Neural Tube Defects Group Research Articles

SELDI-TOF-MS proteomic profiling of serum, urine, and amniotic fluid in neural tube defects.

Neural tube defects (NTDs) are common birth defects, whose specific biomarkers are needed. The purpose of this pilot study is to determine whether protein profiling in NTD-mothers differ from normal controls using SELDI-TOF-MS. ProteinChip Biomarker System was used to evaluate 82 maternal serum samples, 78 urine samples and 76 amniotic fluid samples. The validity of classification tree was then challenged with a blind test set including another 20 NTD-mothers and 18 controls in serum samples, and another 19 NTD-mothers and 17 controls in urine samples, and another 20 NTD-mothers and 17 controls in amniotic fluid samples. Eight proteins detected in serum samples were up-regulated and four proteins were down-regulated in the NTD group. Four proteins detected in urine samples were up-regulated and one protein was down-regulated in the NTD group. Six proteins detected in amniotic fluid samples were up-regulated and one protein was down-regulated in the NTD group. The classification tree for serum samples separated NTDs from healthy individuals, achieving a sensitivity of 91% and a specificity of 97% in the training set, and achieving a sensitivity of 90% and a specificity of 97% and a positive predictive value of 95% in the test set. The classification tree for urine samples separated NTDs from controls, achieving a sensitivity of 95% and a specificity of 94% in the training set, and achieving a sensitivity of 89% and a specificity of 82% and a positive predictive value of 85% in the test set. The classification tree for amniotic fluid samples separated NTDs from controls, achieving a sensitivity of 93% and a specificity of 89% in the training set, and achieving a sensitivity of 90% and a specificity of 88% and a positive predictive value of 90% in the test set. These suggest that SELDI-TOF-MS is an additional method for NTDs pregnancies detection.

Polymorphisms in FZD3 and FZD6 genes and risk of neural tube defects in a northern Han Chinese population.

Neural tube defects (NTDs) are the most common and severe malformations of the central nervous system. The association of single nucleotide polymorphisms (SNPs) of the Frizzled 3 (FZD3) and Frizzled 6 (FZD6) genes and NTDs in the Han population of northern China was principally studied. One synonymous SNP (rs2241802) in FZD3 gene and three nonsynonymous SNPs (rs827528, rs3808553 and rs12549394) in FZD6 gene were analyzed by polymerase chain reaction (PCR) and sequencing methods in 135 NTD patients and 135 normal controls. The allele, genotype and haplotype frequencies were calculated and analyzed to examine the relationship between FZD3/FZD6 SNPs and NTDs. Both T allele and TT genotype frequencies of the FZD6 rs3808553 loci in the NTDs group were significantly higher than those in the controls, and children with T allele and TT genotype were associated with increased NTDs risk (OR = 1.575, 95 % CI 1.112-2.230, P = 0.010 and OR = 2.811, 95 % CI 1.325-5.967, P = 0.023, respectively). There were no differences among different genotypes or alleles in other three SNPs. Haplotypes A-G-C and A-T-C in FZD6 were found associated with NTDs in the case-control study (OR = 0.560, 95 % CI 0.378-0.830, P = 0.004 and OR = 1.670, 95 % CI 1.126-2.475, P = 0.011, respectively). The rs3808553 of FZD6 is obviously associated with NTDs in Han population of northern China. The TT genotype may increase risk for NTDs.

Relationships between maternal plasma levels of homocysteine, nitric oxide synthase, inducible nitric oxide synthase and fetal neural tube defects

Objective To investigate the relationships between fetal neural tube defects (NTD) and maternal plasma homocysteine (Hcy) level,total nitric oxide synthase (NOS) and inducible NOS (iNOS) activity.Methods A total of 28 pregnant women with clinically or prenatal ultrasound diagnosed NTD offspring in Shihezi City and its surrounding areas of the Xinjiang Uygur Autonomous Region from January 6,2008 to May 23,2011 were enrolled as NTD group.Another 41 normal pregnant women,matched in corresponding area and period,were enrolled as the control group.The plasma level of Hcy was determined by rate method,and the activities of total NOS and iNOS were detected by spectrophotometry.Linear correlation analysis and t-test were used as statistical method.Results The plasma level of Hcy in NTD group was higher than that in the control group with statistically significant difference [(15.2±7.9) μmol/L vs (8.4±3.7) μmol/L,t=4.269,P＜0.01].The activity of total NOS was lower in the NTD group than that in the control group [(20.0±9.0) U/ml vs (26.0±4.1) U/ml,t=3.258],so was the activity of iNOS [(7.5±2.9) U/ml vs (12.0±4.5) U/ml,t=4.670],the differences were statistically significant (both P＜0.01).Linear correlation analysis showed a negative correlation between the level of Hcy and the activity of total NOS (r=0.325,P＜0.01),but no correlation was found with iNOS (r=0.205,P＞0.05).Conclusions High level of Hcy and low activity of NOS and iNOS might be correlated with fetal NTD. Key words: Neural tube defects; Nitric oxide synthase; Homocysteine

An association study between SUFU gene polymorphisms and neural tube defects

Neural tube defects (NTDs) in mammals are rooted in aberrant neural tube closure during early embryogenesis, which is caused by multiple environmental and genetic factors. The Sonic Hedgehog pathway is involved in the induction of the floor plate and participates in formation of the neural tube. Mutation of the suppressor of fused gene (SUFU), an essential repressor of Sonic Hedgehog signaling pathway, can result in NTDs. A case-control study was designed to compare the frequencies of the polymorphism at four sites in the SUFU gene in control and NTDs group, as well as in subtype groups, including anencephaly, spina bifida and encephalocele. We also explored the association between polymorphism and NTDs risk in a high prevalence population in China. Rs10786691, but not the other three SNPs, had an association between polymorphisms and NTDs. The heterozygous AG allele of rs10786691 was significantly related with NTDs and encephalocele (OR = 1.60, 95% CI: 1.04–2.48, p = 0.034; OR = 2.83, 95% CI: 1.07–7.47, p = 0.036). In female but not male fetuses, the AG genotype of rs10786691 increased the risk of NTDs (OR = 1.88, 95% CI: 1.03–3.41, p = 0.040). The SUFU rs10786691 A>G polymorphism may be a potential risk factor for NTDs and encephalocele in this high-risk population, but the association between the polymorphism and NTDs was probably influenced by gender.

The relationship between frizzled 6 gene polymorphisms and neural tube defects in children of northern Han Chinese population

Objective To study the association of single nucleotide polymorphisms (SNPs) of the frizzled 6 (FZD6) gene with neural tube defects (NTDs) in a northern Han Chinese population. Methods Three nonsynonymous SNPs in the FZD6 gene (rs827528，rs3808553，rs12549394) were examined.The SNPs were genotyped by polymerase chain reaction (PCR) and sequencing in 135 NTD patients and matched normal controls.The allele，genotype and haplotype frequencies were calculated and analyzed to examine the association between FZD6 SNPs and NTDs. Results Both T allele and TT genotype frequencies of the rs3808553 polymorphism in the NTDs group were significantly higher than those in the controls，and children with T allele and TT genotype were associated with increased risk of NTDs (OR=1.575，95% CI 1.112-2.230，P=0.010 and OR=2.811，95% CI 1.325-5.967，P=0.023 respectively).There were no significant differences among different genotypes or alleles in both rs827528 and rs12549394.Haplotypes A-G-C and A-T-C were found associated with NTDs in the case-control study (OR=0.560，95% CI 0.378-0.830，P=0.004 and OR=1.670，95% CI 1.126-2.475，P=0.011 respectively). Conclusions The rs3808553 polymorphism of FZD6 s obviously associated with NTDs in children of northern Han Chinese population.The TT genotype may increase the risk for NTDs.The rs827528 and rs12549394 polymorphisms of FZD6 may have no association with NTDs. Key words: Neural tube defects; Frizzled receptors; Polymorphisms，single nucleotide

PCMT1 gene polymorphisms, maternal folate metabolism, and neural tube defects: a case–control study in a population with relatively low folate intake

The PCMT1 gene encodes the protein repair enzyme protein-L-isoaspartate (D-aspartate) O-methyltransferase, which is known to protect certain neural cells against Bax-induced apoptosis. Previous studies have produced inconsistent results regarding the effects of PCMT1 (rs4816 and rs4552) polymorphisms on neural tube defects (NTDs). Reduced maternal plasma folate levels and/or elevated homocysteine (Hcy) levels are considered to be risk factors for NTDs. In order to clarify the key factors contributing to the apparent discrepancy and investigate gene-environment interaction, we conducted a case-control study including 121 cases and 146 matched controls to investigate the association between the two PCMT1 polymorphisms in fetuses and the risk of NTDs in the Chinese population of Lvliang, which has low folate intake. Maternal plasma folate and Hcy levels were also measured, and the interaction between fetal PCMT1 gene status and maternal folate metabolites was assessed. Maternal plasma folate concentrations in the NTD group were lower than in controls (10.23 vs. 13.08nmol/L, adjusted P=0.059), and Hcy concentrations were significantly higher (14.46 vs. 11.65μmol/L, adjusted P=0.026). Fetuses carrying the rs4816 AG+GG genotype, combined with higher maternal plasma Hcy, had a 6.46-fold (95% CI 1.15-36.46) increased risk of anencephaly. The results of this study imply that the fetal PCMT1 rs4816 polymorphism may play only a weak role in NTD formation and that gene-environment interactions might be more significant.

Amniotic fluid glial fibrillary acidic protein (AF‐GFAP), a biomarker of open neural tube defects

Neural tube defects (NTDs) are usually identified by ultrasonography and confirmed by alpha-fetoprotein (AFP) assay and acetylcholinesterase (AchE) electrophoresis in amniotic fluid. Yet, both of these biomarkers can be found positive in other etiologies. Here, amniotic fluid glial fibrillary acidic protein (AF-GFAP), which was identified by a proteomic study, is shown to be a useful biomarker for NTD diagnosis. Amniotic fluid glial fibrillary acidic protein was measured by an ELISA assay in 138 cases of NTDs. Seventy samples from normal pregnancies used as controls and 27 samples giving false positive or false negative results either for AchE or AFP and corresponding to fetal death (n = 8), gastroschisis (n = 8), and unexplained etiologies (n = 11) were also tested. Whatever the gestational age, GFAP was below 0.2 ng/mL in control samples, whereas 99.1% of open NTDs (29/29 in the anterior NTD group and 80/81 in the spina bifida group) were above this threshold. Closed NTDs were all negative (28/28). None of the other samples tested were positive, except in case of fetal death (8/8). Amniotic fluid glial fibrillary acidic protein is a sensitive biomarker for open NTD diagnosis with a good negative predictive value for closed NTD. Compared with AFP and AchE, our results indicate that AF-GFAP alone is more efficient than this classical association.

Levels of PAH–DNA adducts in placental tissue and the risk of fetal neural tube defects in a Chinese population

We examined the relationship between PAH–DNA adduct levels in the placental tissue, measured by a highly sensitive 32P-postlabeling assay, and the risk of fetal neural tube defects (NTDs). We further explored the interaction between PAH–DNA adducts and placental PAHs with respect to NTD risk. Placental tissues from 80 NTD-affected pregnancies and 50 uncomplicated normal pregnancies were included in this case-control study. Levels of PAH–DNA adducts were lower in the NTD group (8.12 per 108 nucleotides) compared to controls (9.92 per 108 nucleotides). PAH–DNA adduct concentrations below the median was associated with a 3-fold increased NTD risk. Women with a low PAH–DNA adduct level in concert with a high placental PAH level resulted in a 10-fold elevated risk of having an NTD-complicated pregnancy. A low level of placental PAH–DNA adducts was associated with an increased risk of NTDs; this risk increased dramatically when a low adduct level was coupled with a high placental PAH concentration.

First-Trimester Screening for Neural Tube Defects Using Alpha-Fetoprotein

Objective: To assess the potential value of maternal serum alpha-fetoprotein (AFP) at 11–13 weeks’ gestation in early screening for fetal neural tube defects (NTDs). Methods: Maternal serum AFP at 11–13 weeks’ gestation was measured in 32 cases of fetal NTDs, including 18 cases of acrania and 14 cases of spina bifida, and 1,500 unaffected controls. The measured serum AFP was converted into multiple of the expected median (MoM) after adjustment for gestational age and maternal characteristics and Mann-Whitney test was used to determine the significance of difference in the mean MoM of serum AFP in the NTD group to that in the controls. Results: The mean AFP MoM in the NTD group (1.76, 95% CI 1.39–2.23) was significantly higher than in the controls (p < 0.0001). The mean AFP MoM was not significantly different between the cases of acrania and cases of spina bifida (1.78 vs. 1.75; p = 0.722). The detection rates of NTD in screening by serum AFP were 50.0% (95% CI 31.9–68.1) and 37.5% (95% CI 21.1–56.3) at fixed false-positive rates of 10 and 5%, respectively. Conclusion: Measurement ofmaternal serum AFP at 11–13 weeks’ gestation may be useful in screening for fetal NTDs.

Association of genomic instability, and the methylation status of imprinted genes and mismatch-repair genes, with neural tube defects

We studied the genomic instability and methylation status of the mismatch-repair (MMR) genes hMLH1 and hMSH2, and the imprinted genes H19/IGF2, in fetuses with neural tube defects (NTDs) to explore the pathogenesis of the disease. Microsatellite instability (MSI) was observed in 23 of 50 NTD patients. Five NTD patients showed high-degree MSI (MSI-H) and 18 showed low-degree MSI (MSI-L). The frequencies of mutated microsatellite loci were 3/50 (6%) for BatT-25, 10/50 (20%) for Bat-26, 3/50 (6%) for Bat34C4, 6/50 (12%) for D2S123, 4/50 (8%) for D2S119, and 3/50 (6%) for D3S1611. The promoter regions of the hMLH1 and hMSH2 genes were unmethylated in NTD patients, as determined by methylation-specific PCR. The hMLH1 and hMSH2 promoter methylation patterns, the methylation levels of H19 DMR1, and IGF2 DMR0 were detected by bisulfite sequencing PCR, sub-cloning, and sequencing. The hMSH2 promoter sequence was unmethylated, and the hMLH1 promoter showed a specific methylation pattern at two CpG sites. The methylation levels of H19 DMR1 in the NTD and control groups are 73.3% ± 15.9 and 58.3% ± 11.2, respectively. The methylation level of the NTD group was higher than that of the control group (Student's t-test, P<0.05). There is no significant difference in IGF2 DMR0 methylation level between the two groups. All of the results presented here suggest that genomic instability, the MMR system, and hyper-methylation of the H19 DMR1 may be correlated with the occurrence of NTDs.

Maternal serum vitamin B12, folate and homocysteine and the risk of neural tube defects in the offspring in a high-risk area of China

To examine the association between the risk of neural tube defects (NTD) and maternal serum vitamin B12, folate and homocysteine in a high-risk area of China. A case-control study was carried out in Luliang mountain area of Shanxi Province. A total of eighty-four NTD pregnancies and 110 matched controls were included in the study; their serum vitamin B12 and folate concentrations were measured by chemiluminescent immunoenzyme assay and total homocysteine concentrations by fluorescent polarisation immunoassay. Serum vitamin B12 and folate concentrations were lower in NTD-affected pregnant women than in controls (P < 0.01). Serum total homocysteine was higher in the NTD group than in controls at less than 21 weeks of gestation (P < 0.01). Adjusted odds ratios revealed that women with lower vitamin B12 (adjusted OR=4.96; 95 % CI 1.94, 12.67) and folate (adjusted OR=3.23; 95 % CI 1.33, 7.85) concentrations had a higher risk of NTD compared to controls. Based on dietary analysis, less consumption of meat, egg or milk, fresh vegetables and fruit intake would increase the risk of NTD. Lower serum concentrations of folate and vitamin B12 are related to the increased risk of NTD in high-risk populations. Both folate and vitamin B12 intake insufficiency could contribute to the increased risk of NTD. A dietary supplement, combining folate and vitamin B12, might be an effective measure to decrease the NTD incidence in these areas.

Thrombophilia-associated gene mutations in women with pregnancies complicated by fetal neural tube defects

Neural tube defects (NTDs) are one of the most common fetal defects. The causes of these defects are considered to have multiple factors involving nutritional deficiencies, genetic predisposition, and environmental factors such as drug exposure [1]. The aim of our study was to investigate the frequencies of thrombophilia-associated gene factor V Leiden mutations and prothrombin gene G20210A mutations, as well as methylenetetrahydrofolate reductase MTHFR C677T mutation which has a substantial role in the folate mechanism of women experiencing pregnancies with NTDs. This study consisted of 2 groups: group 1 consisted of 29 women whose previous pregnancies were complicated with NTDs, and group 2 was the control group consisting of 35 women who experienced uncomplicated pregnancies. The ages of patients in the control group matched with those in the NTD group. Case characteristics are displayed in Table 1. The frequency of theMTHFRC677Tmutationwas found to be significantly higher in women who experienced pregnancies withNTDs,while occurrence of factor V Leiden andprothrombin gene G20210A mutations were not significantly different between the study and control groups. The frequency of both homozygous and heterozygous MTHFR C677T mutation was 69.0% inwomenwho experienced pregnancies with NTDs (42.9% in the control group). Thepresence ofMTHFRC677Thad an odds ratio of 2.96 (95.0%CI, 1.05–8.32) for the development of NTDs. The frequencies of factor V Leiden, prothrombin geneG20210A, and MTHFR C677T mutations and allele frequencies with statistical comparisons are shown in Table 1. A study by Akar et al. [2] showed no relationship between MTHFR C677T mutation and spina bifida. However, they suggested that coexpression of MTHFR A1298C and MTHFR C677T mutations increased the risk of spina bifida. A similar association for NTD cases was reported in another study [3]. ⁎ Corresponding author. Department of Obstetrics and Gynecology, Gulhane Military Medical Academy, Etlik, 06010 Ankara, Turkey. Tel.: +90 312 3045818; fax: +90 312 3045800. E-mail address: temelceyhan@yahoo.com (S.T. Ceyhan).

208 Bone Morphogenetic Proteins Genes and Neural Tube Defects

Neural tube defects (NTD) are among the most common and severe congenital defects. The genetic background of a failure in the neural tube closure, which is the cause of NTD remains unknown. Among potential candidate genes which may contribute to the etiology of these defects the family of BMP (bone morphogenetic proteins) genes is considered. The aim of the study was to analyze the possible causative role of mutations of the BMP-2, BMP-4 and BMP-9 genes in the development of NTD. Methods: Genomic sequences of the BMP-2, BMP-4 and BMP-9 genes were amplified by means of PCR technique and subsequently screened for mutations (denaturating high-performance liquid chromatography - DHPLC) in children with NTD. DNA fragments showing an abnormal DHPLC pattern were further directly sequenced to confirm the presence of the mutation. Subsequently, the frequency of the variant was analyzed and compared between the tested group of patients and the control group. Results: 112 children with NTD were enrolled to the study. The control group consisted of 110 healthy children. No mutations were detected within the BMP-2 gene and 1 silent polymorphism (C>T transition in the 142nd codon of the 2nd exon of the gene, no change in protein sequence) was found in the BMP-9 gene. In the BMP-4 gene, the polymorphism was found (538T>C transition with subsequent change of the protein sequence: 147Valine>Alanine). The frequency of 538CC homozygotes in the NTD group was higher (34.8%) than in the controls (26.4%), but the difference did not reach statistical significance (odds ratio 1.49; 95% confidence interval 0.84–2.63; p value in chi-square test 0.17). Conclusion: No mutations within the BMP-2, BMP-4 and BMP-9 genes were detected. The role of these genes in the development of NTD remains uncertain. The study was sponsored by a grant from State Committee for Scientific Research (No. 3P05E13823).

Metabolic effects and the methylenetetrahydrofolate reductase (MTHFR) polymorphism associated with neural tube defects in southern Brazil.

The importance of metabolic factors in neural tube defects (NTDs) has been the focus of many investigations. Several authors have suggested that abnormalities in homocysteine metabolism, such as hyperhomocysteinemia, folate deficiency, and low vitamin B12, may be responsible for these malformations and that both nutritional factors and genetic abnormalities are associated with them. We conducted a case-control study to investigate the influence of biochemical and genetic factors in NTDs in infants in southern Brazil. Levels of folate, vitamin B12, total homocysteine (t-Hcy) and the 677C>T and 1298A>C polymorphisms of the MTHFR gene were analyzed in 41 NTD child-mother pairs and 44 normal child-mother control pairs. Subjects in the case group had a higher mean blood folate level than those in the control group. The level of vitamin B12 was lower in mothers in the NTD group than in control mothers (p = 0.004). The level of t-Hcy was not different in the two groups, but t-Hcy and vitamin B12 were correlated (p = 0.002). There was no difference in the genotype distribution for 677C>T and 1298A>C polymorphisms of MTHFR in the case and control pairs. The level of t-Hcy was correlated with 677TT. Despite the small sample in this study, we suggest that low vitamin B12 and, consequently, hyperhomocysteinemia are important risk factors for NTDs in our population.

The use of drugs in mothers of offspring with neural-tube defects.

To study the risk of maternal drugs use during pregnancy in the origin of isolated neural-tube defects (NTD). 1202 cases with NTD, 38,151 population controls without any defects and 22,475 patient controls with other defects were compared in the population-based data set of the Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA), 1980-1996. The HCCSCA contains 542 drugs, however only those drugs were evaluated which included five or more mothers in the NTD group. Drugs with the same chemical structures were combined. In addition, only drug use in the second month of pregnancy was evaluated because it is the critical period for NTD. Of course, it is necessary to exclude different biases, mainly recall bias at the evaluation of these drugs. Of 121 chemicals, only oxytetracycline, carbamazepine and valproic acid had some association with NTD. High doses of exogenous oestrogens, clomiphene, chorionic gonadotropin, lynesterol and ergotamine also seemed to have some indirect association with NTD because their exposures occurred more frequently before the critical period of NTD due to maternal infertility. Our findings suggest that drugs used during pregnancy do not appear to substantially contribute to the occurrence of isolated NTD but some drugs have a role in the origin of these defects.

Low Levels of Selenium in Mothers and Their Newborns in Pregnancies With a Neural Tube Defect

Very few data are presented in the literature about selenium (Se) in human fetal development. The aim of this paper was to study the relationship between maternal and neonatal Se status and neural tube defects (NTDs). Serum and hair samples were obtained from 20 nonpregnant women, 32 healthy mothers with normal newborns, and 28 mothers who had a newborn with NTD, and their newborns at delivery. Serum Se levels, as ng/mL, and hair Se levels, as microgram/g, were determined on a Perkin-Elmer 1000 spectrophotometer (United Kingdom) by fluorometry. The mean maternal serum and hair Se concentrations in the NTD group (42.9 +/- 1.75 ng/mL, 277 +/- 7.73 ng/g, respectively) were significantly lower than those of the control healthy mothers (50.2 +/- 2.35 ng/mL, 300 +/- 6.10 ng/g, respectively) and the nonpregnant women (58.1 +/- 3.12 ng/mL, 315 +/- 7.64 ng/g, respectively). A significant decrease in concentrations of Se in serum and hair was observed in newborns with a NTD (26.0 +/- 1.55 ng/mL, 181 +/- 3.71 ng/g, respectively) compared with healthy newborns (32.6 +/- 1.70 ng/mL, 204 +/- 4.43 ng/g, respectively). Maternal Se deficiency during pregnancy was thought to be one of the factors responsible for NTDs. However, the lowered serum and hair Se concentrations may be secondary manifestations of an abnormal pregnancy and did not contribute to its production. More studies on maternal Se status during the antenatal period, especially early gestation and neonatal Se status including normal newborns and NTD infants, are needed.

Maternal-Fetal Folate Status and Neural Tube Defects: A Case Control Study

The object of this study was to explore the role of folate in the pathophysiology of neural tube defects (NTD). Maternal and fetal serum and red blood cell folate were assayed in 14 cases of NTDs and compared with 14 controls with other malformations and matched for gestational age (range 18-36 weeks). In mothers of NTD fetuses, serum folate (5.2 ng/ml), red blood cell folate (294 ng/ml) and the folate methylation rate (65%) were significantly lower than in controls (6.6 and 399 ng/ml, respectively, and 77%). However, the fetal folate status was similar in cases and controls. In the NTD group, folate metabolism was altered in the mothers but not in the fetuses. Therefore, a normal folate placental transfer can be assumed in this group. In addition, it could be speculated that decreased maternal folate methylation might be involved in the pathogenesis of NTDs.

Spontaneous abortion--high risk factor for neural tube defects in subsequent pregnancy.

An increased spontaneous abortion rate has been observed in pregnancies preceding that of fetuses or newborn infants with neural tube defects (NTDs). There are 2 suggested explanations for this observation. One is that a trophoblastic cell rest, remaining from a previous aborted pregnancy, interferes with normal embryogenesis. The second is that the previous lost fetus was affected with NTD. We studied the obstetric history of mothers of newborn infants with NTDs compared to those with other birth defects, in low and high risk groups for NTD (Jew and Bedouins). A significantly higher spontaneous abortion rate (48%) in the preceding pregnancy was found in the NTD group compared to the group with other birth defects (20%). This was especially remarkable for spina bifida cases in the Jewish study population. A significantly higher rate of preceding spontaneous abortion was also found in congenital heart defects (CHD) when compared to other congenital malformations. A hypothesis based on the multifactorial threshold model is put forward to explain these findings. Based on the realization that spontaneous abortion constitutes a high risk factor for NTD and possibly also CHD, we recommend a delay of subsequent pregnancy and periconceptional treatment with folic acid following spontaneous abortion.

Upper and lower neural tube defects: an alternate hypothesis.

It has been suggested that neural tube defects (NTDs) of the upper type (anencephaly, encephalocele, and thoracic spina bifida) may have a pathogenesis different from those of the lower type (lumbosacral spina bifida), since recurrent cases within a sibship were said always to be concordant with respect to NTD type. Also, spontaneous abortion, additional malformation, and recurrence rate were observed to be higher in the upper group, and there was an excess of females in upper NTD probands. To test this hypothesis, we measured the above variables in upper and lower NTDs in a sample from Quebec. We found less than full concordance (50%) of NTD type in 18 sib pairs. Recurrence rate was not significantly lower in the lower NTD group (5.6 v 5.8%). The other variables were in general agreement with previous studies, inconsistent findings possibly attributable to different NTD population incidences. These findings can be accounted for if upper and lower NTDs share a similar pathogenesis and the embryo is more susceptible during early than late neural tube formation.

Maternal hair zinc concentration in neural tube defects in Turkey

Hair zinc concentration was measured in samples taken from 57 mothers who delivered infants with neural tube defects (NTD) (mainly anencephaly). Control groups consisted of 30 healthy mothers with normal offspring and 37 nonpregnant women from middle-income backgrounds. Zinc concentration was also measured in the hair of eight infants with NTD (four being anencephalic). The mean maternal hair zinc concentration in the NTD group (128.2 +/- 38.9 micrograms/g) was lower than that of the control women (p less than 0.001), whereas the mean hair zinc level of malformed babies (250.4 +/- 85.2 micrograms/g) was significantly higher than that of normal infants (193.4 +/- 39.2 micrograms/g) (p less than 0.05). Maternal nutritional zinc deficiency was thought to be one of the factors responsible for NTD in Turkey.