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PubMedDate not supplied

Maternal serum and amniotic fluid hydroxyproline levels in neural tube defects.

OBJECTIVE: The present study was aimed to evaluate the alterations of maternal serum and amniotic fluid OH- proline levels in neural tube defects (NTD). METHODS: 38 patients and 23 control subjects were selected from the patients followed up by the Departments of Genetics and Antenatal Care, Zekai Tahir Burak Women's Health, Education and Research Hospital. Amnion fluid and blood samples were synchronously obtained from NTD and control subjects. OH-proline levels were detected spectrophotometrically. RESULTS: Amniotic fluid OH-proline levels were found to be increased in NTD patients compared to control subjects (p < 0.05). There was no statistically significant difference in serum OH-proline levels between the groups. CONCLUSION: The results showed an increase in amniotic fluid OH-proline levels in NTD compared to the control group. It may be suggested that the increased OH-proline levels reflect increased collagen turnover in NTD patients. Indeed, amniotic fluid OH-proline levels may be a candidate as an additional diagnostic parameter in NTD.

Amniotic Fluid↗
PubMed1992

Increased maternal serum alpha-fetoprotein and human chorionic gonadotropin in compromised pregnancies other than for neural tube defects or Down syndrome.

Intrauterine fetal death occurred in four women who were 'screen-positive' in a screening programme for neural tube defects (NTDs) and Down syndrome (DS). These women had very high levels of maternal serum alpha-fetoprotein (MSAFP) and maternal serum human chorionic gonadotropin (MShCG). Therefore, we evaluated all 'screen-positive' women in whom both of these markers were greater than or equal to 2.0 multiples of the median. The cases fulfilling these criteria totalled 11, and only one of them had no complications. High concentrations of both MSAFP and MShCG in a number of these cases might have been caused by an increased placental volume, which, in turn, might have been induced by decreased perfusion of the placenta. We conclude that screening programmes wrongly determine a high risk of fetal NTD or DS if the concentrations of both these parameters are very high. Invasive diagnostic procedures should be avoided in these cases, particularly in view of the increased risk of an adverse pregnancy outcome.

Adult↗
PubMed2004

The Costa Rican experience: reduction of neural tube defects following food fortification programs.

Fortification of wheat flour in 1997 and corn flour in 1999 with folic acid among other micronutrients was implemented in Costa Rica by means of two decrees, resulting in an effective public health impact. A prevalence of 25% of folic acid serum levels deficiency detected in fertile women in 1996 decreased 87% in urban areas two years later, whereas in rural areas diminished by 63%. In addition, a significant reduction of neural tube defects at the national level has been reported, dropping from a rate of 9.7 per 1000 lb during the period 1996-1998 to 6.3 per 1000 lb in the period 1999-2000. Finally, there has been a reported 74% reduction in the number of Neural Tube Defects at Birth (NTB) at the National Children's Hospital, resulting in 105 cases treated in 1995 to 26 cases in 2001.

Costa Rica↗
PubMedDate not supplied

Pregnancy planning: a determinant of folic acid supplements use for the primary prevention of neural tube defects.

OBJECTIVE: Daily consumption of supplements containing 400 micrograms of folic acid in the periconception period may reduce the risk of neural tube defects (NTDs) by as much as 70%. However, despite explicit recommendations, folic acid consumption among women likely to become pregnant remains low. The objectives of this study were: to evaluate women's knowledge and beliefs with regard to folic acid; to estimate the frequency of vitamin supplement consumption; and to identify its determinants during the periconception period. METHODS: In 1999-2000, a questionnaire was completed by 1,240 pregnant women in 10 Quebec hospitals. RESULTS: Seventy percent of the respondents were aware of the preventive role of folic acid but only 25% had taken the recommended dose of supplements during the periconception period. Supplement consumption is associated with the pregnancy planning intensity score (OR: 1.06; 95% CI: 1.02-1.11), knowledge score (OR: 1.11; 95% CI: 1.07-1.16) and belief in the usefulness of supplements (OR: 1.56; 95% CI: 1.02-2.39). CONCLUSION: These results indicate that further efforts are needed to inform the population and promote the optimal use of folic acid supplements.

Dietary Supplements↗
PubMedDate not supplied

[Folic acid deficiency and its association with neural tube defects in northern Mexico].

OBJECTIVE: To evaluate folic acid deficiency and other risk factors and their relationship with the occurrence of neural tube defects (NTD), in the rural population of northern Mexico (Chihuahua, Durango and Zacatecas). MATERIAL AND METHODS: A multicentric case-control study was performed. Cases were both live and stillborn with NTD, and controls were healthy newborns without congenital malformations. Exposure to known risk factors was determined, establishing its association with NTD using multiple logistic regression analysis. RESULTS: Risk factors associated to NTD were: folic acid deficiency (OR 11.1; CI 95% 1.2-106.2, p = 0.04); the antecedents of previous NTD pregnancies (OR 3.3; CI 95% 1.1-18.8, p = 0.05) and stillbirths (OR 7.1; CI 95% 1.1-46.3, p = 0.04). CONCLUSIONS: Folic acid deficiency is one of the major risk factors associated to NTD among the rural population of northern Medico. Further investigations are necessary to determine the role of involved risk factors and implement adequate preventive measures.

Adolescent↗
PubMedDate not supplied

Distribution of neural tube defects as a function of maternal weight: no apparent correlation.

OBJECTIVES: Maternal nutritional deficiency is an important predisposing factor to congenital neural tube defects (NTDs). It was hypothesized that obese women may have an increased risk for NTDs. The aim of the present study was to address this question in a large cohort. METHODS: A total of 72,915 consecutive cases of biochemical screening that had documented maternal weights and pregnancy outcomes were identified from the Quest Diagnostic Laboratories database. Patients were divided into five ranges of maternal weights, and the incidence of NTDs was calculated for each group. Based on the different definitions of maternal overweight, the data were also analyzed based on 2 groups only, obese and nonobese, using three cutoff points. RESULTS: Seventy-nine pregnancies were complicated by NTDs (incidence of 1.08 per 1,000 pregnancies). Differences between maternal weights ranges were not found to be statistically significant (chi2 = 5.997, p = 0.19, power = 0.99). Differences between obese and nonobese mothers were not found to be statistically significant for all three analyses as well. CONCLUSIONS: Our present results do not support an association between maternal obesity and NTDs.

Body Weight↗
PubMed1996

Does periconceptional multivitamin use reduce the risk of neural tube defects associated with other birth defects? data from two population-based case-control studies.

The role of periconceptional folic acid in the prevention of neural tube defects (NTDs) is well established. However, it is not clear whether a protective effect exists for the subset of nonsyndromic NTD with other "unrelated" major structural birth defects (NTD-multiples). This question is important to investigate because of shared pathogenetic mechanisms between NTD and other types of birth defects, and because of the epidemiologic differences that have been shown between NTD-multiples and NTD-singles. We analyzed data from two population-based case-control studies of NTDs, Atlanta 1968-1980, and California 1989-1991, to assess whether periconceptional multivitamin use reduces the risk of NTD-multiples. Maternal vitamin histories were assessed for 47 and 65 NTD-multiples cases and 3,029 and 539 control babies in Atlanta, and California, respectively. There was a substantial risk reduction associated with periconceptional multivitamin use (-3 to +3 months) for NTD-multiples (pooled odds ratio = 0.36, 95% C.I. 0.18-0.72) that persisted after adjustment for maternal race/ethnicity and education. Also, no specific types of NTDs or NTDs with specific defects explained the risk reduction with vitamin use. These data suggest that multivitamins reduce the risk of nonsyndromic NTD cases associated with other major birth defects. The implication of this finding for the role of vitamins in the prevention of non-NTD birth defects should be further explored.

Abnormalities, Multiple↗
PubMed2000

Multicentric study of efficacy of periconceptional folic acid containing vitamin supplementation in prevention of open neural tube defects from India.

BACKGROUND & OBJECTIVES: A folic acid containing multivitamin preparation was evaluated for its efficacy in preventing recurrence of open neural tube defect (NTD) in a blind, placebo-controlled randomized trial. The trial was carried out at the five centres in India, viz., Bangalore, Mumbai, Lucknow, New Delhi and Pune. METHODS: The preparation contained 4 mg of folic acid besides calcium, iron, zinc and vitamins A, B1, B2, B6, C, D and nicotinamide. The placebo contained calcium and iron only. A total of 466 women with previous history of giving birth to a child with open NTD were included in the trial (231 in the vitamin group and 235 in the placebo group). The supplementation was given for at least one month prior to conception and up to three months after conception. All women were offered antenatal diagnosis with screening of maternal serum alpha foetoprotein (AFP) and ultrasound. RESULTS: Pregnancy outcome with reference to recurrence of NTD was unknown in 137 women in the vitamin group and 142 in the placebo group. The recurrence of open NTD in the vitamin group was 2.92 per cent compared to 7.04 per cent in the placebo group, a reduction by about 60 per cent. The difference, however, was not statistically significant (P = 0.06). INTERPRETATION & CONCLUSIONS: The study seems to support the role of periconceptional folic acid supplementation in prevention of recurrence of NTDs in the Indian population. The reason for high recurrence rate observed in the placebo group requires further investigation.

Female↗
PubMed2004

Low erythrocyte folate status and polymorphic variation in folate-related genes are associated with risk of neural tube defect pregnancy.

Previous studies have shown conflicting findings in linking polymorphic variation in folate-related genes to the risk of neural tube defect pregnancy. Recent evidence points to maternal genotype being important in determining NTD risk. A case-control study was undertaken in 97 mothers of NTD cases from the northern region of the UK. Pregnant controls (n = 190) from a regional DNA bank and non-pregnant controls (n = 100) from the same geographical area were recruited. MTHFR 677C >T, MTHFR 1298A >C, MTRR 66A >G, SHMT 1420C >T, CbetaS 844ins68, and RFC-1 80G >A allele and genotype frequencies were determined and odds ratios (OR) calculated. Erythrocyte folate levels for cases and controls were also measured and a comparison made of median erythrocyte folate levels stratified according to genotype. The MTHFR 677C >T variant was not shown to be an independent NTD risk factor in mothers of NTD-affected pregnancy. A second polymorphism in MTHFR, 1298A >C, was less frequently observed in mothers of NTD cases (OR [95% CI]=0.57 [0.33, 0.97]). Possession of compound 1298A >C and 677C >T variants elevated risk of NTD pregnancy considerably (TT/AC+TT/CC vs CC/AA OR [95% CI]=6.56 [1.10, 39.33]). Erythrocyte folate levels were persistently lower in NTD mothers (p = 0.001) despite assays being conducted many years after the index pregnancy (17.6+/-12.6 years). Erythrocyte folate levels were depressed in the presence of the MTHFR 677C >T variant.

Adult↗
PubMed1994

The methylfolate axis in neural tube defects: in vitro characterisation and clinical investigation.

We have investigated various micronutrients important to folate metabolism in women with two previous neural tube defect (NTD)-affected pregnancies. Results suggest the disposition of plasma 5-methyltetrahydrofolate (5CH3-H4PteGlu) with respect to dietary intake may differ from that of the control population. It appears that to achieve a given plasma level of 5CH3-H4PteGlu, the population with a history of NTD pregnancies needs to take in more dietary folate than controls. We discuss this in the context of a potential lesion at or upstream from 5,10-methylenetetrahydrofolate reductase (MTHFR). This metabolic axis, which is responsible for the multienzymic conversion of PteGlu to 5CH3-H4PteGlu, has been investigated in a rat model using liver homogenate. The anticonvulsant drug (ACD) carbamazepine was found to inhibit the reaction in terms of a reduced Vmax and increased Km. Inhibition approaching maximal was found to occur at therapeutic levels of ACD. Various potential inhibitory sites along the methylfolate axis are considered and possible relationships to congenital malformations discussed. We describe folate and one carbon metabolism in relation to potential NTD lesion sites, not only in the light of present findings, but with respect to the published findings of other workers. Based on our hypothesis that an NTD lesion exists upstream from MTHFR, we expound how pteroylmonoglutamate supplementation may protect against NTD (i) by reducing endotoxic homocysteine and (ii) through inhibiting MTHFR (as do dihydrofolates) and thus diverting one carbon units into DNA thymine.

Animals↗
PubMed2001

Impact of folic acid fortification of the US food supply on the occurrence of neural tube defects.

CONTEXT: Daily consumption of 400 microg of folic acid before conception and during early pregnancy dramatically reduces the occurrence of neural tube defects (NTDs). Before food fortification, however, only an estimated 29% of US reproductive-aged women were taking a supplement containing 400 microg of folic acid daily. The US Food and Drug Administration authorized addition of folic acid to enriched grain products in March 1996, with compliance mandatory by January 1998. OBJECTIVE: To evaluate the impact of food fortification with folic acid on NTD birth prevalence. DESIGN, SETTING, AND POPULATION: National study of birth certificate data for live births to women in 45 US states and Washington, DC, between January 1990 and December 1999. MAIN OUTCOME MEASURE: Birth certificate reports of spina bifida and anencephaly before fortification (October 1995 through December 1996) compared with after mandatory fortification (October 1998 through December 1999). RESULTS: The birth prevalence of NTDs reported on birth certificates decreased from 37.8 per 100 000 live births before fortification to 30.5 per 100 000 live births conceived after mandatory folic acid fortification, representing a 19% decline (prevalence ratio [PR], 0.81; 95% confidence interval [CI], 0.75-0.87). During the same period, NTD birth prevalence declined from 53.4 per 100 000 to 46.5 per 100 000 (PR, 0.87; 95% CI, 0.64-1.18) for women who received only third-trimester or no prenatal care. CONCLUSIONS: A 19% reduction in NTD birth prevalence occurred following folic acid fortification of the US food supply. However, factors other than fortification may have contributed to this decline.

Folic Acid↗
PubMed2004

Maternal ethnicity and risk of neural tube defects: a population-based study.

BACKGROUND: Maternal body mass and the presence of diabetes mellitus are probable risk factors for neural tube defects (NTDs). The association between maternal ethnicity and the risk of NTDs remains poorly understood, however. METHODS: We performed a retrospective population-based study and included all women in Ontario who underwent antenatal maternal screening (MSS) at 15 to 20 weeks' gestation between 1994 and late 2000. Self-declared maternal date of birth, ethnicity and weight and the presence of pregestational diabetes mellitus were recorded in a standardized fashion on the MSS requisition sheet. NTDs were detected antenatally by ultrasonography or fetal autopsy and postnatally by considering all live and stillborn affected infants beyond 20 weeks' gestation. The risk of open NTD was evaluated across the 5 broad ethnic groups used for MSS, with white ethnicity as the referent. RESULTS: Compared with white women (n = 290 799), women of First Nations origin (n = 1551) were at increased associated risk of an NTD-affected pregnancy (adjusted odds ratio [OR] 5.2, 95% confidence interval [CI] 2.1-12.9). Women of other ethnic origins were not at increased associated risk compared with white women (women of Asian origin [n = 75 590]: adjusted OR 0.9, 95% CI 0.6-1.3; black women [n = 25 966]: adjusted OR 0.6, 95% CI 0.3-1.1; women of "other" ethnic origin [n = 10 009]: adjusted OR 0.1, 95% CI 0.02-0.9). INTERPRETATION: The associated risk of NTD-affected pregnancies was higher among women of First Nations origin than among women of other ethnic origins. The mechanisms for this discrepancy should be explored.

Adult↗
PubMed2004

A comprehensive evaluation of food fortification with folic acid for the primary prevention of neural tube defects.

BACKGROUND: Periconceptional use of vitamin supplements containing folic acid reduces the risk of a neural tube defect (NTD). In November 1998, food fortification with folic acid was mandated in Canada, as a public health strategy to increase the folic acid intake of all women of childbearing age. We undertook a comprehensive population based study in Newfoundland to assess the benefits and possible adverse effects of this intervention. METHODS: This study was carried out in women aged 19-44 years and in seniors from November 1997 to March 1998, and from November 2000 to March 2001. The evaluation was comprised of four components: I) Determination of rates of NTDs; II) Dietary assessment; III) Blood analysis; IV) Assessment of knowledge and use of folic acid supplements. RESULTS: The annual rates of NTDs in Newfoundland varied greatly between 1976 and 1997, with a mean rate of 3.40 per 1,000 births. There was no significant change in the average rates between 1991-93 and 1994-97 (relative risk [RR] 1.01, 95% confidence interval [CI] 0.76-1.34). The rates of NTDs fell by 78% (95% CI 65%-86%) after the implementation of folic acid fortification, from an average of 4.36 per 1,000 births during 1991-1997 to 0.96 per 1,000 births during 1998-2001 (RR 0.22, 95% CI 0.14-0.35). The average dietary intake of folic acid due to fortification was 70 μg/day in women aged 19-44 years and 74 μg/day in seniors. There were significant increases in serum and RBC folate levels for women and seniors after mandatory fortification. Among seniors, there were no significant changes in indices typical of vitamin B12 deficiencies, and no evidence of improved folate status masking haematological manifestations of vitamin B12 deficiency. The proportion of women aged 19-44 years taking a vitamin supplement containing folic acid increased from 17% to 28%. CONCLUSIONS: Based on these findings, mandatory food fortification in Canada should continue at the current levels. Public education regarding folic acid supplement use by women of childbearing age should also continue.

Journal Article↗
PubMed1987

Value of glial fibrillary acidic protein determination in amniotic fluid for prenatal diagnosis of neural tube defects.

Glial fibrillary acidic protein (GFAp), an intracellular protein specific to astrocytes of the central nervous system, was determined by 2-site immunoradiometric assay in amniotic fluid from 78 pregnancies with a normal, and 100 with an abnormal outcome. GFAp was not detectable in any of the normal pregnancies, but there were measurable, and so raised, levels in 23 out of 25 cases of anencephaly and 4 out of 7 cases of spina bifida, which therefore allowed prenatal diagnosis. GFAp was also increased in 4 of 6 cases of fetal intrauterine death, but not in other congenital malformations associated with elevated alphafetoprotein levels or abnormal acetylcholinesterase banding pattern, such as exomphalos, other gastrointestinal malformations or renal abnormalities. GFAp is therefore specific for diagnosing open neural tube defects. The determination of GFAp in amniotic fluid was slightly less efficient overall than AFP for the prenatal diagnosis of neural tube defects, but can be a useful ancillary test and has the advantage of specificity.

Acetylcholinesterase↗
PubMed1998

Promoter sequence, expression, and fine chromosomal mapping of the human gene (MLP) encoding the MARCKS-like protein: identification of neighboring and linked polymorphic loci for MLP and MACS and use in the evaluation of human neural tube defects.

The MARCKS-like protein (MLP), also known as F52, MacMARCKS, or MARCKS-related protein, is a widely distributed substrate for protein kinase C (PKC). Recent studies using gene disruption in vivo have demonstrated the importance of both MARCKS and MLP to the development of the central nervous system; specifically, mice lacking either protein exhibit a high frequency of neural tube defects. We isolated a genomic clone for human MLP and discovered a directly linked polymorphism (MLP1) useful for genetic linkage analysis. The MLP promoter was 71% identical over 433 bp to that of the corresponding mouse gene, Mlp, with conservation of many putative transcription factor-binding sites; it was only 36% identical over 433 bp to the promoter of the human gene, MACS, which encodes the MLP homologue MARCKS. This 433-bp fragment drove expression of an MLP-beta-galactosidase transgene in a tissue-specific and developmental expression pattern that was similar to that observed for the endogenous gene, as shown by in situ hybridization histochemistry. In contrast to MACS, the MLP and Mlp promoters contain a TATA box approximately 40 bp 5' of the presumed transcription initiation site. MLP was localized to chromosome 1p34-->1pter by analysis of human-mouse somatic cell hybrid DNA and to 1p34 by fluorescence in situ hybridization. Radiation hybrid mapping of MLP placed it between genetic markers D1S511 (LOD > 3.0) and WI9232. MACS was localized to 6q21 between D6S266 (LOD > 3.0) and AFM268uh5 by the same technique. We tested the novel MLP1 polymorphism and the MACS flanking markers in a series of 43 Caucasian simplex families in which the affected child had a lumbosacral myelomeningocele. We found no evidence of linkage disequilibrium, suggesting that these loci were not major genes for spina bifida in these families. Nonetheless, the identification of linked and neighboring polymorphisms for MACS and MLP should permit similar genetic studies in other groups of patients with neural tube defects and other neurodevelopmental abnormalities.

Animals↗
PubMed1994

Prevention of spinal neural tube defects in the curly tail mouse mutant by a specific effect of retinoic acid.

Curly tail mouse mutant embryos (ct/ct) develop spinal neural tube defects (NTD) in 54% of cases, comprising isolated tail flexion defects and spinal bifida with tail flexion defects. Both types of spinal NTD result from delayed closure of the posterior neuropore (PNP). Previous studies (Seller et al. [1979] Proc. R. Soc. Lond. Biol. 206:95-107; Seller and Perkins [1982] Prenat. Diagn. 2:297-300) described a paradoxical effect of retinoic acid (RA) on the phenotypic expression of the ct mutation: Treatment with low doses of RA on day 8 of gestation increased the incidence of total NTD, whereas low doses of RA administered on day 9 resulted in reduced incidence of total NTD. In order to investigate further the reported preventive effect of RA, we have carried out detailed analyses of the effects of maternal treatment with 5 mg/kg RA on the incidence of NTD at different developmental stages, and on the development and growth of ct/ct embryos. We found that 5 mg/kg RA reduces the incidence of spinal NTD in a stage-specific manner, without increasing the incidence of cranial NTD. The effect of RA is specific: There were no other alterations in morphogenesis, growth, development, resorption rate, or litter size. RA was more effective in the prevention of isolated tail flexion defects than of spina bifida. Prevention of isolated tail flexion defects was maximal (50% reduction) when RA was administered between 10 days 4 hours and 10 days 8 hours post coitum (p.c.) inclusive (24 to 34 somite stage).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1996

Role of arsenic as a reproductive toxin with particular attention to neural tube defects.

Arsenic has been recognized as a human toxicant for over 2000 years. More recently it has been readily accepted as a human carcinogen. Animal research has demonstrated arsenic's ability to have profound detrimental effects on the developing embryo in avian and mammalian species. This article comprehensively reviews the human and animal literature on the subject of the reproductive toxicity of arsenic. A variety of endpoints are considered, including spontaneous abortion, cardiovascular defects, and arsenic's role in the causation of neural tube defects (NTDs). A summary of the literature that has examined the various postulated mechanisms by which arsenic may produce NTDs is also considered. In addition, a discussion of literature relative to the presence of arsenic in the general environment and in the workplace is presented. This article reaches the conclusion that while further research is clearly needed, particularly on the potential toxicity of organic arsenical compounds, the current literature suggests it may be prudent and appropriate to treat inorganic arsenic as a probable human reproductive toxin.

Animals↗
PubMed2006

Reclosure of surgically induced spinal open neural tube defects by the intraamniotic injection of human embryonic stem cells in chick embryos 24 hours after lesion induction.

OBJECT: The authors previously reported that human embryonic stem cells (hESCs) injected into the amniotic cavity of chick embryos immediately after neural tube incision in a surgically induced spinal open neural tube defect (ONTD) model promote the reclosure capacity of neural tubes. To simulate more closely the clinical situation of human ONTDs, in which a substantial time period elapses before the prenatal diagnosis of spinal ONTDs, the authors investigated whether this reclosure capacity remains enhanced by the intraamniotic injection of hESCs at 24 hours after ONTD induction. METHODS: One hundred twenty-two chick embryos with ONTDs were randomly assigned to two groups: the control group (59 embryos) and the hESC-injection group (hESC group, 63 embryos). After the neural tubes of both groups had been opened, the hESC group underwent direct intraamniotic injection with hESCs marked with an enhanced green fluorescent protein at 24 hours after ONTD induction. The lengths of the remnant ONTDs were measured and the presence of hESCs was determined at 4, 6, and 8 days after ONTD induction. No difference in survival rates was observed between the two groups. The mean length of the ONTDs, adjusted for body length at the time of death and initial lesion length, was significantly shorter in the hESC group than in the control group (p < 0.001). No hESCs were found within reclosed neural tubes; rather, they covered the defect area during the reclosure process. CONCLUSIONS: The authors demonstrate that hESCs injected into the amniotic cavity at 24 hours after ONTD induction enhance reclosure ability in chick embryos.

Amnion↗