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PubMed2003

Management issues for women with epilepsy: neural tube defects and folic acid supplementation.

For infants exposed to antiepileptic drugs (AEDs) in utero, the risk for congenital malformations is approximately 4 to 6%, twice the rate reported in the general population. A variety of malformations have been reported in association with prenatal exposure to AEDs. However, a particular association of valproate and carbamazepine with neural tube defects (NTDs)--specifically, with spina bifida aperta (SB)--has been identified. The prevalence of SB is approximately 1 to 2% with valproate exposure and 0.5% with carbamazepine. Reported risk factors for NTDs include previous pregnancy with an NTD, maternal insulin-dependent diabetes mellitus, various nutritional deficiencies and occupational exposures, and high prepregnancy weight. Deficiencies of folate have been implicated in the development of birth defects, including NTDs. The value of periconceptional folic acid supplementation for women in the general population is accepted. However, it is unclear whether folic acid supplementation protects against the embryotoxic and teratogenic effects of AEDs because animal and human studies and case reports have shown variable results. Nevertheless, folic acid supplementation is recommended for women with epilepsy as it is for other women of childbearing age. Even with supplementary folic acid, women taking valproate or carbamazepine should undergo perinatal diagnostic ultrasound to rule out NTDs.

Adult↗
PubMed1983

Diagnostic effectiveness of ultrasound in detection of neural tube defect. The South Wales experience of 2509 scans (1977-1982) in high-risk mothers.

2509 pregnant women were investigated between April 1, 1977, and March 31, 1980 (study 1), and April 1, 1980, and March 31, 1983 (study 2), to assess the effectiveness of diagnostic ultrasound in the diagnosis of neural tube defect (NTD) in women judged to be at high risk of NTD on the basis of raised serum alpha-fetoprotein or family history, or of other congenital malformation. The detection rate (sensitivity) for anencephaly was 100% in both studies. The detection rate for open spina bifida (OSB) improved from 33% in study 1 to 80% in study 2, specificity rose from 96% to 99%, the false-positive rate dropped from 57% to 9%, and the false-negative rate fell from 1% to 0.3%. Diagnostic ultrasound is likely to be conducted with greater vigilance and subjected to greater scrutiny than routine ultrasound because the patients have already been selected as being at high risk, the operators are more experienced, and their apparatus is likely to be more refined than that used for routine ultrasound. It is unlikely that the effectiveness levels for detection of OSB of 80% observed in this study could be sustained if diagnostic ultrasound were to be offered to all pregnant women. Consideration will need to be given to the question of whether an improved OSB detection rate will be worth the additional cost incurred in providing diagnostic ultrasound for every pregnant woman.

Anencephaly↗
PubMed1988

Glutathione status and the incidence of neural tube defects elicited by direct acting teratogens in vitro.

Valproic acid (VPA), cytochalasin D (CD) and 7-hydroxy-2-acetylaminofluorene (7-OH-AAF) each caused abnormal closure of the anterior neuropore in rat embryos cultured in vitro in the absence of an exogenous bioactivation system. Morphological comparisons showed that although all three compounds prevented normal neural tube closure, each did so in a distinctive manner. Modulation of GSH in cultured rat conceptuses was evaluated to determine whether common responses occurred relative to the ability of different chemicals to elicit neural tube defects. Malformation incidence in embryos (10-14 somites) varied widely following exposure to CD (44%), 7-OH-AAF (29%) or VPA (17%). The incidence of CD-elicited malformations was increased by 50% following GSH depletion by L-buthionine-S, R-sulfoximine (BSO) and was decreased by nearly 60% when the cysteine pro-drug 2-oxothiazolidine-4-carboxylate (OTC) was added to the culture medium. GSH modulation also exerted significant effects on the incidence of abnormal neurulation caused by VPA or 7-OH-AAF. A relatively low incidence of open neural tubes produced by VPA or 7-OH-AAF alone was shown to be a function of the state of maturation in the embryos. Conceptuses cultured in the presence of VPA or 7-OH-AAF from an earlier gestational age (6-10 somites) showed 2-3 fold increases in the number of embryos with open neural tubes. Differential alterations in protein and DNA content were observed among embryos and yolk sacs after various treatments indicating possible differences in the site of embryotoxicity. These results demonstrate the role of GSH status on the capacity of three chemically diverse compounds to elicit abnormal neurulation in cultured rat embryos and suggest some possible mechanisms by which normal neurulation may be compromised.

2-Acetylaminofluorene↗
PubMed1990

Fallacies of international and national comparisons of disease occurrence in the epidemiology of neural tube defects.

Despite extensive research, little progress has been made in elucidating the etiologies of anencephalus and spina bifida. International and national distributions of disease occurrence have often been used as a basis for generating etiological hypotheses (e.g., potato blight, tea consumption, and zinc deficiency hypotheses). However, few of the epidemiological studies of neural tube defects (NTDs) have been conducted with scientific rigor in design, and most are of dubious validity, often with low precision in the estimates. This paper shows that the accepted geographic patterns of NTDs may be attributable to variations in the validity of studies used to describe these patterns. The nonuniformity in the duration and diligence of case ascertainment, the lack of a standardized nomenclature and classification, and the definition of the denominator remain principal problems in evaluating the epidemiology of NTDs. For example, the distinction between incidence and prevalence is not always made, and there is no consistency in the placement of the gestational boundary between late fetal deaths and spontaneous abortions. Findings are compared from studies conducted at different times, without due regard to the effect of secular trends, and using studies that have varying levels of case ascertainment. In etiological research, it is important to perform studies that are accurate and precise, but the literature used to define the spatial distribution of NTDs has often been accepted without due regard to the effect of these factors.

Anencephaly↗
PubMed2001

The curly tail mouse model of human neural tube defects demonstrates normal spinal cord differentiation at the level of the meningomyelocele: implications for fetal surgery.

The paralysis associated with lumbosacral meningomyelocele has been attributed both to myelodysplasia and to degeneration of the exposed neural tissue. Surgically created dysraphism shows that exposure of an intact spinal cord in a genetically normal animal results in degeneration of the normal nervous tissue and subsequent paralysis. Our objective was to study neuronal differentiation in the curly tail mouse mutant model, which develops lumbosacral meningomyelocele naturally and is a phenocopy of nonsyndromic human neural tube defects. Prenatal repair of meningomyelocele assumes that the normal neuronal differentiation program occurs despite failure of neurulation. Here we demonstrate that this most suitable animal model has normal differentiation of neuronal structures at the level of the meningomyelocele. TuJ1, an antibody to neuronal specific class III beta-tubulin, an early marker of neuronal differentiation, was used to stain paraffin-embedded sections of curly tail mouse embryo meningomyelocele. Embryos were examined at embryonic day 13.5 (E13.5). The inbred mouse strain, C57BL6/J, which is genetically similar to the curly tail mouse, was used as a control in these studies. We show that early neuronal differentiation appears intact within the meningomyelocele. TuJ stains structures within the open neural tube. Motor neurons are present in the ventral horn and ventral roots. Dorsal root ganglia are present and of similar size to controls. The staining pattern is similar to that seen in the C57BL/6J control mouse, although dorsal structures are laterally displaced in the curly tail meningomyelocele. Based on this model, fetal surgery to repair human meningomyelocele may preserve neurological function in those cases where there is not an inherent genetic defect of the neural tissue.

Animals↗
PubMed1977

Maternal serum-alpha-fetoprotein measurement in antenatal screening for anencephaly and spina bifida in early pregnancy. Report of U.K. collaborative study on alpha-fetoprotein in relation to neural-tube defects.

Nineteen centres collaborated in a study to determine the efficiency of maternal serum-alpha-fetoprotein (A.F.P.) measurement as a method of screening for neural-tube defects (N.T.D.S.) between 10 and 24 weeks of pregnancy. Data were collected on 18 684 singleton pregnancies and 163 twin pregnancies without fetal N.T.D.s, and on 301 singleton pregnancies with fetal N.T.D.s (146 with anencephaly, 142 with spina bifida, and 13 with encephalocele). The best time for detecting open spina bifida by measuring maternal serum-A.F.P. is at 16-18 weeks of pregnancy. In clinical practice, serum-A.F.P. cut-off levels expressed as multiples of the normal median may be more convenient to use than percentiles because they are easier to derive and more stable. Also, the proportion of affected pregnancies with serum-A.F.P. levels exceeding a given multiple of the median is unlikely to vary significantly from centre to centre or over time. In contrast, the proportion of unaffected pregnancies with A.F.P. levels exceeding a given multiple of the normal median will vary depending on the precision with which serum-A.F.P. and gestation are measured. At 16-18 weeks of pregnancy 88% of cases of anencephaly, 79% of cases of open spina bifida, and 3% of unaffected singleton pregnancies had A.F.P. levels equal to or greater than 2-5 times the median for unaffected singleton pregnancies. At this gestation age the numbers of unaffected pregnancies with A.F.P. levels above 2-5 times the normal median can be reduced by about a third if women with borderline A.F.P. levels are retested, although this would not greatly change the detection-rate of affected pregnancies. In the United Kingdom as a whole, women with serum-A.F.P. levels above 2-5 times the normal median at 16-18 weeks of gestation will have an approximately 1-in-20 chance of having a fetus with open spina bifida; the risk of having any N.T.D. will be approximately 1 in 10. The results of this study indicate that screening pregnant women by measuring the concentration of A.F.P. in their serum is an effective method of selecting women for ultrasonography and amniocentesis so that N.T.D.s can be diagnosed in utero.

Anencephaly↗
PubMed2000

Reproductive factors, subfertility, and risk of neural tube defects: a case-control study based on the Oxford Record Linkage Study Register.

Periconceptual exposure to subfertility treatments is increasingly common, raising concerns about the possibility of malformations in the offspring. The authors conducted a case-control study to determine whether subfertility or its treatment was associated with increased risk of neural tube defects (NTDs). Cases were 694 women diagnosed with an NTD-affected pregnancy in Oxfordshire or West Berkshire, England, between 1970 and 1987. Cases were individually matched on maternal year of birth and year of index pregnancy to controls randomly selected from a computerized database. Data on demographic, reproductive, and obstetric factors were abstracted from patient hospital records. Overall, the period prevalences of subfertility and of subfertility treatment were 7% and 3%, respectively, No evidence was found that the risk of NTD-affected pregnancies was increased by either subfertility (odds ratio (OR) = 1.2, 95% confidence interval (CI): 0.7, 2.1) or its treatment (OR = 0.9, 95% CI: 0.4, 2.0). After adjustment, NTD-affected pregnancies were associated with female offspring (OR = 2.3, 95% CI: 1.8, 3.1), multiple birth (OR = 4.8, 95% CI: 1.2, 18.8), and higher numbers of pregnancies (p for trend = 0.005). The findings from this large, population-based study were wholly consistent with those from smaller studies that found no increased risk of NTD associated with exposure to fertility treatments but reported associations with various pregnancy outcomes.

Adult↗
PubMed2003

Genetic determinants of folate and vitamin B12 metabolism: a common pathway in neural tube defect and Down syndrome?

One-carbon metabolism is under the influence of folate, vitamin B12 and genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR 677 C --> T and 1298 A --> C), of methionine synthase (MTR 2756 C --> G), methionine synthase reductase (MTRR 66 A --> G) and transcobalamin (TCN 776 C --> G). The pathogenesis of neural tube defect (NTD) may be related to this metabolism. The influence of the MTHFR 677 C --> T polymorphism reported in The Netherlands and Ireland can be questioned in southern Italy, France and Great Britain. MTRR, combined with a low level of vitamin B12, increases the risk of NTD and of having a child with NTD in Canada, while TCN 776 GG and MTRR 66 GG mutated genotypes associated with the MTHFR 677 CC wild-type are predictors of NTD cases in Sicily. Down syndrome (DS) is due to a failure of normal chromosomal segregation during meiosis, possibly related to one-carbon metabolism. MTHFR 677 C --> T and MTRR 66 A --> G polymorphisms are associated with a greater risk of having a child with DS in North America, Ireland and The Netherlands. In contrast, MTHFR 677 C --> T has no influence on DS risk in France and Sicily, while homocysteine and MTR 2756 AG/GG genotypes are predictors of DS risk in Sicily. In conclusion, NTD and DS are influenced by the same genetic determinants of one-carbon metabolism. The distinct data produced in different geographical areas may be explained by differences in the nutritional environment and genetic characteristics of the populations.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1989

Survey of neural tube defects in spontaneously aborted embryos.

Although variations in the incidence and types of central nervous system abnormalities have been demonstrated between early and late pregnancy, the reason for this finding has not yet been determined. Among 569 spontaneously aborted embryos, we describe 38 central nervous system lesions, many of which are different from those observed at birth. The importance of correlating morphology and cytogenetic studies in the understanding of pathogenesis of embryonic neural tube defects is emphasized.

Abortion, Spontaneous↗
PubMed1998

Exploring gene-gene interactions in the etiology of neural tube defects.

The role of susceptibility genes in the etiology of birth defects is unclear, but may involve in some cases multiple alleles at multiple loci. We suggest a simple epidemiologic approach to explore gene-gene interactions, and use it to reevaluate data from a recent case-control study on the possible association of neural tube defects (NTDs) with specific mutations of two genes, 5,10-methylene-tetrahydrofolate reductase (MTHFR) and cystathionine-beta synthase (CBS). We found that, compared with the common genotype, homozygosity for the MTHFR mutation alone was associated with a two-fold increased risk for NTDs, while homozygosity for the CBS mutation alone was not a risk factor. However, homozygous individuals for the mutations at both loci had a five-fold greater risk for NTDs than those with the reference genotype. Though the original study was too small to detect statistically significant differences among most of the risk estimates, these results, if confirmed by independent and larger studies, suggest that gene-gene interaction may play a role in modulating the susceptibility to NTDs in a proportion of affected individuals. This approach, moreover, could be a valuable adjunct to the study of gene gene interactions in the etiology of human disease.

Cystathionine beta-Synthase↗
PubMed2007

Fetal anomaly scan potentially will replace routine AFAFP assays for the detection of neural tube defects.

OBJECTIVES: Introduction of the second-trimester fetal anomaly scan and the decision to offer this scan to every woman in the 18th-22nd week of pregnancy necessitates a re-evaluation of the diagnostic value of the measurement of alpha-fetoprotein (AFP) concentrations in the amniotic fluid (AF) for the detection of neural tube defects (NTDs). METHODS: In this study of 6501 women who underwent amniocentesis, amniotic fluid AFP (AFAFP) concentrations were measured. The women were divided into three categories: group I, without any increased risk of fetal NTD (N = 6188); group II, with an increased risk of fetal NTD (N = 258); and group III, with a clinically diagnosed fetal NTD with known AFAFP concentrations (N = 55). RESULTS: In 27 women of group I (0.4%), the MoM (multiple of the median) level was > 2.5 times the median AFP concentration for the corresponding gestational age, and in two fetuses this was related to NTD. In two pregnancies of group II (0.8%), an increased AFAFP was related to NTD. In group III, 44 of the 55 (80%) samples had an increased AFAFP. CONCLUSION: In the near future, it is likely that imaging will replace AFAFP assays for the detection of fetal NTDs because high quality ultrasound imaging will detect NTDs accurately.

Amniocentesis↗
PubMed1988

Amniotic fluid folate, vitamin B12 and transcobalamins in neural tube defects.

Levels of folate, vitamin B12, the vitamin B12 binding proteins, apotranscobalamin I, II and III (TC I, II and III) and the unsaturated vitamin B12 binding capacity (UBBC) were measured in mid-trimester amniotic fluids from normal pregnancies, and from those where the fetus had open spina bifida, anencephaly or omphalocoele, and where the fetus was normal but the mother had had a previous neural tube defect pregnancy. At 15-19 weeks' gestation, vitamin B12 levels were low in the fluids of all the types of abnormal fetuses, and also of normal fetuses where there had been a previous NTD sib. In contradistinction, TC I, II and III and UBBC levels were generally abnormally high in all these groups. Low vitamin B12 levels in the face of high carrier protein levels suggest deranged vitamin B12 production or transport. Since these abnormalities are present in fluids from normal sibs of NTD individuals as well as from those with midline lesions, an inherited defect is implied. We propose that at least part of the genetic predisposition to NTD, and possibly other midline defects, could reside in an abnormality connected with vitamin B12 production, transport or metabolism, and a mechanism is suggested.

Amniotic Fluid↗
PubMed2001

Maternal obesity and risk of neural tube defects.

QUESTION: One of my patients is taking olanzapine for schizophrenia. She has gained a lot of weight, which, I understand, often happens with some of the new atypical antipsychotics. Due to her weight gain, she failed to notice she had become pregnant. Is she at risk? ANSWER: Experience with olanzapine is relatively slight, but available prospective data do not show increased teratogenic risk. Adiposity, on the other hand, is associated with increased risk of neural tube defects. Only some of this risk can be reduced by folate supplementation.

Antipsychotic Agents↗
PubMed2006

Using record linkage and manual follow-up to evaluate the Victorian maternal serum screening quadruple test for Down's syndrome, trisomy 18 and neural tube defects.

OBJECTIVES: The Genetic Health Services Victoria maternal serum screening (MSS) quadruple test has been available to pregnant women in Victoria since 1996. The objectives of this study were to follow up the pregnancies screened by MSS between July 1998 and June 2000 and to determine the performance characteristics of the test for Down's syndrome, trisomy 18 and neural tube defects (NTDs). METHODS: MSS results were matched to pregnancy outcome information from the Perinatal Data Collection Unit and Birth Defects Register, using automated probabilistic record linkage. For unmatched pregnancies, manual follow-up was carried out by contacting referring doctors and hospitals, resulting in a very high follow-up rate of 99.2% (18,989/19,143). RESULTS: The sensitivity of MSS for Down's syndrome was 85% (23/27-95%CI 72-99%) with a falsepositive rate (FPR) of 6.8% (risk threshold >or= 1 in 250). While using a fixed 5% FPR, the sensitivity for Down's syndrome was slightly lower (78%). The sensitivity for trisomy 18 was 44% (4/9 - 95% CI 12-77%) with a FPR of 0.5% (risk threshold of >or= 1 in 200). 11 of the 15 (73 - 95%CI 51-97%) cases of open NTDs were detected from screening, with a 1% FPR (risk threshold alpha-fetoprotein [AFP] >or=2.5 MoM). All cases of anencephaly had increased AFP levels. CONCLUSION: Probabilistic record linkage and manual follow-up is an efficient method for ascertainment of pregnancy outcomes, with a higher follow-up rate than that reported in similar studies. MSS should remain an available option for all pregnant women in Victoria, with test characteristics comparable with other recent reports of the quadruple test.

Adult↗
PubMed2003

Somites, spinal Ganglia, and centra. Enumeration and interrelationships in staged human embryos, and implications for neural tube defects.

Serial sections of 99 human embryos from Carnegie stages 8-23 were investigated and 38 graphic reconstructions were evaluated. At stage 9 somite 1 is of appreciable size and is separated from the otic disc, as also in the next several stages by rhombomeres and pharyngeal arches 3 and 4, thereby differing from the chick. At stage 10 somite 1 begins to differentiate into sclerotome and dermatomyotome. At stage 11 spinal neural crest begins to develop. At stage 12 parts of somites 1-4 are being transformed into the hypoglossal cell cord. It is stressed that the numbers of somites present at stages 9-12 are part of the definition of those stages. At stage 13 dense and loose zones begin to be detectable rostrally in the sclerotomes and also, although out of phase, in the perinotochord. Spinal ganglia begin to develop in phase with the somites. At stages 14-16 the maximum number of somites observed was 38-39 rather than 42-44, as usually given. Moreover, they did not extend to the tapered end of the trunk, which is not a (vertebrated) 'tail'. At stages 17-23 the maximum number of centra was 38-39, including coccygeal vertebrae 4-5. Although most of the somites appear during primary development, all of the spinal ganglia develop during secondary development (stages 13-18). The number of ganglia was at a maximum of 35 at stage 18, but was reduced to 32 already by stage 23. Important points confirmed in this study are that the number of occipital somites in the human is four, and that the level of final closure of the caudal neuropore is future somite 31, which represents approximately future sacral vertebra 2. The interpretation of relevant neural tube defects is discussed in the light of the findings. The ascensus of the conus medullaris during the fetal period is well established, but a concomitant ascent of the situs neuroporicus is proposed here, and has implications for defects that involve tethering of the spinal cord. The main results are integrated in comprehensive graphic representations of the levels and the interrelationships of (a) somites and centra, and (b) somites, neural crest, and spinal ganglia. These may aid in the elucidation of some frequently occurring anomalous conditions.

Embryonic and Fetal Development↗
PubMed1987

Determination of maternal serum acetylcholinesterase in pregnancies with fetal neural tube defects.

We have investigated the occurrence of acetylcholinesterase (AChE) (E.C. 3.1.1.7) in fetal serum, amniotic fluid and maternal serum using an immuno-chemical assay-technique employing both polyclonal and monoclonal antibodies. Fetal serum had increased amounts of AChE, which is due to an increase in the 10.5S form of the enzyme. This form was also found in amniotic fluids of pregnancies with a fetal neural tube defect (NTD), but not in normal amniotic fluid. The increase in amniotic fluid AChE was however, not reflected in the maternal serum.

Acetylcholinesterase↗
PubMed2004

Chronic sorrow and depression in parents of children with neural tube defects.

Chronic sorrow has been described in the caregivers of individuals with myelomeningocele, multiple sclerosis, Parkinson's disease, cancer, and premature infants. Most studies have reported small numbers of fathers for comparison with mothers. One unpublished study compared chronic sorrow and depression. The purpose of the current study was to describe parental chronic sorrow following the birth of a child with neural tube defect and to explore the relationship between chronic sorrow and depression. One hundred and thirty-two parents (63 mother/father pairs and 6 single parents) responded to 3 measures of chronic sorrow and 1 measure of depression. Multivariate analysis of variance demonstrated significant differences between mothers and fathers in chronic sorrow. In addition, a relationship between chronic sorrow and depression was demonstrated. Chronic sorrow is a potential barrier to parental understanding of their child's care and diagnosis. Based on these findings, separate assessments of each parent and timely interventions are warranted. Further research should include more than 1 measure of chronic sorrow and delineate the dimensions being measured.

Adaptation, Psychological↗
PubMed1984

Neural-tube defects produced in Syrian hamsters by potato glycoalkaloids.

Keeler et al. (78) showed that potato sprouts could be teratogens for the central nervous system in the Syrian hamster. We demonstrate here the same teratogenic effect from a British cultivar, Arran Pilot. Most of the activity was traced to the two solanidine triglycosides, alpha-chaconine and, at a higher dose level, alpha-solanine. Some possible implications for the study of human neural-tube defects are considered.

Abnormalities, Drug-Induced↗