Neural Tube Defects Group Research Articles

Study on the relationship between genetic polymorphism of reductive folic acid carrier and the risk of neural tube defects

BackgroundTo investigate the association of folate metabolism gene polymorphism with neural tube defects (NTDs) in Chinese population.MethodsThe subjects were divided into two groups, 495 children with NTDs (NTD group) and 255 healthy children (control group).ResultsThe levels of folic acid, s-adenosine methionine (SAM), and Sam/s-adenosine homocysteine (SAH) in NTD group were lower than those in control group. There were significant differences in hey, SAH, and Sam levels between two groups, but there was no significant difference in folic acid content. High fever in early pregnancy, taking antiepileptic drugs, father’s exposure to organic solvents, folic acid deficiency, and mother’s diabetes were the important risk factors in NTDs. MTHFR 677C > T gene was a risk factor for NTD in children, while 1298A > C gene was a protective factor.ConclusionFolic acid metabolism markers were different in NTD children and their mothers, and the overall trend showed that folate, SAM, and SAM/SAH levels were decreased, while Hcy and SAH levels were increased; MTHFR 677C > T gene of SNPs was a risk factor for the occurrence of NTDs, and MTHFR 1298A > C gene was a protective factor, and the environmental risk factor had a synergistic effect on occurrence of NTDs.

Prenatal uranium exposure and risk for fetal neural tube defects: A case-control study in women living in a rural area of northern China

The adverse effects of uranium exposure on human health are well-known; less is known, however, regarding its association with congenital malformations. We conducted a case-control study to examine the association between prenatal exposure to uranium and risk for fetal neural tube defects (NTDs) using the concentration of uranium in placental tissue as an exposure marker in 408 NTD cases and 593 healthy controls. Uranium concentration was quantified with an inductively coupled plasma mass spectrometer. The odds ratios of NTDs for uranium exposure levels, categorized into quartiles, were estimated using logistic regression. The median concentration of uranium in the NTD group (0.409 ng/g) was significantly higher than that in the control group (0.218 ng/g). The risk for NTDs increased 2.52-fold (95% CI, 1.85–3.45) for concentrations of uranium above the median value for all participants. After adjusting for confounders, the risk for NTDs increased 1.36-fold (95% CI, 1.25–6.17), 1.77-fold (95% CI, 1.09–2.85), and 3.60-fold (95% CI, 2.30–5.64) for the second, third, and fourth quartiles of uranium concentrations compared to the lowest quartile, respectively. Prenatal exposure to uranium is a risk factor for NTDs in this population. Prospective studies are needed to further validate this finding.

A comparison of the maternal levels of serum proprotein convertase subtilisin/kexin type 9 in pregnant women with the complication of fetal open neural tube defects.

It was aimed to evaluate the levels of maternal serum proprotein convertase subtilisin/kexin type 9 (PCSK9) in pregnant women with a fetus diagnosed with open neural tube defects (NTDs). This case-control study included 38 pregnant women carrying fetuses with open NTDs and 44 age-matched, pregnant women with no specified risk factors. Comparisons were made of the groups in respect of demographic and clinical data and PCSK9 levels. To examine the performance of PCSK9 levels in the prediction of fetal open NTDs, receiver operating characteristic (ROC) curve analysis was used. In the first and second trimesters, PCSK9 levels were determined to be lower in the NTD group than in the control group (p=0.010 and p=0.015, respectively). In the first trimester, the lower PCSK9 levels in the NTD group were not statistically significant (p=0.575). In the second trimester, the ROC curve value with the best balance of sensitivity/specificity for PCSK9 was 71.9ng/ml (84.6% sensitivity, 51.7% specificity) and in the first and second trimester combined, 74.4ng/ml (81.6% sensitivity, 45.5% specificity) (p=0.015, p=0.036, respectively). PCSK9 may be involved in the etiopathogenesis of open NTDs at the critical steps of fetal neuronal differentiation. Although it has limitations, PCSK9 may be used as an additional biomarker for the screening of NTDs.

Associations between prenatal exposure to cadmium and lead with neural tube defect risks are modified by single-nucleotide polymorphisms of fetal MTHFR and SOD2: a case\u2013control study

BackgroundPrenatal exposure to heavy metals is implicated in the etiology of birth defects. We investigated whether concentrations of cadmium (Cd) and lead (Pb) in umbilical cord tissue are associated with risk for neural tube defects (NTDs) and whether selected genetic variants of the fetus modify their associations.MethodsThis study included 166 cases of NTD fetuses/newborns and 166 newborns without congenital malformations. Umbilical cord tissue was collected at birth or elective pregnancy termination. Cd and Pb concentrations were assessed by inductively coupled plasma-mass spectrometry, and 20 single-nucleotide polymorphisms (SNPs) in 9 genes were genotyped. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to estimate the risk for NTDs in association with metal concentrations or genotype using logistic regression. Multiplicative-scale interactions between the metals and genotypes on NTD risk were assessed with logistic regression, and additive-scale interactions were estimated with a non-linear mixed effects model.ResultsHigher concentrations of Cd were observed in the NTD group than in the control group, but no difference was found for Pb. Concentrations of Cd above the median level showed a risk effect, while the association between Pb and NTD risk was not significant in univariate analyses. The association of Cd was attenuated after adjusting for periconceptional folic acid supplementation. Fetuses with the AG and GG genotypes of rs4880 in SOD2 (superoxide dismutase 2) tended to have a lower risk, but fetuses with the CT and TT genotypes of rs1801133 in MTHFR (5,10-methylenetetrahydrofolatereductase) have a higher risk for NTDs when compared to their respective wild-type. rs4880 and Cd exhibited a multiplicative-scale interaction on NTD risk: the association between higher Cd and the risk for NTDs was increased by over fourfold in fetuses carrying the G allele [OR 4.43 (1.30–15.07)] compared to fetuses with the wild-type genotype. rs1801133 and Cd exposure showed an additive interaction, with a significant relative excess risk of interaction [RERI 0.64 (0.02–1.25)].ConclusionsPrenatal exposure to Cd may be a risk factor for NTDs, and the risk effect may be enhanced in fetuses who carry the G allele of rs4880 in SOD2 and T allele of rs1801133 in MTHFR.

Essential trace elements in umbilical cord tissue and risk for neural tube defects

Deficient or excessive quantities of essential trace elements (ETEs)1 in the fetal environment can compromise developmental processes. We investigated whether concentrations of zinc (Zn), manganese (Mn), selenium (Se), cobalt (Co), molybdenum (Mo), and nickel (Ni) in umbilical cord tissue are associated with risk for neural tube defects (NTDs). Umbilical cord tissues from 166 cases of NTD cases and 166 matched controls were collected and element concentrations were measured using inductively coupled plasma-mass spectrometry. Associations between ETE concentrations and the risk for NTDs were estimated using multivariate logistic regression while adjusting for potential confounders. Bayesian kernel machine regression (BKMR) was used to examine the joint effects of these ETEs. We found that median concentrations of Ni were higher but those of Mo and Co were lower in the NTD group than in the control group. Co was the only element that was associated with NTD risk after adjusting for confounders (OR 0.31, 95 % CI 0.12–0.79 for the second and OR 0.37, 95 % CI 0.15–0.91 for the top tertile relative to the lowest tertile). The association between Co and NTD risk was confirmed with the BKMR model. In addition, a joint effect of the six ETE mixture on NTD risk was observed: the risk decreased with the levels of the mixture from 25th percentile through 75th percentile. In conclusion, higher levels of Co were associated with lower risk for NTDs, and NTD risk decreased with the levels of the six ETEs as a co-exposure mixture, suggesting a protective effect.

Inositol Deficiency Increases Neural Tube Defect Susceptibility by PI3K/AKT Signaling Pathway (P11-009-19)

ObjectivesTo explore the possible mechanisms of inositol deficiency in neural tube defects (NTDs). MethodsThe gas chromatography–mass spectrometry (GC-MS) analysis was used to detect the plasma inositol levels of NTD pregnancies and non-NTD controls from a high-prevalence area of Shanxi Province in northern China. A maternal MI deficient mouse model was established by using intraperitoneal injection of Li2CO3, which act as an inhibitor of inositol 1-phosphatase (IMPase) and a key enzyme for the synthesis and recycling of inositol in vivo. Using the phospho-protein array to find the possible differential phosphorylated proteins between the NTD and control group in MI deficiency human and mouse respectively. We performed pathway analysis on the differential phosphorylated proteins using KEGG databases of human NTDs with MI deficiency. ResultsWe found that maternal MI deficiency was associated with an increased risk of NTDs (Pearson correlation coefficient r = –0.19, P < 0.05). The MI levels of the pregnant mouse decreased significantly after Li2CO3 injection and reach to the lowest level at 8h after the injection (23.72mg/L vs 44.15 mg/L P < 0.05). Repeat trials showed that the average incidence of NTDs was 26.7%. The NTD phenotypes included encephalocele (85.8%), anencephaly (5.7%) and spina bifida (8.5%). The result of phospho-protein array displayed that PI3K-Akt signaling pathway (hsa04151) was the most enriching pathway. We then validated the proteins involved in the PI3K-Akt signaling pathway using a mouse phospho-protein array. A total of 21 proteins were found to be differentially phosphorylated (Fold change > 1.5), and 14 of them were differentially phosphorylated in both the human and mouse, including YWHAZ, AKT1, AKT2, BCL2, CCND1, NOS3, PTK2, IRS1, MTOR (mTOR), TP53, RPS6KB1 (p70S6K), PDPK1, PPP2CA and PTEN. Further pathway analysis on the 14 common differentially phosphorylated protein found that PI3K/Akt/mTOR/p70S6K pathway was the most disturbed signaling pathway induced by MI deficiency. ConclusionsOur study indicated that PI3K-Akt signaling pathway might be one of the important regulatory mechanisms of inositol deficiency-induced NTDs. Funding SourcesThis study was supported by The National Key Basic Research Program (2018YFC1002500), National Nature Science Foundation of China (81571443 to JW, 81801451 to JG).

Temporal expression of genes involved in folate metabolism and transport during placental development, preeclampsia and neural tube defects.

Folate is an essential micronutrient during pregnancy. The differential expression of genes related to folate transport and metabolism during the advancing gestation and pregnancy complications is not well established. Hence, we studied the gene expression of folate metabolism and transport proteins in the placenta with advancing gestation, preeclampsia and neural tube defects (NTD). The expression of folate transporters and enzymes involved in folate metabolism in the placenta with advancing gestation and pregnancy-related disorders were studied by 2-step RT-PCR. Folate levels were estimated by microbiological assay using Lactobacillus casei. Significant changes in levels of placental folate metabolizing enzymes were found in both physiological and pathological pregnancies during advancing gestation. Expression of methyltetrahydrofolate reductase (MTHFR) (p < 0.001) and cystathionine-β-synthase (CBS) (p < 0.001) was decreased while that of methionine synthase (MS) (p < 0.001) was increased with advancing gestation. A much-reduced expression of MTHFR (p < 0.01) and an abnormally high expression of methionine synthase reductase (p < 0.001) were observed in the NTD group. In NTDs, there was an adaptive up-regulation of folate transporters mainly reduced folate carrier (p < 0.001) and folate receptor alpha (p < 0.001). MTHFR expression showed a strong positive correlation (r = 0.96, p < 0.01) with folate levels in placenta. Pregnant women with preeclampsia had low expression of MS (p < 0.01) in association with low folate levels. Placental folate metabolizing enzymes exhibited a differential pattern during advancing gestation. Deficient folate status in association with alteration in expression of enzymes involved in folate metabolism might be associated with pregnancy complications such as preeclampsia and NTDs.

Frequency and Risk Factors of Neural Tube Defects In Samsun Province

Abstract Background: Neural tube defects (NTD) are a group of severe human congenital malformations and complex disorders appear to be affected by multiple factors, both genetic and environmental contributions. Aim: To asses the frequency of NTD in Samsun province and investigate the relationship between NTD and sociodemographic properties of families, maternal eating habits, maternal serum folic acid, and vitamin B12 levels. Study design : Case- control study Method: The women who gave birth to infants with NTDs and whose pregnancies were terminated due to having fetuses with NTDs between July 2007 and September 2008 were included in the study. The frequency of NTD was calculated from medical records for Samsun province. Sociodemographic characteristics, nutritional status, obstetric histories teratogen exposure and vitamin B12 and folic acid levels of study group were compared with controls. Results: In the study period, 63 fetuses with isolated NTD were noted. The frequency of NTD in Samsun region was %o3,4. In the study group, family incomes , maternal education and consumption of meat, milk, egg, cheese, vegetable, and legumes were lower than the control group (p<0.05). Sharing of the house with grandparents, unemployment rate, rate of febrile diseases, use of antipyretics, exposure to radiation were higher (p<0.05). Both maternal serum vitamin B12, folic acid in NTD group were lower than controls. Conclusion: The frequency of NTD in Samsun region was relatively high. NTD was more frequent in individuals with poor maternal education, low income, and insufficient nutrition. Low serum vitamin B12 and folic acid levels posed an increased risk for NTD. The importance of the vitamin supplements during pregnancy is to be better appreciated by the health authorities as well as the families.

Inhibition of NRF2 signaling and increased reactive oxygen species during embryogenesis in a rat model of retinoic acid-induced neural tube defects

Exposure to retinoic acid (RA) during pregnancy increases the risk of serious neural tube defects (NTDs) in the developing fetus. The precise molecular mechanism for this process is unclear; however, RA is associated with oxidative stress mediated by reactive oxygen species. Nuclear factor erythroid 2-related factor 2 (NRF2) is a master regulator of oxidative stress that directs the expression of antioxidant genes and detoxifying proteins to maintain redox homeostasis. We established a rat model of NTDs in which pregnant dams were administered all-trans (at)RA on gestational day 10, and oxidative stress levels and the spatiotemporal expression of NRF2 and its downstream targets were examined in the resulting embryos and in maternal blood. In the NTD group, total antioxidative capacity decreased and 8-hydroxy-2′-deoxyguanosine increased in maternal serum and fetal spinal cord tissues. Plasma GSH content, the GSH/GSSG ratio, and glutathione peroxidase activity in fetal spinal cords were lower in the NTD group relative to controls. We detected NRF2 protein reduction and concomitant upregulation of Kelch-like ECH-associated protein 1 (KEAP1) - a cytoplasmic inhibitor of NRF2 - in the NTD group. The mRNA and protein levels of downstream targets of NRF2 were downregulated in the spinal cords of NTD embryos. These data demonstrate substantial oxidative stress and NRF2 signaling pathway disruption in a model of NTDs induced by atRA. The inhibitory effects of atRA on NRF2 signaling may lower cellular defenses against RA-induced oxidative stress and could play important roles in NTD occurrence during embryonic development.

English

Background: The most common congenital malformations are Neural tubedefects (NTDs) occurring in 0.6 per 1,000 live births in the United States, and almost 4000pregnancies are recorded of babies with neural tube defects, among them anencephalyand Spina bifida are the most common and their annual incidence is 2,500 to 3,000 births inthe United States. The etiology of NTDs is still an enigma, however, in the past few decadesvaluable advances has been made in understanding the causation and measures to preventNTDs and many risk factors are indentified which are associated with it. Objectives: This studywas designed to determine the risk factors and their association with neural tube defects. StudyDesign: Case control study. Place and Duration of Study: This study was conducted at unit111 Lady Willingdon Hospital Lahore and duration was one year from 1.1.2016 to 31.12.2016.Methodology: A total of 120 mothers were included in the study, of which 30 were having ofbabies delivered with NTDs, matched with 90 mothers delivered babies without NTDs (Threecontrols for each NTD case). Informations were collected on special Performa, data was analyzedon SPSS version 20. Results: Majority of the patients in both groups were found between 31-40 years of age, 43.33 %( n13) in patients with NTD group and 56.67 %( n51) in controls whileonly 16.67% (n5) in NTD and 17.78 % (n16) were found between 21-30 years. The mean agewas recorded as 33.06+1.21 and 32.12+ 0.89 respectively. Regarding parity, 23.33% (n7) werefound between P1-2, 26.67% (n11) were P2-3 while 40% (n12) with Parity &gt;4 in the NTD group,while 21.11% (n19) were p1-2, 37.77% (n 34) with P 3-4 and 41.12% (n37) were P &gt;4 in controlgroup. 86.67% (n 26) were found with poor economic status and 13.33% (n4) were found withrich status in NTDs, while 18.89% (n17) were found with poor and 81.11% (n73) with rich statusin control group. Distribution of fetuses according to their gender revealed that 20% (n6) weremales, and 80% (n24) were females in NTDs while 47.77 %( n43) were found males and 52.23%(n47) were females in controls. Regarding family history 80% (n24) with positive history of NTDsin patients of NTD group and 20% (n6) with no history while 4.44% (n4) had positive history and95.56% (n86) had no familial history of NTD in control cases. About previous history of NTDs,93.33% (n28) were found with positive previous history of NTDs and only 6.67% (n2)with noprevious history of NTDs in NTD group, while only 5.56% (n5) were found with positive previoushistory of NTDs and 94.44%(n85) with no previous history in controls. Conclusions: Poor socioeconomic status, family history and previous history of a baby with Neural tube defects are themajor risk factors.

NEURAL TUBE DEFECTS (NTDS);

Background: The most common congenital malformations are Neural tubedefects (NTDs) occurring in 0.6 per 1,000 live births in the United States, and almost 4000pregnancies are recorded of babies with neural tube defects, among them anencephalyand Spina bifida are the most common and their annual incidence is 2,500 to 3,000 births inthe United States. The etiology of NTDs is still an enigma, however, in the past few decadesvaluable advances has been made in understanding the causation and measures to preventNTDs and many risk factors are indentified which are associated with it. Objectives: This studywas designed to determine the risk factors and their association with neural tube defects. StudyDesign: Case control study. Place and Duration of Study: This study was conducted at unit111 Lady Willingdon Hospital Lahore and duration was one year from 1.1.2016 to 31.12.2016.Methodology: A total of 120 mothers were included in the study, of which 30 were having ofbabies delivered with NTDs, matched with 90 mothers delivered babies without NTDs (Threecontrols for each NTD case). Informations were collected on special Performa, data was analyzedon SPSS version 20. Results: Majority of the patients in both groups were found between 31-40 years of age, 43.33 %( n13) in patients with NTD group and 56.67 %( n51) in controls whileonly 16.67% (n5) in NTD and 17.78 % (n16) were found between 21-30 years. The mean agewas recorded as 33.06+1.21 and 32.12+ 0.89 respectively. Regarding parity, 23.33% (n7) werefound between P1-2, 26.67% (n11) were P2-3 while 40% (n12) with Parity &gt;4 in the NTD group,while 21.11% (n19) were p1-2, 37.77% (n 34) with P 3-4 and 41.12% (n37) were P &gt;4 in controlgroup. 86.67% (n 26) were found with poor economic status and 13.33% (n4) were found withrich status in NTDs, while 18.89% (n17) were found with poor and 81.11% (n73) with rich statusin control group. Distribution of fetuses according to their gender revealed that 20% (n6) weremales, and 80% (n24) were females in NTDs while 47.77 %( n43) were found males and 52.23%(n47) were females in controls. Regarding family history 80% (n24) with positive history of NTDsin patients of NTD group and 20% (n6) with no history while 4.44% (n4) had positive history and95.56% (n86) had no familial history of NTD in control cases. About previous history of NTDs,93.33% (n28) were found with positive previous history of NTDs and only 6.67% (n2)with noprevious history of NTDs in NTD group, while only 5.56% (n5) were found with positive previoushistory of NTDs and 94.44%(n85) with no previous history in controls. Conclusions: Poor socioeconomic status, family history and previous history of a baby with Neural tube defects are themajor risk factors.

A pilot study on the association between rare earth elements in maternal hair and the risk of neural tube defects in north China

Rare earth elements (REEs) have many applications in industry, agriculture, and medicine, resulting in occupational and environmental exposure and concerns regarding REE-associated health effects. However, few epidemiological studies have examined the adverse effects of REEs on pregnancy outcomes. Therefore, this study examined the relationship between the REE concentrations in maternal hair growing during early pregnancy and the risk of neural tube defects (NTDs) in offspring. We included 191 women with NTD-affected pregnancies (cases) and 261 women delivering healthy infants (controls). The cases were divided into three subtypes: anencephaly, spina bifida, and encephalocele. Four REEs in maternal hair were analyzed by inductively coupled plasma-mass spectrometry: lanthanum (La), cerium (Ce), praseodymium (Pr), and neodymium (Nd). A questionnaire was used to collect information about maternal sociodemographic characteristics and dietary habits. The median concentrations of Ce and Pr in the NTD group were higher than those in the control group, whereas there were no significant differences for La and Nd. The adjusted odds ratios (ORs) for the four REE concentrations above the median in the case groups were not significantly > 1. An increasing frequency of the consumption of beans or bean products and fresh fruit was negatively correlated with the four REE concentrations. Our results did not suggest that the concentrations of REEs in maternal hair were associated with the risk of NTDs or any subtype of NTDs in the general population.

The association and significance of H3K27me3 and a folate metabolic gene ACat2 in neural tube defects.

AimTo study the association between the expression of H3K27me3 and ACat2 (a folate metabolic protein), in order to elucidate the protective mechanism of folic acid (FA) in neural tube defects (NTDs).MethodsEighteen female SD rats were randomly divided into normal, NTD and FA group. NTD group was induced by all-trans retinoic acid (ATRA) at E10d. FA group was fed with FA supplementation since 2 weeks before pregnancy, followed by ATRA induction. At E15d, FA level in the embryonic neural tube was determined by ELISA. Neural stem cells (NSCs) were isolated. Cell proliferation was compared by CCK-8 assay. The differentiation potency was assessed by immunocytochemical staining. H3K27me3 expression was measured by immunofluorescence method and Western blot. ACat2 mRNA expression was detected by qRT-PCR.ResultsCultured NSCs formed numerous Nestin-positive neurospheres. After 5 days, they differentiated into NSE-positive neurons and GFAP-positive astrocytes. When compared with controls, the FA level in NTD group was significantly lower, the ability of cell proliferation and differentiation was significantly reduced, H3K27me3 expression was increased, and ACat2 mRNA expression was decreased (P <0.05). The intervention of FA notably reversed these changes (P <0.05). H3K27me3 expression was negatively correlated with the FA level (rs = −0.908, P <0.01) and ACat2 level (rs = −0.879, P <0.01) in the neural tube.ConclusionThe increased H3K27me3 expression might cause a disorder of folate metabolic pathway by silencing ACat2 expression, leading to reduced proliferation and differentiation of NSCs, and ultimately the occurrence of NTD. FA supplementation may reverse this process.

Maternal 25-hydroxyvitamin D level and the occurrence of neural tube defects in Tunisia

ObjectiveTo determine whether low vitamin D levels in pregnant women are associated with the occurrence of neural tube defects (NTDs) in Tunisia. MethodsIn a prospective study, pregnant women were recruited at a center in Tunis between January 1, 2012, and December 30, 2013. Women carrying a fetus with a severe NTD were recruited before elective termination. Matched, healthy pregnancy women were enrolled into a control group. Plasma levels of 25-hydroxyvitamin D were measured by a competitive chemiluminescence immunoassay. ResultsOverall, 68 women formed the NTD group and 64 the control group. The mean maternal vitamin D level was significantly lower in the NTD group (20.65±10.25nmol/L) than in the control group (28.30±13.82nmol/L; P<0.001). Vitamin D deficiency was recorded for 53 (78%) women in the NTD group and 39 (61%) in the control group. Vitamin D insufficiency was recorded for 15 (22%) women in the NTD group and 20 (31%) in the control group. Vitamin D sufficiency was found only in the control group (n=5 [8%]; P<0.001). ConclusionThe findings confirm an association between a decreased vitamin D level in pregnant women and the risk of fetal NTDs.

Evaluation of maternal serum folate, vitamin B12, and homocysteine levels andfactor V Leiden, factor II g.20210G>A, and MTHFR variations in prenatallydiagnosed neural tube defects.

Neural tube defects (NTDs) are common congenital malformations that develop as a result of interactions between several genes and environmental factors. Many factors have been investigated in order to understand the etiology of NTDs, and many studies have identified folate intake as a common contributing factor. The exact etiology of the disease is still unknown. In this study, we compared serum folate, vitamin B12, and homocysteine levels, along with common thrombophilia-related genetic variations, including factor V Leiden, factor II g.20210G>A, MTHFR c.677C>T, and MTHFR c.1298A>C, in 35 pregnant women with fetal NTDs and 38 pregnant women with healthy fetuses. A significant difference in serum vitamin B12 level and factor V Leiden frequency was detected between the two groups. On the other hand, serum folate, homocysteine levels, and factor II g.20210G>A, MTHFR c.677C>T, and MTHFR c.1298A>C were not significantly different in the NTD group compared to the controls. These results indicate that vitamin B12 supplementation along with folate may help in lowering NTD frequency. In addition, this is the first study that provides evidence for a possible relationship between increased NTD risk and factor V Leiden.

Folic Acid Intake and Neural Tube Defects: Two Egyptian Centers Experience.

Neural tube defects (NTDs) are a group of congenital malformations with worldwide distribution and complex etiopathogenesis. Folic acid plays a pivotal role in their prevention. We aimed to identify the protective effect of folic acid intake against NTDs and its dependence on different socioeconomic and environmental factors in a cohort of mothers in Egypt.A cross-sectional study was carried over a period of 12 months on mothers who gave birth to babies with NTDs (group 1) and a control group with healthy offsprings (group 2). Both groups completed 2 questionnaires: food frequency questionnaire targeting the daily folate intake, and socioeconomic status and medical history questionnaire.Both groups of mothers received folate <800 μg/day, recommended for pregnant women. A strong association was detected between NTDs and urban residency with medium educated mothers, with negative consanguinity, who had folate intake < 400 μg daily, and who had their food long cooked. Each of these factors separately had a limited impact to cause NTDs, but when present together they did augment each other. Interestingly enough is the role of fava bean, cauliflower, spinach, and mango in predisposing of NTDs in the presence of the above-mentioned factors.The protective effect of folic acid intake against NTDs may depend on the synergism of different socioeconomic and environmental factors (which differ from country to another). In Egypt, females especially the medium-educated who live in urban areas should be well-informed with the value of folate intake in the periconceptional period.

Association of maternal homocysteine and vitamins status with the risk of neural tube defects in Tunisia: A case-control study.

This study was conducted to determine whether low folate and vitamin B12 levels, as well as high homocysteine levels in pregnant women are associated with neural tube defects (NTDs) in Tunisia. A total of 75 NTDs pregnancies and 75 matched controls were included in the study. Their vitamin B12, folate, and red blood cell folate concentrations were measured using a radio-immunoassay kit and total homocysteine concentrations were determined using a fluorescent polarization immunoassay. Vitamin B12 and folate concentrations were lower in NTD-affected pregnant women than in controls (respectively, p = 0.009 and p < 0.001). Total homocysteine concentration was significantly higher in the NTDs group than in controls (p = 0.008). In the case group, the folate levels were positively related with vitamin B12 levels (r = 0.54; p < 0.001) and negatively correlated with total homocysteine levels (r = -0.19; p = 0.04). Besides, red blood cell folate levels were positively correlated with folate levels (r = 0.24; p = 0.02) and negatively correlated with total homocysteine levels (r = -0.37; p = 0.001). Lower concentrations of folate and vitamin B12 are related to the increased risk of NTDs. Both folate and vitamin B12 intake insufficiency could contribute to the increased risk of NTDs. A dietary supplement, combining folate and vitamin B12, might be an effective measure to decrease the NTDs incidence in Tunisia.

Poor sleep during the periconceptional period increases risk for neural tube defects in offspring.

Poor sleep has been studied in relation to various diseases. Few studies have investigated the effect of poor sleep on birth defects. We examined the association of maternal poor sleep during periconceptional period and the risk of neural tube defects (NTDs) in offspring based on a large case-control study in northern China. The subjects included 629 NTD cases and 858 normal controls investigated between 2002 and 2007. Maternal sleep status was collected by health workers within first week after delivery. Logistic regression was used to estimate the odds ratio (OR) and 95% confidence interval (CI) of NTDs in association with poor sleep. The proportion of mothers with frequent poor sleep (≥4 days/week on average) was markedly higher in NTDs group (5.9%) than in control group (1.2%). In the multivariate analysis, frequent poor sleep was significantly associated with an increased risk of total NTDs (adjusted OR, 4.1; 95% CI, 1.9-8.8) and spina bifida subtype (adjusted OR, 6.4; 95% CI, 2.8-14.5). Frequent poor sleep showed a significant interaction with body mass index (BMI). Relative to women who reported poor sleep <4 days/week and with BMI < 24, frequent poor sleep showed a markedly higher increased risk of NTDs among overweight or obese women (adjusted OR, 11.8; 95% CI, 1.4-97.6) than women with BMI < 24 (adjusted OR, 2.5; 95% CI,1.1-5.9). Maternal frequent poor sleep during the periconceptional period may increase the risk for all NTDs and spina bifida. The association appears to be independent of some lifestyle factors that are closely associated with sleep quality.

Markers of macromolecular oxidative damage in maternal serum and risk of neural tube defects in offspring

Neural tube defects (NTDs) are among the most common and severe congenital malformations. To examine the association between markers of macromolecular oxidative damage and risk of NTDs, we measured levels of 8-hydroxy-2′-deoxyguanosine (8-OHdG), protein carbonyl (PC), and 8-iso-prostaglandin F2α (8-iso-PGF2α) in maternal serum samples of 117 women with NTD-affected pregnancies and 121 women with healthy term newborns. We found higher levels of 8-OHdG and PC in the NTD group than in the control group; however, we did not observe a statistically significant difference in 8-iso-PGF2α levels between the NTD and the control groups. NTD risk increased with increasing quartiles of 8-OHdG [odds ratio (OR)=1.17; 95% confidence interval (CI) 0.39–3.51; OR=2.19; 95% CI, 0.68–7.01; OR=3.70; 95% CI, 1.30–10.51, for the second, third, and fourth quartile relative to the lowest quartile, respectively; P=0.009], and with increasing quartiles of PC (OR=2.26; 95% CI, 0.66–7.69; OR=3.86; 95% CI, 1.17–12.80; OR=5.98; 95% CI, 1.82–19.66, for the second, third, and fourth quartile relative to the lowest quartile, respectively; P=0.002]. Serum levels of 8-OHdG were higher in women who did not take folic acid supplements during the periconceptional period. These results suggest that oxidative stress is present in women carrying pregnancies affected by NTDs.

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

IntroductionMaternal exposure to polycyclic aromatic hydrocarbons (PAHs) has been shown to be associated with an elevated risk for neural tube defects (NTDs). In the human body, PAHs are bioactivated and the resultant reactive epoxides can covalently bind to DNA to form PAH–DNA adducts, which may, in turn, cause transcription errors, changes in gene expression or altered patterns of apoptosis. During critical developmental phases, these changes can result in abnormal morphogenesis. ObjectivesWe aimed to examine the relationship between the levels of PAH–DNA adducts in cord blood and cord tissue and the risk of NTDs. MethodsFrom 2010 to 2012, 60 NTD cases and 60 healthy controls were recruited from a population-based birth defects surveillance system in five counties of Shanxi Province in Northern China, where the emission of PAHs remains one of the highest in the country and PAHs exposure is highly prevalent. PAH–DNA adducts in cord blood of 15 NTD cases and 15 control infants, and in cord tissue of 60 NTD cases and 60 control infants were measured using the 32P-postlabeling method. ResultsPAH–DNA adduct levels in cord blood tend to be higher in the NTD group (28.5 per 108 nucleotides) compared with controls (19.7 per 108 nucleotides), although the difference was not statistically significant (P=0.377). PAH–DNA adducts in cord tissue were significantly higher in the NTD group (24.6 per 106 nucleotides) than in the control group (15.3 per 106 nucleotides), P=0.010. A positive dose-response relationship was found between levels of PAH–DNA adducts in cord tissue and the risk of NTDs (P=0.009). When the lowest tertile was used as the referent and potential confounding factors were adjusted for, a 1.03-fold (95% CI, 0.37–2.89) and 2.96-fold (95% CI, 1.16–7.58) increase in the risk of NTDs was observed for fetuses whose cord tissue PAH–DNA adduct levels were in the second and highest tertile, respectively. ConclusionsHigh levels of PAH–DNA adducts in fetal tissues were associated with increased risks of NTDs.