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PubMed2001

Neural tube defects in relation to use of folic acid antagonists during pregnancy.

Periconceptional folic acid supplementation reduces the risk of neural tube defects (NTDs). To determine whether periconceptional exposure to folic acid antagonists (FAAs) might therefore increase the risk of NTDs, the authors examined data from an ongoing case-control study of birth defects (1979-1998) in the United States and Canada. They compared data on 1,242 infants with NTDs (spina bifida, anencephaly, and encephalocele) with data from a control group of 6,660 infants with malformations not related to vitamin supplementation. Mothers were interviewed within 6 months of delivery about demographic, reproductive, medical, and behavioral factors and about medication use. The adjusted odds ratios of NTDs related to exposure to FAAs (including carbamazepine, phenobarbital, phenytoin, primidone, sulfasalazine, triamterene, and trimethoprim) during the first or second months after the last menstrual period, compared with no use in either month, were 2.8 (95% confidence interval: 1.7, 4.6) for FAAs as a group, 4.8 (95% confidence interval: 1.5, 16.1) for trimethoprim (based on five exposed cases), and 6.9 (95% confidence interval: 1.9, 25.7) for carbamazepine (six exposed cases). These results are adjusted for region, interview year, periconceptional folic acid supplementation, maternal age, weight, education, and infections early in pregnancy. These findings suggest that a number of FAAs may increase NTD risk, and they provide estimates of risk for selected drugs.

Adult↗
PubMed1998

VPA-induced neural tube defects in mice. I. Altered metabolism of sulfur amino acids and glutathione.

Valproate (VPA) has been shown to induce neural tube defects (NTDs) in humans and mice, but the mechanism of action has not been elucidated. Folate supplementation has been reported to prevent the defect. It was the aim of our experiment to reveal effects of VPA and of folate coadministration on amino acid metabolism in an NTD mouse model. After treating pregnant mice intraperitoneally with 2.1 mmol VPA/kg body weight, plasma homocysteine concentrations were found to be increased. Coadministration of 4 mg/kg folate decreased this level. Plasma methionine levels were reduced under both experimental conditions. Fifteen min after treating mice with 3 mmol VPA/kg body weight, hepatic levels of both S-adenosylmethionine (SAM) and S-adenosylhomocysteine were found to be increased by +175% and +348%, respectively; but the levels had normalized again 30 min after VPA injection. Simultaneously, plasma methionine and serine levels had decreased by -43% and -51%, respectively, while homocysteine and cysteine increased by +71% and +81%, respectively. Reduced glutathione (GSH) decreased by -45%, but total glutathione did not change. These changes were statistically significant, and they occurred dose-dependently. We proposed that VPA induces methionine deficiency inhibition of folate metabolism and homocysteine remethylation, increase in aminothiols, and suppression of the GSH system in maternal blood within 1 h after application. These changes may be responsible for the teratogenic potential of VPA. Folate may prevent NTDs by changing homocysteine catabolism.

Abnormalities, Drug-Induced↗
PubMed1979

Neural tube defects in curly-tail mice. I. Incidence, expression and similarity to the human condition.

The incidence of neurovertebral defects in mutant mice of the curly-tail strain was investigated and found to be similar to that observed in the same mice twenty-five years ago. The results of breeding experiments support the hypothesis of Grüneberg that the defects in these mice are probably caused by a recessive gene, the expression of which is markedly affected by the genetic background. Selection against the curly-tail phenotype for six generations did not affect the incidence of abnormalities. A marked excess of females was found among exencephalic mice, as among humans with neural tube defects. Similarly, polyhydramnios, hydrocephaly, high levels of amniotic fluid alphafoetoprotein and distinctive, rapidly adhering cells in the amniotic fluid also occurred in these mice, as in humans. The curly-tail mice thus provide a useful model for the investigation of neural tube defects in man.

Amniotic Fluid↗
PubMedDate not supplied

[Prenatal diagnosis and prevention of neural tube defects].

Measurement of the alpha-fetoprotein level (A.F.P.) in amniotic fluid is the best test to diagnose a neural tube defect (N.T.D.) in early pregnancy of women who have had one N.T.D. infant. Measurements of the serum-A.F.P. level, which might be performed in all pregnancies, have a high rate of false positive results. Serum-A.F.P. and amniotic fluid-A.F.P. both are raised only in open spina-bifida and/or anencephaly. The prospective studies about a possible prevention of N.T.D. by periconceptional vitamin supplementation are discussed. The first results are encouraging. So we recommend a multivitamin supplementation at least 28 days before the conception.

Acetylcholinesterase↗
PubMed1994

[Risk related to methodologically disputable studies: the example of vitamin therapy for the prevention of neural tube defects].

Due to the non acceptance by ethics committees of its double blind controlled study for prevention of neural-tube defects recurrence by vitamin supplementation versus mineral components, a British group underwent methodologically debatable epidemiological study which has become quite controversial. This survey concluded that vitaminotherapy is effective. The aim of this article was to analyze the consequences induced by such a procedure which probably resulted in delaying the onset of the Medical Research Council controlled trial, performed with the necessary rigorous methodology, and which gave the final answer only 11 years later, a time during which concerned women could not take advantage of a valuable preventive treatment.

Ethics, Medical↗
PubMed2003

The use of folic acid for the prevention of neural tube defects and other congenital anomalies.

OBJECTIVE: To provide information regarding the use of folic acid for the prevention of neural tube defects (NTDs) and other congenital anomalies, in order that physicians, midwives, nurses, and other health-care workers can assist in the education of women in the preconception phase of their health care. OPTION: Folic acid supplementation is problematic, since 50% of pregnancies are unplanned and the health status of women may not be optimal. OUTCOMES: Folic acid supplementation has been proven to decrease or minimize specific birth defects. EVIDENCE: A systematic review of the literature, including review and peer-reviewed articles, government publications, the previous Society of Obstetricians and Gynaecologists of Canada (SOGC) Policy Statement of March 1993, and statements from the American College of Obstetrics and Gynecology, was used to develop a new clinical practice guideline for the SOGC. VALUES: Peer-review process within the committee structure. BENEFITS, HARMS, AND COSTS: The benefit is reduced lethal and severe morbidity birth defects and the harm is minimal. The personal cost is of vitamin supplementation on a daily basis and eating a healthy diet. RECOMMENDATIONS: 1. Women in the reproductive age group should be advised about the benefits of folic acid supplementation during wellness visits (birth control renewal, Pap testing, yearly examination), especially if pregnancy is contemplated. (III-A) 2. Women should be advised to maintain a healthy nutritional diet, as recommended in Canada's Food Guide to Healthy Eating (good or excellent sources of folic acid: broccoli, spinach, peas, Brussels sprouts, corn, beans, lentils, oranges). (III-A) 3. Women who could become pregnant should be advised to take a multivitamin containing 0.4 mg to 1.0 mg of folic acid daily. (II-1A) 4. Women taking a multivitamin with folic acid supplement should be advised not to take more than 1 daily dose of vitamin supplement, as indicated on the product label. (II-2A) 5. Women in intermediate- to high-risk categories for NTDs (NTD-affected previous pregnancy, family history, insulin-dependent diabetes, epilepsy treatment with valproic acid or carbamazepine) should be advised that high-dose folic acid (4.0 mg-5.0 mg daily) supplementation is recommended. This should be taken as folic acid alone, not in a multivitamin format, due to risk of excessive intake of other vitamins such as vitamin A. (I-A) 6. The choice of a 5 mg folic acid daily dose for women considering a pregnancy should be made under medical supervision after minimizing the risk of undiagnosed vitamin B12 deficiency (hypersegmentation of polymorphonuclear cells, macrocystic indices, large ovalocytes, leukopenia, thrombocytopenia, markedly elevated lactate dehydrogenase level, confirmed red blood cell folate level). (II-2A) 7. Signs or symptoms of vitamin B12 deficiency should be considered before initiating folic acid supplementation of doses greater than 1.0 mg. (III-A) 8. A three-generation pedigree on the families of both the pregnant woman and the biological father should be obtained to identify increased risk for congenital birth defects (i.e., NTD, cardiac, chromosomal, genetic). (III-A) 9. Women who become pregnant should be advised of the availability of noninvasive screening tests and invasive diagnostic tests for congenital birth defects (including NTDs): maternal serum "triple marker screen" at 15 to 20 weeks, ultrasound at 16 to 20 weeks, and amniocentesis after 15 weeks of pregnancy if a positive screening test is present. (I-A) VALIDATION: This is a revision of a previous guideline and information from other consensus reviews from medical and government publications has been used.

Canada↗
PubMed1996

Prolonged induction to delivery time in termination of pregnancy using 16, 16-dimethyl-PGE1-methyl ester (gemeprost) for fetuses with a neural tube defect or hydrocephalus.

A retrospective study is reported comparing the induction to delivery interval using gemeprost for termination of pregnancy, in the second trimester, in 3 groups of patients. It was observed that the mean induction to delivery interval was significantly longer in 75 pregnancies where there was a fetus with a neural tube defect and or hydrocephalus (31.7 hours) compared with 88 pregnancies with other fetal abnormalities (19.7 hours) and 84 pregnancies where there was an intrauterine death (11.3 hours). There was also an increase in the requirements for further intervention to obtain delivery in the group with a neural tube defect or hydrocephalus (n = 33) compared with where there was an intrauterine fetal death (n = 4) and other abnormality (n = 14). We believe these results should be considered when counselling patients who have requested termination of pregnancy for fetal abnormalities.

Abortifacient Agents, Nonsteroidal↗
PubMed1993

Neural tube defects: a survey of lesion descriptions made by different European pathologists.

Recent epidemiological interest has focused on separation of neural tube defects (NTD) into subgroups which may differ pathogenetically and aetiologically, for example, 'upper' and 'lower' spina bifida. In order to validate the use of pathologists' lesion descriptions by epidemiologists and others, a postal survey of 18 European perinatal pathologists, identified by EUROCAT registries, was conducted. Pathologists were asked, anonymously, to describe and identify the lesions in 15 photographs of midtrimester termination fetuses. There was a 50% response rate. Even taking into consideration the limitations of dealing with photographs rather than the fetuses themselves, there was often marked variation in the descriptions. Standardisation of terminology and international consensus about the type of detail recorded for NTD are urgently needed.

Abortion, Therapeutic↗
PubMed2004

Occurrence of neural tube defects and Down syndrome among siblings.

A recent study had reported increased risk of Down syndrome among siblings of Infants with neural tube defects (NTDs) and vice versa. However Hawaii Birth Defects Registry data indicate no elevated risk of Down syndrome among older siblings of infants with NTDs and vice versa, contradicting the findings of the previous study. Further investigation of the potential relationship is warranted.

Child↗
PubMed1977

Screening for fetal neural tube defects by maternal plasma alpha-fetoprotein determination.

A total of 5539 consecutive pregnant patients at three maternity units in the City and Hackney District of London were screened for fetal neural tube defect by measurement of maternal plasma alpha-fetoprotein (AFP) levels. Only 25-7% of women booked at 16 to 22 weeks, the optimum time for this screening test; 54-1% booked before 16 weeks and 20-2% after 22 weeks. Of the women tested before 23 weeks, 300 had elevated levels of AFP in plasma and 14 of them had fetuses with abnormalities known to cause a rise in AFP levels (12 fetuses had a neural tube defect and 2 had alimentary tract abnormalities). Of women examined before 23 weeks, half of those with twin pregnancies had elevated levels of plasma AFP as did 16-7% of those who ultimately had a spontaneous abortion.

Abortion, Spontaneous↗
PubMed2005

[Epidemiological study on reduced folate carrier gene(RFC1 A80G) polymorphism and other risk factors of neural tube defects].

OBJECTIVE: To study the reduced folate carrier gene (RFC1) A80G polymorphism and other factors influence on children with neural tube defects (NTDs) and provide the epidemiological evidence for finding genetic marker of NTDs. METHODS: RFC1(A80G) genotypes were detected using polymerase chain reaction-restriction fragment length polymorphism (RFLP-PCR) for blood DNA of 104 trios with NTDs-affected by child, and the 100 control families without child-affected by any birth defects. We performed the analysis of multifactors logistic regression for RFC1 genotypes and other factors in order to investigate the RFC1 genotype of the nuclear families and maternal periconceptional folic acid supplementation influence on NTDs independently. Transmission/disequilibrium test (TDT) for the RFC1 genotype of NTDs and control pedigree were carried out. RESULTS: The RFC1 G allele frequency of children with NTDs (64.42%) was higher than that of the control children (52.53%), and there was the significant difference between them (chi(2)=5.9198, P<0.05). We observed that the infants of the GG genotype were associated with a 2.56-fold increased risk of NTDs when compared with the AA genotype (95% CI=1.04-6.36), The risk of mothers who did not take folic acid for having an NTDs-affected infants was 7.69 (95% CI=2.86-21.75). There were significant differences between cases and controls in the other risk factors, such as paternal age (> or =30), maternal fever during the early pregnancy, the history of maternal spontaneous abortion. In the logistic regression analysis, of multifactors the three factors, for example, the offspring of the RFC1 GG genotype (OR=2.91, 95% CI=1.35-6.30), maternal periconceptional folic acid supplementation (OR=4.32, 95% CI=1.62-11.55), maternal fever during the early pregnancy, had the statistic significance for the risk of NTDs. There was the evidence of an association between G allele and the risk of the maternal having a child with NTDs (OR=1.56, 95% CI=1.07-2.28) in TDT analysis. CONCLUSION: Our findings indicate that the RFC1 genotype (GG) is a possible susceptible gene marker for an increased NTDs risk in this Chinese population, and there is a potential influence on the risk of NTDs in maternal periconceptional folic acid supplementation, and maternal fever during the early pregnancy.

Adult↗
PubMed1997

Are omphalocele and neural tube defects related congenital anomalies?: Data from 21 registries in Europe (EUROCAT).

We have analyzed the association between omphalocele and neural tube defects (O/NTD) previously reported in epidemiological studies of EUROCAT registry data [Dolk et al., 1991; Calzolari et al., 1995]. By examining differences in prevalence between the United Kingdom and Ireland (UKI) and Continental Europe and Malta (CEM) and differences in sex ratio, the possible etiopathogenetic differences between O/NTD association and omphalocele without NTD and NTD without omphalocele were investigated. The distribution of O/NTD cases according to NTD site in the two geographic areas shows in the UKI a tendency for omphalocele to associate with anencephaly/spina bifida and with anencephaly. In CEM centers, these types of NTD are much rarer. The pattern of other anomalies occurring in combination with O/NTD association in the same babies was also analysed.

Birth Rate↗
PubMed2001

Is the re-closure of surgically induced open neural tube defect the repetition of primary neurulation? An experimental study with chick embryos.

It is well known that surgically induced open neural tube defects (ONTDs) tend to re-close in early embryonic stages. To investigate whether the process of re-closure is a repetition of primary neurulation, the morphological changes of surgically induced ONTDs were chronologically examined in early chick embryos. Longitudinal incisions of 3-somite length were made in the neural tubes of chick embryos at Hamburger and Hamilton stage 18 or 19. About half of the embryos showed complete closure of the skin on surgical microscopic examination. The re-closed neural tubes showed no remarkable differences from the controls on histological examination. The process of re-closure involved a zipper-like (ventral to dorsal) closure in the transverse sections of neural tubes. The results indicate that the re-closure of surgically induced ONTDs does not repeat the process of natural primary neurulation.

Age Factors↗
PubMed2002

A polymorphism, R653Q, in the trifunctional enzyme methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthetase is a maternal genetic risk factor for neural tube defects: report of the Birth Defects Research Group.

Women who take folic acid periconceptionally reduce their risk of having a child with a neural tube defect (NTD) by >50%. A variant form of methylenetetrahydrofolate reductase (MTHFR) (677C-->T) is a known risk factor for NTDs, but the prevalence of the risk genotype explains only a small portion of the protective effect of folic acid. This has prompted the search for additional NTD-associated variants in folate-metabolism enzymes. We have analyzed five potential single-nucleotide polymorphisms (SNPs) in the cytoplasmic, nicotinamide adenine dinucleotide phosphate-dependent, trifunctional enzyme methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthetase (MTHFD1) for an association with NTDs in the Irish population. One SNP, R653Q, in this gene appears to be associated with NTD risk. We observed an excess of the MTHFD1 "Q" allele in the mothers of children with NTD, compared with control individuals. This excess was driven by the overrepresentation of QQ homozygotes in the mothers of children with NTD compared with control individuals (odds ratio 1.52 [95% confidence interval 1.16-1.99], P=.003). We conclude that genetic variation in the MTHFD1 gene is associated with an increase in the genetically determined risk that a woman will bear a child with NTD and that the gene may be associated with decreased embryo survival.

Aminohydrolases↗
PubMed1998

[Homocysteine-induced neural tube defects in chick embryos and protection of folic acid].

To reveal whether homocysteine(HCY) will be able to induce neural tube defects (NTDs) and possible teratogenic mechanisms, and identify the interventional effects of folic acid and vitamin B12 on HCY-induced NTDs, 1274 chick embryos treated with L. D-HCY (0-16 mumol/embryo) were detected by the methods of teratogenic trial, scanning electron microscopy(SEM), Nile blue sulfate vital staining, TdT-mediated dUTP nick end labeling(TUNEL) methylgreen-pyronine special staining for showing nucleic acid, and interventional assay of folic acid and VB12 in different developmental stage. Results showed that HCY could induce teratogenesis in chick neurulation and organogenetic period, in dose-response relationship (P < 0.0001). The main forms of NTDs were exencephaly, cranioschisis and spina bifida. It has been first found that HCY could target excessive apoptosis of cells of embryonic nervous system, which consists with the sites of embryos developing NTDs. HCY could inhibit chick yolk sac vessel formation and blood circulation, and damage amniotic membrane. Under SEM it was observed that HCY resulted in abnormal ultrastructures, for example cavernous damages, atrophied microvilli and so on. After the injection of 5 micrograms/embryo folic acid, the teratogenicity of HCY (8 mumol/embryo) was significantly antagonized, the occurrence rate of NTDs was down from 43.5% to 0(P < 0.05). However, vitamin B12 (1 microgram/embryo) did not obviously attenuate the teratogenicity of HCY in day 6 chick embryos. These data prove that HCY per se causes dymorphogenesis of the neural tube. Apoptosis may play an important role in the etiopathology of NTDs. Folic acid can effectively prevent from the homocysteine-induced NTDS. Causes of homocysteine-induced NTDs may result from interaction or combination of different mechanisms.

Animals↗
PubMed1983

Further experience of vitamin supplementation for prevention of neural tube defect recurrences.

In accordance with a previous protocol, a second cohort of 254 mothers with a history of previous neural tube defect (NTD) births was before a subsequent conception and continued until the time of the second missed menstrual period. There were 2 NTD recurrences (0.9% of 234 infants/fetuses examined), which is significantly fewer than the 11 NTD recurrences (5.1% of 215 infants/fetuses examined) born to 219 unsupplemented (US) mothers in the same centres over the same period. When the data for the two cohorts were combined, the overall recurrence rates were 0.7% for 454 fully supplemented (FS) mothers and 4.7% for 519 US mothers. The recurrence rates after 1 previous NTD were 0.5% for FS and 4.2% for US mothers: after 2 or more previous NTDs, 2.3% for FS and 9.6% for US. There were no recurrences among the offspring of a further 114 mothers whose duration of supplementation fell short of the full regimen (partially supplemented, PS).

Female↗
PubMed2002

SNPs in the CpG island of NAP1L2: a possible link between DNA methylation and neural tube defects?

Deletion of the murine X-linked Nap1l2 gene causes lethality from midgestation onwards. The affected embryos exhibit neural tube defects (NTDs) closely resembling spina bifida and anencephaly in humans. X-linked familial and spontaneous cases of NTD were analyzed for sequence alterations in the human NAP1L2. No differences were found in the familial cases. However, a number of single nucleotide polymorphisms (SNPs) within the 5' region of NAP1L2 were identified both in cases of spontaneous NTD and in normal controls. Most of these SNPs lead to the replacement of guanidines or cytosines within a CpG island that is conserved between the human and the mouse promoter regions. Demethylation in vitro activates Nap1l2 transcriptional activity, suggesting the importance of the CpG island in regulating the activity of the Nap1l2/NAP1L2 genes, and the potential importance of the polymorphisms in modifying their transcriptional activity. NAP1L2/Nap1l2 expression may therefore depend on the genetic-environmental factors that are frequently associated with NTDs.

Animals↗