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Induction of neural tube defects and skeletal malformations in mice following brief hyperthermia in utero.

Hyperthermia was induced in ICR mice on day 8.5 of gestation by immersing them in hot water. Control mice were immersed in water at 38 degrees C for 15 min. In dams exposed to 42 degrees C for 12.5-15 min or to 43 degrees C for 7.5-10 min, externally malformed fetuses increased significantly and in a dose-related manner. Anterior neural tube defects (exencephaly, anencephaly, encephalocele, and cranial neural tube defect with facial cleft) were induced most frequently. Embryonic and fetal death and skeletal malformations also increased following heat stress. At intervals after heat exposure, sections of embryonic prosencephalon were prepared for light microscopy. At 2 h after heat stress, mitotic figures disappeared almost completely in embryonic tissues. Mitotic activity was inhibited for at least 3 h. At 6 h, there was a burst of new mitotic activity. Some damaged cells became pyknotic and abnormal cells were encountered in the neuroepithelial tissue after 3-12 h. Thus, neural tube defects in mouse embryos following maternal hyperthermia may result from a temporary cessation of cell proliferation and partial necrosis of the embryonic neuroepithelium.

Animals↗

Common hierarchies of susceptibility to the induction of neural tube defects in mouse embryos by valproic acid and its 4-propyl-4-pentenoic acid metabolite.

The teratogenic effects of valproic acid and its 4-propyl-4-pentenoic acid (4-en) metabolite were investigated in three inbred mouse strains that were known to possess differing sensitivity to heat-induced neural tube defects. In the heat-resistant DBA/2J strain, administration of either valproic acid or the metabolite during the critical period of neural tube development failed to produce any abnormal offspring. Similar treatment in the moderately heat-sensitive LM/Bc strain resulted in up to 19.8% exencephalic fetuses. The highly heat-sensitive SWV strain was also very susceptible to the induction of neural tube defects by either valproic acid or its 4-en metabolite. When administered on gestational day 8 plus 12 hours, the parent compound produced 35% exencephalic fetuses, while the metabolite had a response frequency of 32.4%. Thus, the hierarchy of susceptibility for the induction of neural tube defects in these inbred mouse strains was exactly the same whether the teratogen was a physical agent such as hyperthermia or a chemical compound such as valproic acid. If such diverse agents as these should interact to produce malformations, then it is possible that a wide variety of other agents might interact in a similar manner to produce neural tube defects.

Animals↗

The relationship of supplemental iodine to neural tube defects in Rochester, New York, 1924-1932.

The geographic distribution of infants born with anencephaly and spina bifida in Rochester, New York, in 1924-1932, was examined to test the hypothesis that iodine supplemented water may have reduced the prevalence of these defects. During this period the region had a high prevalence of iodine deficiencies. Comparing the prevalence of neural tube defects in an area with iodine supplemented water to one without iodine supplementation, we found no significant difference in prevalence at birth of neural tube defects. Because the prevalence rates for these defects in children of foreign-born parents (except the Irish) was low, we reexamined the data, excluding these cases. There remained no differences in rates. Iodine supplemented water thus appears to have had no effect on the occurrence of neural tube defects.

Adult↗

Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. MRC Vitamin Study Research Group.

A randomised double-blind prevention trial with a factorial design was conducted at 33 centres in seven countries to determine whether supplementation with folic acid (one of the vitamins in the B group) or a mixture of seven other vitamins (A,D,B1,B2,B6,C and nicotinamide) around the time of conception can prevent neural tube defects (anencephaly, spina bifida, encephalocele). A total of 1817 women at high risk of having a pregnancy with a neural tube defect, because of a previous affected pregnancy, were allocated at random to one of four groups--namely, folic acid, other vitamins, both, or neither. 1195 had a completed pregnancy in which the fetus or infant was known to have or not have a neural tube defect; 27 of these had a known neural tube defect, 6 in the folic acid groups and 21 in the two other groups, a 72% protective effect (relative risk 0.28, 95% confidence interval 0.12-0.71). The other vitamins showed no significant protective effect (relative risk 0.80, 95% Cl 0.32-1.72). There was no demonstrable harm from the folic acid supplementation, though the ability of the study to detect rare or slight adverse effects was limited. Folic acid supplementation starting before pregnancy can now be firmly recommended for all women who have had an affected pregnancy, and public health measures should be taken to ensure that the diet of all women who may bear children contains an adequate amount of folic acid.

Abortion, Induced↗

Neural tube defects and elevated homocysteine levels in amniotic fluid.

OBJECTIVE: Our purpose was to study maternal blood and amniotic fluid concentrations of homocysteine and relevant vitamins in relation to neural tube defects. STUDY DESIGN: Concentrations of total homocysteine, folate, and vitamins B12 and B6 were measured in maternal blood and amniotic fluid of 27 women carrying a fetus with a neural tube defect and 31 control women carrying a healthy fetus. RESULTS: The mean total homocysteine concentration in amniotic fluid of the study group was significantly higher than that of the control group. The mean concentrations of total homocysteine in blood and the vitamins folate, B12, and B6 in, respectively, blood and amniotic fluid were not significantly different between the groups. The mean concentrations of homocysteine and vitamin B6 were significantly lower in amniotic fluid than in blood in both groups, whereas vitamin B12 in amniotic fluid was higher than in blood. CONCLUSION: These results support the hypothesis that at least the cause of a subset of neural tube defects could reside in a primary or secondary maternal or fetal derangement of homocysteine metabolism.

Adult↗

Puerto Rican primary physicians' knowledge about folic acid supplementation for the prevention of neural tube defects.

BACKGROUND: We conducted a study of a group of primary physicians in Puerto Rico to evaluate their knowledge about folic acid supplementation to prevent neural tube defects. METHOD: The study design was transverse-correlational. A total of 66 primary physicians in two hospitals (public and private) participated in the study. The sample was nonrandom and opportunistic, and only those physicians present in the hospitals at the moment of distribution of the questionnaires participated. A self-administered and anonymous questionnaire was used. Descriptive statistics and cross-tabular analysis were used to describe the results of this study. Inferential statistics were also used, including Chi square and t-tests to establish the associations/differences between physician knowledge and the independent variables. RESULTS: Of the participants, 87.9% demonstrated an inadequate knowledge about folic acid supplementation for the prevention of neural tube defects as part of preconception care and only 12.1% demonstrated adequate knowledge. Older physicians had greater knowledge about folic acid. Also, women demonstrated greater knowledge about folic acid than did men. Most of the physicians who always recommend supplementation to their patients demonstrated a greater knowledge about folic acid, and all participants with adequate knowledge came from the public hospital. CONCLUSIONS: Despite a concerted effort by the Health Department of Puerto Rico to provide education in the importance of folic acid supplementation to reduce the incidence of neural tube defects, primary physicians in two Puerto Rican hospitals generally have not availed themselves of this training and showed a lack of knowledge on this important clinical issue.

Adult↗

[Prenatal detection of open neural tube defects in a mass screening program by determination of alpha-fetoprotein concentration in maternal serum].

A partially automatized ultramicroencymimmunoassay developed by the GDR and Cuba should be tested in a mass screening for the prenatal detection of open neural tube defects by measurement of maternal alphafetoprotein concentration (MS-AFP). In the screening program 24,271 pregnant women were included (Berlin/District of Schwerin). In 18,144 patients AFP-concentration in maternal serum was measured as a routine procedure in the care for all pregnant women of the district of Schwerin. The time of MS-AFP determination in this connection was limited from 15th to 18th completed gestational week. 1986 already in 84.9 per cent of all pregnant women of the district of Schwerin MS-AFP concentration could be measured in early pregnancy. The detective rate of open neural tube defects among 24,271 tested pregnant women was 86.1 per cent. AFP concentration was expressed in ng/ml and the "cut off" was set at 2.0 MOM. Infants born with open neural tube defects were reduced by 75 per cent under the conditions of MS-AFP screening. Better results are possible in connection with a progress in the qualification of the following diagnostic steps, if MS-AFP-levels are elevated. Not unexpected and unspecific MS-AFP-elevation was found in connection with twin pregnancies and a higher risk of abortion and the delivery of infants with very low birth-weight less than 1,500 g. A general MS-AFP-screening is recommended for prenatal detection of open neural tube defects all over the country.

Anencephaly↗

Prevalence of neural tube defects in 16 regions of Europe, 1980-1983. The EUROCAT Working Group.

A total of 1633 cases of neural tube defects were analysed, registered between 1980 and 1983 in liveborn and stillborn babies and in fetuses aborted as a result of prenatal diagnosis of malformation in 16 EUROCAT Registries (total births = 766,603). A clear geographical pattern was observed. The highest neural tube defect (NTD) rates were seen in Dublin (Ireland), Belfast (UK) and Glasgow (UK) with 40 cases per 10,000 births and in these centres there was a significant decrease in prevalence over the years. In Galway (Ireland) and Liverpool (UK), the rates were approximately 20 cases per 10,000 births, the rate decreasing over years in Liverpool. In the registries situated in continental Europe, the prevalence varied between 6 and 13 cases per 10,000 births and there was no apparent change in the prevalence with time. The spina bifida/anencephaly ratio and the male proportion among the NTD cases were both lower in the British Isles than in continental Europe. Cases of prenatal diagnosis of NTD resulting in termination of pregnancy formed 19% of the total NTD cases, this proportion increasing over years. A large variation between centres was seen in the effectiveness of prenatal screening for NTD.

Abortion, Induced↗

Improved discrimination in the detection of neural tube defects: five biochemical tests compared.

Five biochemical tests, which have been proposed as possible adjuncts to the measurement of amniotic fluid alphafetoprotein for the identification of neural tube defects, have been measured in 49 normal and 46 neural tube defect affected pregnancies. One test, the alphafetoprotein component non-reactive with concanavalin A, was ineffective in differentiating normal and abnormal. The remaining four procedures, the activity of acetyl and total cholinesterase, the concentration of alpha 2 macroglobulin and the electrophoretic identification of acetyl cholinesterase effectively separated the normal and abnormal populations. The relative merits of these four latter tests in the evaluation of false positive and false negative amniotic fluid alphafetoprotein results, as well as in liquor samples with high alphafetoprotein levels associated with abnormalities not of neural origin, are discussed.

Abortion, Missed↗

Effect of estimating gestational age by ultrasound cephalometry on the specificity of alpha-fetoprotein screening for open neural-tube defects.

A total of 1268 women had a maternal serum alpha-fetoprotein (AFP) screening test for open neural-tube defects between 15 and 22 weeks gestation and a routine ultrasound examination at their first antenatal visit. All had a singleton infant without a neural-tube defect. AFP values were expressed as multiples of the normal median at the relevant gestational age (MoM). The percentage of women with raised maternal serum AFP levels was less when gestation was estimated by the fetal biparietal diameter (BPD) than when the time since the first day of the last menstrual period (LMP) was used; 1.8% compared with 2.3% at a serum AFP cut-off level of 2.5 MoM. Different ultrasound policies were compared for their effect on AFP screening and the best was found to be routine BPD measurement used together with a higher cut-off level than usual. For example, using a cut-off level of 3.0 MoM the detection rate for open spina bifida at 16-18 weeks gestation would be about 88% and the proportion of unaffected singleton pregnancies with raised levels only 0.9%. These results are materially better than those achieved by a policy of scanning only those women with a raised AFP level (79% and 1.4% respectively with a more conventional cut-off level of 2.5 MoM) or, in addition, scanning those with doubtful gestational ages (82% and 1.7% respectively with a cut-off level of 2.5 MoM).

Cephalometry↗

[Plasma and red blood cell folate levels among women in their first trimester of pregnancy from rural areas with high or low prevalence of neural tube defects, China].

OBJECTIVE: To compare plasma and red blood cell folate levels among women in their first trimester of pregnancy from rural areas with high or low prevalence of neural tube defects. METHODS: A cross-sectional study was performed, among women in their first trimester of pregnancy from rural areas with high or low prevalence of neural tube defects in 2003. Non-fasting blood sample were collected and analyzed for plasma and red blood cell folate concentrations for 688 women. RESULTS: The median plasma (10.53 nmol/L) and red blood cell folate (389.2 nmol/L) among women from the high prevalence rural area were lower than those of women from the low prevalence rural area (plasma folate: 30.39 nmol/L, red blood cell level folate: 926.0 nmol/L). Among women from the high prevalence area, about 50% and 43% were respectively, deficient for plasma and red blood cell folate, compared with 6% and 4% respectively, for women from the low prevalence area. The median plasma folate levels among women who took periconceptional folic acid supplements in both high and low prevalence areas were about twice higher than those who did not take the folic acid. The median red blood cell folate level of the folic acid users was 40% higher than those of the non-users. Among those who took folic acid, women in the low prevalence area had 70%-90% higher plasma folate concentration and twice higher red cell folate concentration than women in the high prevalence area. CONCLUSION: Women from the rural area with a high prevalence of neural tube defects had low plasma and red blood cell folate levels. Periconceptional supplementation with folic acid could substantially improve folate status of reproductive-aged women. However, supplementation with 0.4 mg of folic acid per day might be inadequate for women in the high prevalence rural area.

Dietary Supplements↗

Epidural analgesia for labour in a patient with a neural tube defect.

This report describes the use of epidural analgesia in a patient with a known neural tube defect. The patient had a severe form of spina bifida cystica which had been operated on in childhood. She had a neurogenic bladder but otherwise had preserved neurological function. She had an epidural catheter inserted in early labour; providing effective analgesia for an uneventful birth. This case outlines the severity of the cystica category of neural tube defects, the added anatomical challenges of previous surgery and the difficulties that may arise from the utilization of epidural analgesia. The case demonstrates that epidural analgesia can be utilized despite such a disorder A thorough history and examination are essential, as are the patient's informed consent and knowledge of possible complications.

Adult↗

[Maternal age and neural tube defects: evidence for a greater effect in spina bifida than in anencephaly].

BACKGROUND: Recent evidence from birth order data suggest that maternal factors can differently influence anencephaly and spina bifida. AIM: To study the influence of maternal age on the risk for neural tube defects. MATERIAL AND METHODS: A meta-analysis of published data on neural tube defects (NTDs) was carried out to determine whether there is an increased risk to have a child with NTDs for younger and older mothers and if this risk differs depending on the type of NTD. All data available with information regarding the frequency of live births and NTDs cases by maternal age (five- or ten-year intervals) were included in the analysis. Effect sizes calculations were performed. RESULTS: The analysis supports the hypothesis that there is an increased risk of having an offspring with NTDs for mothers 40 years of age or older. However, this effect is stronger for spina bifida than for anencephaly. There is also evidence that mothers 19 years old or younger have a higher risk for having a child with spina bifida. CONCLUSIONS: Maternal age influences the risk of having an offspring with neural tube defects.

Adolescent↗