt signaling pathway and Hox genes have also been explored without positive results. More than 90 mouse candidates have been identified through spontaneous and knockout mutations, but only the T locus (mouse Brachyury gene) showed association in an initial study that was not confirmed on follow-up. Positional candidates have been derived from cytogenetic evidence, but preliminary genomic screens have limited power due to small sample sizes. Future studies would increase their power to detect association by using more samples. In addition a clarification of the phenotype would be beneficial as many studies used different inclusion criteria. Incorporating several types of data could highlight better candidates, as would looking beyond the traditional sources for candidate genes. Recent studies of an energy metabolism gene (UCP2) and vitamin B metabolism (Transcoalbumin) have produced promising results. Utilizing other model organisms may also be beneficial, as in a recent study from a chick model of NTDs in NCAM1. New approaches combined with traditional methods and increased sample sizes will help prioritize human NTD candidate genes and clarify the complex etiology of this condition.

Animals↗
PubMed1996

Folic acid and prevention of neural tube defects: a study of Canadian mothers of infants with spina bifida.

OBJECTIVES: To determine the diffusion of information about preventing neural tube defects (NTDs) through folic acid consumption by examining whether mothers of Canadian children born with spina bifida, who had become pregnant at least a year after evidence of the preventive effect of folic acid had been published, had taken sufficient amounts of folic acid in the periconceptional period and were aware of this important new information. DESIGN: Validated food-frequency questionnaire to assess folate intake. SETTING: The Hospital for Sick Children in Toronto between Jan. 4 and Aug. 16, 1994. PARTICIPANTS: Thirty mothers whose infants were being treated for spina bifida. MAIN OUTCOME MEASURES: The mothers' mean folate intake and knowledge about the protective effect of folic acid; demographic and health information. RESULTS: The mothers' mean folate intake was 0.182 mg/d (standard deviation 0.076 mg/d, range 0.02 to 0.53 mg/d), less than half the protective dose. Only 4 (13%) of the mothers had been aware of the relation between nutritional folate and NTDs when they conceived, but even they did not supplement their diets with sufficient folic acid. The medical data showed that, in addition to the failure of primary prevention of NTDs, secondary prevention through diagnostic tests during pregnancy were also inadequate. CONCLUSIONS: Our study, one of the first to be conducted after the role of folate in preventing NTDs was confirmed, reveals that, in one of the most advanced countries in the world, this new information has had no effect on patients' folate intake. Unless food is fortified with folate, the estimated 400 to 800 annual cases of NTDs in Canada will not be prevented.

Canada↗
PubMed1998

Molecular genetic analysis of the gene encoding the trifunctional enzyme MTHFD (methylenetetrahydrofolate-dehydrogenase, methenyltetrahydrofolate-cyclohydrolase, formyltetrahydrofolate synthetase) in patients with neural tube defects.

It is now well recognized that periconceptional folic acid or folic acid containing multivitamin supplementation reduces the risk of neural tube defects (NTDs). Recently we were able to show that homozygosity for a thermolabile variant of the enzyme methylenetetrahydrofolate reductase is associated with an increased risk for spina bifida in patients recruited from the Dutch population. However, this genetic risk factor could not account for all folic acid preventable NTDs. In an attempt to identify additional folate related enzymes that contribute to NTD etiology we now studied the methylenetetrahydrofolate dehydrogenase gene on chromosome 14q24 which encodes a single protein with three catalytic properties important in the folate metabolism. The cDNA sequence of 38 familial and 79 sporadic patients was screened for the presence of mutations by single strand conformation polymorphism (SSCP) analysis followed by sequencing. Two amino acid substitutions were identified. The first one (R293H) was detected in a patient with familial spina bifida and not in 300 control individuals. The mutation was inherited from the unaffected maternal grandmother and was also present in two younger brothers of the index patient, one of them displaying spina bifida occulta and the other being unaffected. The second change turned out to be an amino acid polymorphism (R653Q) that was present in both patients and controls with similar frequencies. Our results so far provide no evidence for a major role of the methylenetetrahydrofolate-dehydrogenase (MTHFD) gene in NTD etiology. However, the identification of a mutation in one family suggests that this gene can act as a risk factor for human NTD.

Aminohydrolases↗
PubMed1992

Retinoic acid-induced neural tube defects with multiple canals in the chick: immunohistochemistry with monoclonal antibodies.

When retinoic acid was injected into chicken yolks before incubation, various types of neural tube defect (NTD) were induced in 38-46% of the embryos after 48-96 h of incubation. The cranial NTD consisted of a delay in closing of the neural plate in 48-h embryos and some remained as disorganized, hyperplastic masses in older embryos. In spinal NTD of 48-h embryos the posterior neuropore remained widely open. In older embryos with a closed posterior neuropore, the neural tube appeared dissociated or disorganized locally at the trunk level. The tissue consisted of a dorsally-situated, neural-plate-like structure and a ventrally-located cell mass containing multiple canals. Although the location was different, this arrangement was similar to the overlap zone which appears between primary and secondary neurulation in normal development. Immunohistochemistry was performed using monoclonal antibodies which selectively stained various components of chick tissue. Considering the similarity in neural tube formation between chick and human, this experimental NTD may provide clues to understanding the etiology of human myelomeningocele.

Animals↗