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Mutant curly-tail mice are genetically predisposed to produce offspring with neural tube defects. Estimation of alpha-fetoprotein in the amniotic fluid of fetuses of these mutants has shown that the levels are raised in fetuses with exencephaly and open spina bifida. This suggests that these mice are a valid model for studies of the aetiology and genesis of neural tube defects in man.
An earlier preliminary paper is expanded. Women who had given birth to one or more infants with a neural tube defect were recruited into a trial of per conceptional vitamin supplementation. Two hundred mothers attending five centres were fully supplemented (FS), 50 were partially supplemented (PS), and 300 were unsupplemented (US). Neural tube defect recurrences in the study pregnancies were 1 (0.5%), in FS, none in PS, and 13 (4%) in US mothers. The difference in outcome between FS and US mothers is significant. The most likely explanation is that supplementation has prevented some neural tube defects, but further studies are needed.
Since the publication of randomised trials showing firm evidence of prevention of neural tube defects with periconceptional folic acid, there have been population health promotion programmes to encourage women to take folic acid supplements, and the introduction of voluntary fortification of some foods with folic acid in Australia. In order to evaluate these two strategies, we collected data by self-administered questionnaire from a random sample of recently pregnant women in Western Australia between September 1997 and March 2000. Response to health promotion was measured in three ways: (1) knowledge of the association between periconceptional folate and prevention of spina bifida (the 'correct message'); (2) use of periconceptional vitamin supplements of folic acid daily in the periconceptional period; and (3) daily folate intake from fortified foods in the 6 months before pregnancy. We examined the relationship of maternal demographic and behavioural characteristics with these three measures. Overall, 62.3% of women were aware of the correct message before pregnancy, 28.5% reported taking 200 microg or more of folic acid from supplements daily in the periconceptional period and 56.6% of women obtained 100 microg or more of folic acid from fortified foods. Women who first became aware of the correct message during pregnancy or who were unaware of the correct message before or during pregnancy were more likely than women aware before pregnancy to be younger, having their first pregnancy, be single or in a de facto relationship, have no tertiary education, and be a public patient. Similar associations were seen for women taking either no folic acid or < 200 microg of folic acid in supplements daily in the periconceptional period. There were no significant associations between these demographic variables and amount of folate obtained from fortified foods. Women who were unaware of the correct message and did not take folic acid supplements were more likely to have smoked, not to have engaged in exercise, and not to have planned their pregnancy, whereas there was no association with these behavioural characteristics and intake of folate from fortified foods. These results indicate that health promotion strategies have not reached all segments of the target population equally, but there is no such disparity with folate-fortified foods, and they suggest that mandatory fortification of a staple food is likely to reach all women regardless of demographic and behavioural characteristics, and hence provide improved opportunity for prevention of neural tube defects in Australia.
The present study was undertaken to examine the role of heat shock response in the development of tolerance and cross-tolerance in an in vivo murine model of teratogen-induced neural tube defects. The experimental paradigm designed to address this question was to utilize inbred mouse strains that differed in their sensitivity to hyperthermia and valproic acid induced neural tube defects, subjecting the dams to subteratogenic pretreatments with either heat or valproic acid at two different timepoints during development prior to the administration of the teratogenic insult. A statistically significant reduction in the frequency of neural tube defects and/or embryolethality following a pretreatment in dams subsequently exposed to a teratogenic treatment was considered evidence for the induction of tolerance. This was observed in the SWV embryos exposed to the 38 degrees C pretreatment at 8:06 and to embryos exposed to either pretreatment temperature at 8:10 prior to a teratogenic heat shock at 8:12. In the LM/Bc embryos, only the 41 degrees C pretreatment at 8:06 induced thermotolerance. There was no evidence of tolerance induced in either mouse strain using valproic acid. On the other hand, cross-tolerance was clearly demonstrated in this study, with a low temperature (41 degrees C) pretreatment successfully protecting SWV fetuses from a subsequent teratogenic treatment with valproic acid, while valproic acid (200 mg/kg) was effective in reducing the risk of hyperthermia-induced neural tube defects in the LM/Bc fetuses. In all instances, tolerance was induced in the absence of significant induction of hsp synthesis. The lack of concordance between hsps and thermotolerance suggests that some other factor(s) is involved in conferring thermotolerance on developing murine embryos.
OBJECTIVE: Folate deficiency in early pregnancy and maternal adiposity, independent of folate intake, lead to a greater risk of neural tube defects in infants. Atypical antipsychotics cause various degrees of weight gain. The authors assessed folate status and obesity among patients with schizophrenia receiving atypical antipsychotics. METHOD: A sample of 70 inpatients and outpatients (21 of them women) who were taking antipsychotics was randomly selected. Body weight, body mass index, daily folate intake, and folate serum concentrations were determined. RESULTS: The majority of the patients were overweight. Only eight of 37 patients had folate intake above 400 microg/day, the level shown to be protective against neural tube defects. Mean serum folate was significantly lower than in a general hospital group of 810 patients. CONCLUSIONS: Women with schizophrenia who take atypical antipsychotics have a higher risk of neural tube defects in their infants because of the associated low intake of folate and obesity.
The study aimed to find out how frequent is brain tissue aspiration and if brain tissue heterotopia could be found in the lung of human neural tube defect cases. Histological sections of each lobe of both lungs of 22 fetuses and newborn with neural tube defect were immunostained for glial fibrillary acidic protein (GFAP). There were 15 (68.2%) females and 7 (31.8%) males. Age ranged from 18 to 40 weeks of gestation (mean = 31.8). Ten (45.5%) were stillborn, the same newborn, and 2 (9.1%) were abortuses. Diagnosis were: craniorachischisis (9 cases, 40.9%), anencephaly (8 cases, 36,4%), ruptured occipital encephalocele and rachischisis (2 cases, 9.1% each), and early amniotic band disruption sequence (1 case, 4.5%). Only one case (4.5%) exhibited GFAP positive cells inside bronchioles and alveoli admixed to epithelial amniotic squames. No heterotopic tissue was observed in the lung interstitium. We concluded that aspiration of brain tissue from the amniotic fluid in neural tube defect cases may happen but it is infrequent and heterotopia was not observed.
OBJECTIVE: The coexistence of three neural tube defects (NTDs) in a single child is an exceptional event. A review of the literature revealed nine published "double" NTD cases, but no cases of "triple" NTDs have been reported to date. CASE REPORT: The rare case of a two-year-old boy with three distinct NTDs is presented. The boy had a 17x15x15-cm(3) parieto-occipital encephalocele, a small cervical myelomeningocele, and a 11x11x8-cm(3) thoracolumbar myelomeningocele. Hydrocephalus and Chiari II malformation accompanied the NTDs. All three lesions were surgically treated with good cosmetic results and satisfactory neurologic outcome. CONCLUSIONS: Current neural tube closure theories and models are reviewed in an attempt to better understand this extremely unusual coexistence. The multi-site closure model is clearly more useful in our understanding of NTDs.
OBJECTIVE: To investigate maternal and fetal folate and vitamin B12 concentrations in pregnancies affected by neural tube defects (NTD). DESIGN: Measurement of folate and vitamin B12 concentrations in amniotic fluid, fetal blood and maternal blood samples in midgestation. SUBJECTS: 32 women undergoing termination of pregnancy at 14-21 weeks gestation for social reasons (n = 24) or for fetuses with neural tube defects (n = 8). INTERVENTIONS: Fetoscopy before intra-amniotic injection of prostaglandins. RESULTS: In normal pregnancies there was a positive correlation between maternal and fetal serum folate, and the fetal serum and red blood cell folate concentrations were higher than the maternal. There were no differences in amniotic fluid, maternal blood or fetal blood folate concentrations between pregnancies with NTD and normal pregnancies. Although amniotic fluid vitamin B12 was lower in pregnancies with NTD, maternal serum vitamin B12 concentration was not reduced. CONCLUSION: In this small group of pregnancies with NTD at mid-gestation there is no evidence to suggest folate or vitamin B12 deficiency.
BACKGROUND: Folate deficiencies have been associated with many adverse congenital abnormalities. It is not clear, however, whether these defects are due to a folate deficiency or to an increase in homocysteine. Homocysteine has been shown to be teratogenic in the chicken-embryo model and it has been suggested that homocysteine-induced defects are mediated by inhibiting the N-methyl-D-aspartate (NMDA) receptor on neural crest cells. The majority of the teratology studies have been carried out using the chicken embryo model. In an effort to develop a murine model of homocysteine-induced neural tube defects, several inbred mouse strains were treated with homocysteine or the NMDA inhibitor MK801 and the fetuses examined for any induced-NTD. METHODS: Several in-bred mouse strains were administered homocysteine once on gestational day (GD) E8.5 or once daily on GD 6.5-10.5. Additionally, because homocysteine was been reported to mediate its effects through the NMDA receptor, the effect of MK801, an antagonist of this receptor, was also investigated. RESULTS: Regardless of the mouse treatment time, homocysteine failed to induce neural tube defects in our in-bred mouse strains. Homocysteine also failed to increase the number of neural tube defects in the splotch strain, regardless of the genotype. CONCLUSIONS: Irrespective of the mouse strain or treatment, homocysteine failed to induce neural tube defects in our mouse models, which is in contrast to what has been reported in the chicken embryo models.
The European Registration Of Congenital Anomalies and Twins (EUROCAT), a network of 40 European registries of congenital anomalies, has published a special report on the prevention of neural-tube defects by, periconceptional folic-acid supplementation in Europe. This report reviews the progress made in 17 European countries since i99I in terms of developing and implementing public health policies to raise periconceptional folate status. Data on the prevalence of neural-tube defects in 1980-2000 were also analysed. - At the beginning of 2002, 10 of the 17 countries had an official government recommendation that women planning a pregnancy should take folic-acid supplementation daily. Only 7 countries implemented official health-education initiatives. - Despite the various measures taken to date, the majority of women in all countries surveyed are not taking periconceptional folic-acid supplements. Even in the Netherlands, where the percentage of planned pregnancies is estimated at 85%, only 36% of women take folic-acid supplements during the advised period. - Overall, the number of neural-tube defects has not decreased in Europe. A slight decrease was seen in those countries with an official policy regarding periconceptional folic-acid supplementation. - It is clear from the report that more effective prevention of neuraltube defects could be achieved with folic-acid fortification of staple foods; this approach has led to a reduction in the prevalence of neuraltube defects in the US and Canada. This approach can also prevent the majority of neural-tube defects in unplanned pregnancies and reduce the socioeconomic differences in prevalence.
The observation of elevated maternal plasma homocysteine concentration in pregnancies affected by neural tube defects (NTD) suggests that folate metabolism may be disturbed in NTD cases. In addition, studies on the chick embryo suggest that hyperhomocysteinaemia may contribute directly to the development of NTD. In order to test the hypothesis that homocysteine may cause NTD, we cultured mouse embryos in the presence of homocysteine thiolactone during the period of cranial neural tube closure. At doses of 0.5 mM or above, exposure to homocysteine thiolactone caused growth retardation, blisters and abnormalities of somite development. Despite the teratogenic effects of homocysteine we did not detect any increase in the incidence of neural tube defects. Neither was there an effect on the incorporation of thymidine into DNA, a potential marker of alterations in the folate or homocysteine/methionine cycles. These observations suggest that homocysteine is unlikely to be a direct cause of NTD in humans. Rather, the elevated levels of homocysteine in human NTD pregnancies may reflect a disturbance in folate-related metabolism.
The aim of this study was to determine whether there is increased leakage of neuron-specific enolase (NSE) and S-100 protein into amniotic fluid in pregnancies with neural tube defects, since both these proteins are produced by neural tissue, and to compare the value of these substances for detecting such defects with that of the more conventional techniques of alpha-fetoprotein (AFP) and acetylcholinesterase (AChE) gel electrophoresis. Amniotic samples from 25 mid-pregnancies (15-17 weeks' gestation) with neural tube defects (14 with open spina bifida and 11 with anencephaly) and from seven mid-pregnancies with abdominal wall defects were compared with a control material consisting of 80 amniotic fluid samples from 80 consecutive mid-pregnancy amniocenteses, with normal karyotypes and AFP concentrations. All of the above cases of abnormalities were primarily detected through increased AFP levels in the amniotic fluid. Amniotic fluid samples from 13 pregnancies with fetuses with autosomal chromosomal abnormalities and seven amniotic fluid samples contaminated with blood were also included in the investigation. It is concluded from the results that the conventional AFP assay combined with AChE gel electrophoresis is the best method for screening amniotic fluid for neural tube defects and defects of the abdominal wall. Neither NSE nor S-100 assay alone proved to be superior for the detection of these cases in mid-trimester amniotic fluid. The S-100 assay, however, could give additional information in cases where AChE gel electrophoresis is not decisive; for example, in samples contaminated with blood.
OBJECTIVE: To determine the accuracy of antenatal ultrasound investigation in the detection of neural tube defects. DESIGN: Prospective study. SETTING: University Hospital Utrecht. METHOD: Specific ultrasound investigation was carried out in 739 patients at risk for carrying a fetus with a neural tube defect. RESULTS: The sensitivity of ultrasound investigation was 91.7%, the specificity 99.8%, the positive predictive value 84.6% and the negative predictive value 99.9%. CONCLUSION: In our view expert ultrasonographic examination with appropriate counselling is an acceptable alternative for patients with a moderately increased risk of having a foetus with NTD and sufficiently accurate to replace invasive diagnostic procedures.
Amniotic fluid cells from 31 pregnancies with fetuses having open neural tube defects (NTDs) and from 43 pregnancies with fetuses free of NTDs were studied with the use of the immunoperoxidase method for alpha-fetoprotein (AFP) and glial fibrillary acidic protein (GFAP). The authors also used cytochemical stains for endogenous peroxidase and nonspecific esterase activity. In cases of NTDs, macrophages were present in the amniotic fluid, and in the authors' system they showed intense immunoreactivity for both AFP and GFAP and showed very strong activity for peroxidase and nonspecific esterase, whereas the epithelial cells and red blood cells showed no activity. In six cases of anencephaly, sections from the margin of the cranial end of defective spinal cords at the aperture of the open lesion were also studied for AFP and GFAP. In these cases, AFP- and GFAP-positive cells were found, indicating the possible neural (glial) origin of a part of amniotic fluid macrophages. Although the determination of AFP levels in maternal blood and amniotic fluid is widely used in the prenatal diagnosis of NTDs, demonstration of AFP in amniotic fluid cells by means of immunocytochemistry has not been described.
Recent studies have resolved the debate over the role of vitamins in preventing neural tube defects. The British Medical Research Council trial demonstrated that 4 mg of folate daily, but not other vitamins, prevented 72% of recurrences. The Hungarian trial prevented neural tube defects in women who had not previously had affected children by giving multivitamins containing 0.8 mg of folate. The US Public Health Service currently recommends that women at risk for becoming pregnant take 0.4 mg of folate daily. Unfortunately, most pregnancies are unplanned, and women not planning to become pregnant may not follow this recommendation. Therefore, the US Food and Drug Administration is exploring methods of food fortification. Because large doses of folate have been reported to ameliorate B12 deficiency anemia while allowing neurologic damage to progress, and to cause electroencephalogram abnormalities in epileptics, it is important to plan fortification carefully and to monitor both toxicity and benefits.
The Lp mouse mutant provides a model for the severe human neural tube defect (NTD), cranio-rachischisis. To identify the Lp gene, a positional cloning approach has been adopted. Previously, linkage analysis in a large intraspecific backcross was used to map the Lp locus to distal mouse chromosome 1. Here we report a detailed physical map of this region. The interval surrounding Lp has been cloned in a yeast artificial chromosome (YAC) contig consisting of 63 clones spanning approximately 3.2 Mb. Fifty sequence tagged sites (STSs) have been used to construct the contig and establish marker order across the interval. Based on the high level of conserved synteny between distal mouse chromosome 1 and human 1q21-q24, many of these STSs were designed from expressed sequences identified by cross-screening human and mouse databases of expressed sequence tags. Added to other known genes in the region, a total of 29 genes were located and ordered within the contig. Seven novel polymorphisms were identified within the region, allowing refinement of the genetic map and a reduction in the size of the physical interval containing the Lp gene. The Lp interval, between D1Mit113 and Tagln2, can be spanned by two nonchimeric overlapping YACs that define a physical distance of approximately 1 Mb. Within this region, 10 potential candidate genes have been mapped. The materials and genes described here will provide a resource for the identification and further study of the mutated Lp gene that causes this severe neural tube defect and will provide candidates for other defects known to map to the homologous region on human chromosome 1q.
We previously reported that among neural tube defects (NTDs) with no known causes the ones that occur alone (singles) have different epidemiologic characteristics from those that occur in combination with other defects (multiples), suggesting an underlying causal heterogeneity. In this study, we compared family histories of 223 single NTD cases and 66 multiple cases ascertained through the Metropolitan Atlanta Congenital Defects Program (MACDP) between 1970 and 1979. Compared with siblings of multiples, siblings of singles had a higher precurrence rate for NTDs (2.0% vs. 0.0%) and for birth defects in general (10.9% vs. 3.0%). Furthermore, siblings of singles that were born within 2 years before the birth of the index case had a higher precurrence rate for NTDs (8.0% vs. 1.1%) and for major birth defects (20.0% vs. 2.9%) than had those born earlier. These results further suggest that NTDs are etiologically heterogeneous, depending on the presence of associated defects, and point to important environmental influences in the increased risk for birth defects among siblings of singles. Larger studies are needed to confirm these data and show that single and multiple NTDs have different recurrence rates, not only for NTDs but also for other birth defects.
Congenital malformations, including neural tube defects (NTDs), are significantly increased in the offspring of diabetic mothers. We previously reported that in the embryos of a mouse model of diabetic pregnancy, NTDs are associated with reduced expression of the gene Pax-3, which encodes a transcription factor that regulates neural tube development, and that reduced expression of Pax-3 leads to neuroepithelial apoptosis. In this study, we used three approaches to test whether glucose alone could be responsible for these adverse effects of diabetes on embryonic development. First, primary culture of embryo tissue in medium containing 15 mmol/l glucose inhibited Pax-3 expression compared with culture in medium containing 5 mmol/l glucose. Second, inducing hyperglycemia in pregnant mice by subcutaneous glucose administration significantly inhibited Pax-3 expression (P < 0.05), as demonstrated by quantitative reverse transcription-polymerase chain reaction assay of Pax-3 mRNA, and also increased neural tube apoptosis (P < 0.05). NTDs were significantly increased in glucose-injected pregnancies when blood glucose levels were >250 mg/dl (P < 0.002) but not in moderately hyperglycemic pregnancies (150-250 mg/dl, P = 0.37). Third, phlorizin administration to pregnant diabetic mice reduced blood glucose levels and the rate of NTDs. As seen with glucose-injected pregnancies, the rate of NTDs in phlorizin-treated diabetic pregnancies was related to the severity of hyperglycemia, since NTDs were significantly increased in severely hyperglycemic (>250 mg/dl) diabetic pregnancies (P < 0.001) but not in moderately hyperglycemic pregnancies (150-250 mg/dl, P = 0.35). These two findings, that elevated glucose alone can cause the changes in Pax-3 expression observed during diabetic pregnancy and that the NTD rate rises with significant increases in blood glucose levels, suggest that congenital malformations associated with diabetic pregnancy are caused by disruption of regulatory gene expression in the embryo in response to elevated glucose.