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PubMed1994

Epidemiologic characteristics of phenotypically distinct neural tube defects among 0.7 million California births, 1983-1987.

Isolated neural tube defects (NTDs) appear to have different risk factors compared to nonisolated NTDs. To extend those observations, we explored routinely collected child and parental characteristics as possible risk factors among isolated versus nonisolated NTD cases, among high versus low spina bifida cases, and among open versus skin-covered spina bifida case. Fetuses and liveborn infants with anencephaly or spina bifida among the 1983-87 cohort of births and fetal deaths (n = 712,863) were ascertained by the California Birth Defects Monitoring Program. One hundred and ninety-three anencephalic cases and 272 spina bifida cases were compared to a random sample of 5,000 liveborn infants. Among anencephalic cases, 55% were livebirths and 85% were isolated. The proportion of males was similar to females across all subgroups. Increased risks were found for Hispanic whites, with risk estimates highest for nonisolated cases (odds ratio = 4.0, 95% confidence interval [1.5, 10.5]). Among spina bifida cases, 92% were livebirths, 81% isolated, 82% open, and 86% were low. More males were found among the group with isolated high open defects, and fewer males were found among the group of all closed defects. The proportion of males was similar to females in all other subgroups. Cases were more likely to be Hispanic with risks largest for high open defects (odds ratio = 2.9, [1.2,6.6]), particularly for nonisolated cases. This study provides some evidence that further classifications of NTDs may reveal subgroupings of cases with different etiologies.

Abnormalities, Multiple↗
PubMedDate not supplied

Improvements in the status of folate and cobalamin in pregnant Newfoundland women are consistent with observed reductions in the incidence of neural tube defects.

BACKGROUND: Historically, the province of Newfoundland and Labrador had one of the highest rates of neural tube defects (NTDs) in North America (1976-1991: 3.2/1000 births), which could be partially explained by the sub-optimal status of folate and cobalamin in this population. In order to gain evidence of the impact of folate fortification programs, as well as prenatal education programs, a cross-sectional study was conducted to obtain data on the folate and cobalamin status of pregnant Newfoundland women in the post-folate fortification era. Additionally, the rates of NTDs were determined. METHODS: Blood samples were collected during the first prenatal clinic (at approximately 16 weeks gestation) from 365 pregnant women in Newfoundland in 2002. Samples were analyzed for serum folate, cobalamin and homocysteine. In addition, rates of neural tube defects were calculated from data collected from the Provincial Medical Genetics Program, Newfoundland. Data were compared to historical data from a similar population of pregnant women in Newfoundland. RESULTS: The status of both folate and cobalamin has significantly improved (p<0.0001) in the post-fortification era, concurrent with a significant reduction in the number of neural tube defects (NTDs), from 4.67 (years 1992-1996) to 1.01 (years 1998-2002) per 1000 total births. INTERPRETATION: These data provide evidence that both folate and cobalamin status of pregnant Newfoundland women have improved since 1997. The data for cobalamin provide evidence that strategies in addition to folate fortification programs are contributing to the improvements of poor water-soluble vitamin status in this population, thus providing a partial explanation for the dramatic reductions in NTD rates observed since 1995.

Adolescent↗
PubMed1988

Origin of the dorsal surface of the neural tube by progressive delamination of epidermal ectoderm and neuroepithelium: implications for neurulation and neural tube defects.

Knowledge of the morphogenetic events involved in the development of the dorsal portion of the neural tube is important for understanding neural tube closure, neural crest cell formation and emigration, and the origin of neural tube defects. Here, I characterize the progressive development of the tips of the neural folds during fold elevation in the trunk of mouse and chick embryos and the events leading to formation of the dorsal portion of the neural tube as the epidermal ectoderm (EE) and neuroepithelium (NE) separate from each other. The nature and timing of appearance of collagen IV, laminin and fibronectin were analysed by immunofluorescent and immunogold labelling, and ruthenium red and tannic acid were used to enhance staining for proteoglycans and glycosaminoglycans. As the neural folds elevate, the NE and EE delaminate progressively beginning at the basal surface of the lateral extremes of the neural plate. Nevertheless, the two epithelia remain connected across the zone of delamination by their previously existing basal laminae. In each fold, proteoglycan granules appear at the interface between the NE and EE before delamination begins, and then an (interepithelial) space begins to open and propagate dorsally. Other extracellular matrix (ECM) molecules appear within the space a short distance behind its tip and basal lamina deposition begins shortly thereafter. As fusion occurs, the interepithelial spaces of the two folds coalesce and the final separation of the EE from the NE is accomplished. These observations suggest that the previously recognized delay in deposition of ECM and basal lamina on the dorsal portion of the neural tube and on the overlying EE is a direct consequence of the delamination of the two epithelia and the establishment of two new basal surfaces. The observation that the surface of the dorsal third of the neural tube forms by delamination rather than by juxtaposition of previously existing basal surfaces of the two epithelial is discussed in terms of possible implications for models of neurulation and the origin of neural tube defects.

Animals↗
PubMed1996

Regional variations in neural tube defects and alfa-fetoprotein screening in Denmark 1983-88.

BACKGROUND: An effect of maternal serum alpha-fetoprotein screening on prevalence rates for neural tube defects (NTD's) has been demonstrated in some populations. The present study tests the hypothesis that regional rates in the Danish low risk population reflects screening activities. METHODS: Cross-sectional survey for neural tube defects through the Danish Malformation Register. RESULTS: The prevalence rate for all neural tube defects was 5.8 pr 10(4) births which is lower than in most other populations. Standardized risk ratios for NTD in two regions with a program for alfa-fetoprotein screening were 0.1 (95% c.i. 0.0-0.7) and 0.4 (95% c.i. 0.2-0.9). Relative risk at 0.6 (95% c.i: 0.4-1.1) was found in one county with screening of approximately one third of pregnancies. In most other counties < 5% of pregnant women had been examined and point estimates of relative risks varied from 0.9-1.7. CONCLUSION: There was a good agreement between prevalence of neural tube defects at birth and regional alfa-fetoprotein screening activity. This can be taken as a strong indication of a secondary preventive effect from screening in a population with a priori low risk for NTD's. However, other aspects of screening should also be taken into consideration before general programs are forwarded.

Biomarkers↗
PubMed1982

Current trends in the incidence of neural tube defects.

To verify and investigate the reported decline of neural tube defects (NTDs) in the last decade, data from three different sources were examined: the Birth Defects Monitoring Program (BDMP), composed of newborn discharge diagnoses; the population-base Metropolitan Atlanta Congenital Defects Program (MACDP); and the National Center for Health Statistics (NCHS), whose data include only live births. Although the three systems use different methods of ascertaining cases, all data bases showed a decreasing trend in NTD rates, with annual percent decreases of 3.1% for NCHS, 5.7% for BDMP, and 7.7% for MACDP. The decrease was noted in all variables examined: race, sex, and birth status for each defect. NTD rates appear to be declining more rapidly in females than in males. Further, the rate among stillborn infants decreased more than the rate among live-born infants. The exclusion of stillbirths in the NCHS data may contribute to its low rate of decline for female anencephalics. Data from England showed a larger average annual decrease (10.6%) than did data from the United States. Although reasons for the overall decline are not verifiable, a variety of explanations are suggested for this decline and for the difference in NTD rate decline noted between live births and stillbirths. The overall decline in NTD rates should be investigated with respect to etiology; recognition of the decline is useful for planning and evaluating health care programs.

Anencephaly↗
PubMed1991

Valproic acid-induced neural tube defects in mouse and human: aspects of chirality, alternative drug development, pharmacokinetics and possible mechanisms.

Administration of the antiepileptic drug valproic acid (VPA) during early pregnancy can result in a 1-2% incidence of spina bifida aperta, a closure defect of the posterior neural tube in the human. The predominant defect produced by VPA in the mouse is exencephaly, a closure defect of the anterior neural tube. Recent experiments demonstrate that an appropriate dosing regimen (consecutive doses of VPA on day 9 of gestation) can also result in a low incidence of spina bifida aperta, and a high incidence of spina bifida occulta in the mouse as a potential animal model. Relatively high doses and concentrations of VPA are needed in the mouse to produce neural tube defects, the human appears to be more sensitive in this regard. Maximal concentrations and not AUC (area under the concentration-time curve) values correlate with the incidence of neural tube defects in the mouse which could in part be explained by saturation of plasma protein binding, increased free drug available for placental transfer and the embryonic neuroepithelium acting as a "deep compartment". It is likely that the parent drug and not a metabolite is the proximate teratogen. Structure-activity relationships show a strict structural requirement for high teratogenic potency: the molecule must contain an alpha-hydrogen atom, a carboxyl function, branching on carbon atom 2 with two chains containing 3 carbon atoms each for maximum activity. If these two carbon chains are different, then enantiomers are present such as the R- and S-enantiomers of 2-n-propyl-4-pentenoic acid (4-en-VPA), 2-n-propyl-4-pentynoic acid (4-yn-VPA) and 2-ethylhexanoic acid. These enantiomers were synthesized and shown to be significantly different in regard to teratogenic potency. Pharmacokinetic studies indicate that both enantiomers of each compound reach the embryo to the same degree. Therefore, the intrinsic teratogenic activity of the enantiomers differ, suggesting a stereoselective interaction between the drugs and a chiral structure within the embryo, is involved in the mechanism of action. In sharp contrast to the teratogenic effect, the anticonvulsant activity and neurotoxicity of this compound class show broad structural specificity, opening the possibility for development of novel antiepileptic agents with low teratogenic potency such as 2-n-propyl-2-pentenoic acid (2-en-VPA). The molecular mechanism of the teratogenicity of VPA is quite unknown; of the several hypothesis suggested, the interaction of VPA with embryonic folate metabolism is discussed here.

Abnormalities, Drug-Induced↗
PubMed2005

Initial findings on teratological and developmental relationships and differences between neural tube defects and facial clefting. First experimental results.

Unless genetically caused, the occurrence of neural tube defects and clefts of the lip, alveolus and palate are not associated. These malformations do, however, share some common causes, one of which is folic acid deficiency. Nevertheless, it is not known why a neural tube defect resulting from folic acid deficiency does not occur in combination with facial clefts. Based on animal experiments and a review of the literature, it is assumed that other factors--such as vitamin B6 deficiency--though clinically not diagnosed, can more often cause malformations.

Alveolar Process↗
PubMed1989

Prevalence of neural tube defects in the Yorkshire Region.

The birth prevalence of neural tube defects (NTD) in the Yorkshire Region was determined for 1985 and 1986 by ascertainment of cases in live-and stillborn babies and of pregnancies terminated for NTD. Sixty-seven cases of anencephaly, 82 of spina bifida and 11 others were identified, a prevalence of 1.54 per 1000 total births. Eighty-eight per cent of pregnancies associated with anencephaly and 48 per cent of those with spina bifida were terminated.

Cross-Sectional Studies↗
PubMed1993

Upper and lower neural tube defects: an alternate hypothesis.

It has been suggested that neural tube defects (NTDs) of the upper type (anencephaly, encephalocele, and thoracic spina bifida) may have a pathogenesis different from those of the lower type (lumbosacral spina bifida), since recurrent cases within a sibship were said always to be concordant with respect to NTD type. Also, spontaneous abortion, additional malformation, and recurrence rate were observed to be higher in the upper group, and there was an excess of females in upper NTD probands. To test this hypothesis, we measured the above variables in upper and lower NTDs in a sample from Quebec. We found less than full concordance (50%) of NTD type in 18 sib pairs. Recurrence rate was not significantly lower in the lower NTD group (5.6 v 5.8%). The other variables were in general agreement with previous studies, inconsistent findings possibly attributable to different NTD population incidences. These findings can be accounted for if upper and lower NTDs share a similar pathogenesis and the embryo is more susceptible during early than late neural tube formation.

Anencephaly↗
PubMed1985

Amniotic fluid acetylcholinesterase activity and alpha-fetoprotein in chromosomal anomalies and neural tube defects.

Measurement of alpha-fetoprotein concentration and acetylcholinesterase activity in amniotic fluid can be used to identify chromosomal defects as well as neural tube defects. In seven cases of trisomy 21 and one case of partial trisomy 3, alpha-fetoprotein concentrations were below the reference range but values for acetylcholinesterase activity were normal for the appropriate gestational age. One case of trisomy 13 had an increase in acetylcholinesterase activity and normal alpha-fetoprotein concentration.

Acetylcholinesterase↗
PubMed2005

Incidence of neural tube defects among neonates at King Hussein Medical Centre, Jordan.

Neural tube defects (NTDs) are important factors in fetal and infant mortality. There have been no studies on the incidence of NTDs in Jordan. A one-year prospective study was therefore conducted in King Hussein Medical Centre neonatal unit (April 2002-April 2003) to determine the incidence of NTDs among Jordanian neonates. All liveborn babies, both term and preterm, were assessed for NTDs. Mothers of babies with NTDs were interviewed postnatally regarding antenatal care and family history of NTDs. Of 5088 live births, 33 had NTDs, giving an incidence of 6.5/1000 live births. None of the women with affected babies had a history of NTDs and all had received antenatal care, but none had taken folate supplementation. The majority of the women had not had a diagnosis before the birth, despite having had ultrasound scans throughout their pregnancies.

Academic Medical Centers↗
PubMedDate not supplied

[Risk factors associated with neural tube defects: exposure during the first trimester of gestation].

The neural tube defects (NTD) are a group of malformations of multifactorial etiology. Their high incidence in Mexico and the etiologic heterogeneity observed in several studies, prompted the present investigation with the main objective of looking for risk factors associated to NTD. We analyzed maternal exposure during the first trimester of pregnancy to different environmental factors, such as acute or chronic illnesses, immunizations, smoking, alcoholism, maternal or paternal occupation and exposure to chemicals. The sample include 360 patients with anencephaly, 249 with spina bifida and 44 with encephalocele, ascertained from a total of 230 635 live births and 4,020 stillborns, studied in the Mexican program of Registro y Vigilancia Epidemiológica de Malformaciones Congénitas Externa. Of the risk factors considered, significant differences with the control group were found for anencephaly in relation to maternal viral upper respiratory infection, hyperthermia, ingestion of analgesics, antiemetics and paternal occupation. In the case of spina bifida, significant differences were found only for viral upper respiratory infections.

Female↗
PubMed1998

Amniotic fluid B12 and folate levels associated with neural tube defects.

Amniotic fluid levels of B12 and folate in neural tube defect (NTD) affected pregnancies were compared with the weekly group mean +/-SD changes in amniotic fluid B12 and folate levels of 10 unaffected pregnancies each week between 15 and 20 weeks' gestation age. Comparison was by analysis of variance (ANOVA) and Pearson's correlation to B12 and folate levels and to the NTD samples of corresponding gestation age. Amniotic fluid B12 and folate decreased 67 and 62%, respectively, between 15 and 20 weeks' gestation in the unaffected pregnancies, associated with an increase in amniotic fluid volume. The mean +/-SD B12 and folate of the NTD affected pregnancies (308+/-156 pg/mL and 3.1+/-1.6 ng/mL) were below the mean +/-SD B12 and folate of the total population of unaffected pregnancies (453+/-155 pg/mL and 3.9+/-1.2 ng/mL). The correlation between gestation age and amniotic fluid B12 was -0.9914 (p< or =.0001) and -0.9599 (p< or =.002) for amniotic fluid folate. The B12 levels of the affected pregnancies were below the range of unaffected pregnancies in four of the nine affected pregnancies, and folate levels in two of the nine affected pregnancies.

Amniotic Fluid↗
PubMed1999

Folate status and neural tube defects.

Periconceptional folic acid supplementation prevents approximately 70% of neural tube defects (NTDs). While most women carrying affected fetuses do not have deficient blood folate levels, the risk of having an NTD affected child is inversely correlated with pregnancy red cell folate levels. Current research is focused on the discovery of genetic abnormalities in folate related enzymes which might explain the role of folate in NTD prevention. The first candidate gene to emerge was the C677T variant of 5,10-methylenetetrahydrofolate reductase. Normal subjects who are homozygous for the mutation (TT) have red cell folate status some 20% lower than expected. It is now established that the prevalence of the TT genotype is significantly higher among spina bifida cases and their parents. Nevertheless, our studies show that the variant does not account for the reduced blood folate levels in many NTD affected mothers. We conclude that low maternal folate status may in itself be the most important risk factor for NTDs and that food fortification may be the only population strategy of benefit in the effort to eliminate NTDs.

5,10-Methylenetetrahydrofolate Reductase (FADH2)↗
PubMed2003

Updated investigations of the role of methylenetetrahydrofolate reductase in human neural tube defects.

Folate supplementation appears to reduce the risk for neural tube defects (NTDs). Methylenetetrahydrofolate reductase (MTHFR) is a candidate gene in the folate metabolism pathway that has been extensively studied in different human populations. We examined the risk associated with having the thermolabile variant (TT) of MTHFR in a study of 175 American Caucasians with NTDs and their families. We found a significant association in patients compared with 195 unrelated controls [odds ratio (OR) = 2.13, 95% confidence interval (95% CI) = 1.11-4.09)], but not in mothers (OR = 1.29, 95% CI = 0.622-2.67) or in fathers (OR = 1.45, 95% CI = 0.681-3.09). We found no evidence for unequal transmission from parents to an affected child (p > 0.10). We failed to find a previously reported association for a combined haplotype for MTHFR and cystathionine beta-synthase, except in subjects with NTDs compared with 559 pooled controls (OR = 2.87, 95% CI = 1.03-8.03). We found no evidence for an association for a novel CA-repeat polymorphism identified in a gene closely linked to MTHFR (p > 0.10). Our studies continue to suggest that additional candidate genes other than MTHFR may be responsible for an increased risk to NTD in some American Caucasian families.

Cystathionine beta-Synthase↗
PubMed2003

Antisense modulation of the coding or regulatory sequence of the folate receptor (folate binding protein-1) in mouse embryos leads to neural tube defects.

BACKGROUND: Although folic acid decreases the incidence of neural tube defects (NTDs) in humans, the mechanism for this protection is unknown. We have employed antisense technology to alter expression of the gene for the folate receptor (folate binding protein-1 [Folbp1]) in mouse embryos cultured in vitro. METHODS: Embryos were explanted on day 8 of gestation and cultured for 44 hr. Several oligodeoxyribonucleotides designed to modulate the coding region or a regulatory sequence in the 5'-untranslated region of Folbp1 were microinjected into the amniotic sac of embryos at the beginning of the culture period. RESULTS: Two different antisense sequences to the 5' and 3' coding region in Folbp1 produced concentration-dependent increases in the number of embryos with NTDs. Coinjection of 5-methyltetrahydrofolate with these sequences decreased the frequency of abnormal embryos. A semi-quantitative RT-PCR technique used to measure the amount of Folbp1 mRNA in treated and control embryos confirmed that the mRNA level was decreased by treatment with the antisense sequences. An antisense oligodeoxyribonucleotide to a 17 base cis regulatory element also generated a concentration-dependent increase in the frequency of embryos with NTDs, and a decrease in the level of Folbp1 mRNA. CONCLUSIONS: These results demonstrate that alterations in expression of Folbp1 by perturbing either the coding sequence or a critical regulatory cis-element can play a role in NTDs.

5' Untranslated Regions↗
PubMed2001

Reduced vitamin B12 binding by transcobalamin II increases the risk of neural tube defects.

Periconceptional folic acid supplementation reduces the risk of neural tube defects (NTD). Homocysteine levels are elevated in mothers of NTD children, which may be due to decreased cellular vitamin B12 levels, as vitamin B12 is a cofactor for the methylation of homocysteine. Transcobalamin II (TC II) transports vitamin B12 to the tissues. To examine whether altered plasma transcobalamin levels are a risk factor for NTD, we determined the apo and holo form of TC II and haptocorrin (TCI+TCIII), vitamin B12 and homocysteine concentrations in the plasma of 46 mothers with NTD children, and in 73 female controls. Holo-tc II levels and holo-tc II percentages (holo-tc II/total tc II) in the first quartile of the control distribution were related to a three-fold (OR 2.9, 95%CI 0.9-9.2) and five-fold (OR 5.0, 95%CI 1.3-19.3) risk, respectively, for having a child with NTD, when compared with the last quartile. Homocysteine levels were significantly higher among individuals with low holo-tc II, low total vitamin B12 concentrations and low holo-tc II percentages. These low holo-tc II percentages are probably caused by reduced affinity of TC II for vitamin B12, which may be explained by genetic variation in the TC II gene. Vitamin B12 supplementation might therefore be warranted, in addition to folate, in the prevention of NTD.

Adult↗
PubMed2007

Plasma vitamin values and antiepileptic therapy: case reports of pregnancy outcomes affected by a neural tube defect.

BACKGROUND: Folic acid supplementation reduces the occurrence of neural tube defects (NTDs); however, it is not clear whether it protects against teratogenic effects of antiepileptic drugs. METHODS: We report the cases of four pregnant women receiving valproic acid therapy, who all had NTD-affected offspring, despite periconceptional 5 mg/day of folic acid supplementation (cases), and investigated homocysteine metabolism, linked with folate metabolism. Their plasma homocysteine, folates, and vitamin B6 and B12 results were compared with values of two other women, who were also receiving valproic acid and folic acid complement, but who had normal pregnancies (valproic acid controls), and values of 40 pregnant women who had normal pregnancies and were not receiving any therapy (controls without therapy). Because of the possible existence of a genetic susceptibility, polymorphisms in homocysteine metabolism were sought. RESULTS: Two cases showed a decreased phosphopyridoxal level, compared with levels in the controls not receiving therapy. The genotype TT (C677T) is an NTD genetic susceptibility, but it was observed in only one valproic acid control. Various polymorphisms were observed in the cases, but were also common in the controls. Several studies have reported that valproic acid therapy lowers vitamin B6 levels. Our case with the greatest decrease in plasma phosphopyridoxal, who was taking periconceptional folic acid plus pyridoxine therapy, had a normal second pregnancy outcome. CONCLUSIONS: In addition to folates, other vitamins, such as vitamin B6, may have played a role in NTDs in our patients taking an antiepileptic drug.

Adult↗