Use of Maternal Race and Weight Provides Equitable Performance in Serum Screening for Open Neural Tube Defects.

BACKGROUND: Maternal serum alpha-fetoprotein (AFP) levels are used in screening for open neural tube defects (ONTD). Historical reports show that AFP levels and maternal weights are higher in self-reported Black than White individuals, but recent reports question the need to account for these variables in screening. Our study compares screening performance with and without accounting for race. METHODS: Retrospective analysis was performed on deidentified prenatal screening records including maternal weight and self-reported race of White or Black. Gestational age-specific medians and weight-adjusted multiples of the median levels were calculated separately for each group and using a race-agnostic analysis. Outcome measures included the proportion of screen-positive results. RESULTS: Records for analysis (n = 13 316) had an ultrasound confirmed gestational age between 15 and 21 completed weeks, singleton pregnancy, and self-reported race. Race was Black for 26.3%. AFP levels for pregnancies in Black individuals were higher than in White individuals: 6% to 11% depending on gestational age. Race-specific gestational age and maternal weight analyses resulted in similar screen-positive rates for self-reported White and Black individuals at 0.74% vs 1.00%, respectively (P = 0.14). However, use of race-agnostic analyses resulted in a screen-positive rate that was 2.4 times higher in Black than White individuals (P < 0.001). CONCLUSION: These data show that the historical method of accounting for maternal race and weight in prenatal screening for ONTD provides equitable performance. Using a race-agnostic methodology results in an increased screen-positive rate and a disproportionate rate of required follow-up care for individuals who self-identify as Black.

NEURAL TUBE DEFECTS AND MICRONUTRIENTS DEFICIENCY PREVALENCE IN GEORGIA.

Until 2015, systematic statistical data on micronutrient deficiency was not available in Georgia, to provide developing national strategy. In the same year, the National Centre for Disease Control and Public Health of Georgia (NCDC) in collaboration with the USA CDC launched the project "Strengthening surveillance of micronutrient deficiency in Georgia". In 2015 we did choose sentinel surveillance approach. For setting nutrition surveillance system 8 sentinel sites (2 sites in each region/children and pregnant health facilities) in four regions of Georgia (Tbilisi, Kakheti, Achara, and Samegrelo) were selected, using the criteria of geographical, social, ethnical, urban/rural, and religion. Also, existing information about malnutrition and dietary habits from the above mentioned regions. The project protocols was approved by the Institutional review board (IRB) at the NCDC and by the Research Review Committee and Ethical review committee of the US CDC. As a result of surveillance system functioning (2016-2019) we reviled that, about 36% out of 1021 studied children U2 (12-23 months) were anemic, 74% of them were identified as iron deficient. Hemoglobin was tested among 963 pregnant women and about 21% of them were found anemic, 57% were iron deficient, and 28% tested positive for folate deficiency. Neural tube defects (NTDs) prevalence per 1000 live births registered in sentinel sites was high 3.7. Our results show that anemia and iron deficiency are prevalent among both pregnant women and children of the specified age group in Georgia. Additionally, folate deficiency was quite common during the1st trimester of pregnancy. Our findings will inform public health policy decision makers to take relevant decisions on required interventions, such as health education, distribution of relevant supplements, and food fortification.

Expression of Sigma-Class Glutathione-S-Transferase in Fetal and Pediatric Filum Terminale Samples: A Comparative Study.

Background and objectives: The pathophysiology of tethered cord syndrome (TCS) in children is not well elucidated. An inelastic filum terminale (FT) is the main factor underlying the stretching of the spinal cord in TCS. Our study aimed to investigate the expression of glutathione-S-transferase (GST) in children and fetal FT samples in order to understand the relationship between this enzyme expression and the development of TCS. Materials and Methods: FT samples were obtained from ten children with TCS (Group 1) and histological and immunohistochemical examinations were performed. For comparison, FT samples from fifteen normal human fetuses (Group 2) were also analyzed using the same techniques. Statistical comparison was made using a Chi-square test. Results: Positive GST-sigma expression was detected in eight (80%) of 10 samples in Group 1. The positive GST-sigma expression was less frequent in nine (60%) of 15 samples from Group 2. No statistically significant difference was detected between the two groups (p = 0.197). Conclusions: Decreased FT elasticity in TCS may be associated with increased GST expression in FT. More prospective studies are needed to clarify the mechanism of the GST-TCS relationship in children.

Digenic variants of planar cell polarity genes in human neural tube defect patients.

Neural tube defects (NTDs) are considered to be a complex genetic disorder, although the identity of the genetic factors remains largely unknown. Mouse model studies suggest a multifactorial oligogenic pattern of inheritance for NTDs, yet evidence from published human studies is surprisingly absent. In the present study, targeted next-generation sequencing was performed to screen for DNA variants in the entire coding regions and intron-exon boundaries of targeted genes using DNA samples from 510 NTD cases. These candidate genes were PCP genes, including VANGL1, VANGL2, CELSR1, SCRIB, DVL2, DVL3 and PTK7. Candidate variants were validated using Sanger sequencing. A total of 397 single nucleotide variants(SNVs) were identified with a mean depth of approximately 570×. Of these identified SNVs, 74 were predicted to affect protein function and had a minor allele frequency of <0.01 or unknown. Among these 74 missense SNVs, 10 were identified from six NTD cases that carried two mutated genes. Of the six NTD cases, three spina bifida cases and one anencephaly case carried digenic variants in the CELSR1 and SCRIB gene; one anencephaly case carried variants in the CELSR1 and DVL3 gene; and one spina bifida case carried variants in the PTK7 and SCRIB genes. Three cases that parental samples were available were confirmed to be compound heterozygous. None of the digenic variants were found in the 1000 genome database. The findings imply that genetic variation might interact in a digenic fashion to generate the visible NTD phenotypes and emphasize the importance of these genetic interactions in the development of NTDs in humans.

LRP2 gene variants and their haplotypes strongly influence the risk of developing neural tube defects in the fetus: a family-triad study from South India.

Neural tube defects (NTDs) are the leading cause of infant deaths worldwide. Lipoprotein related receptor 2 (LRP2) has been shown to play a crucial role in neural tube development in mouse models. However, the role of LRP2 gene in the development of human NTDs is not yet known. In view of this, family-based triad approach has been followed considering 924 subjects comprising 124 NTD case-parent trios and 184 control-parent trios diagnosed at Institute of Genetics and Hospital for Genetic Diseases, Hyderabad. Blood and tissue samples were genotyped for rs3755166 (-G759A) and rs2544390 (C835T) variants of LRP2 gene for their association with NTDs. Assessment of maternal-paternal genotype incompatibility risk for NTD revealed 3.77-folds risk with a combination of maternal GA and paternal GG genotypes (GAxGG = GA,p < 0.001), while CT genotypes of both the parents showed 4.19-folds risk for NTDs (CTxCT = CT,p = 0.009). Haplotype analysis revealed significant risk of maternal A-T (OR = 4.48,p < 0.001) and paternal G-T haplotypes (OR = 5.22,p < 0.001) for NTD development. Further, linkage analysis for parent-of-origin effects (POE) also revealed significant transmission of maternal 'A' allele (OR = 2.33,p = 0.028) and paternal 'T' allele (OR = 6.00,p = 0.016) to NTDs. Analysis of serum folate and active-B12 levels revealed significant association with LRP2 gene variants in the causation of NTDs. In conclusion, the present family-based triad study provides the first report on association of LRP2 gene variants with human NTDs.

Homocysteine and vitamin B12: Other causes of neural tube defects in Eastern Uttar Pradesh and Western Bihar population.

BACKGROUND: Neural tube defects (NTDs) are congenital malformations with an incidence of 1-10/1000 live births. Homocysteine and vitamin B12 metabolism have been shown to be associated with NTDs. AIM: To investigate the status of maternal and neonate's folic acid, homocysteine, and vitamin B12 levels and their association with the risk of development of NTDs in the population of Eastern Uttar Pradeshand Western Bihar, India. MATERIALS AND METHODS: This study is a cross-sectional, retrospective study where 96 mothers who either had a first NTD child or had a history of NTD child in the family and 126 neonates with spina bifida were recruited during the period 2012-2015. Eighty-four control mothers whose previous and current pregnancies were normal, and 87 control neonates who had no defects and were within the same age range as the NTD affected neonates, recruited from the department of pediatric surgery, were enrolled in the study. Plasma concentrations of folic acid, vitamin B12, and homocysteine were compared between cases and controls. RESULTS: The folic acid level in the mothers and neonates was within the normal limit. A significant increase in the level of homocysteine in mothers with affected pregnancy and in neonate cases in comparison to control mothers was obseved. Further, a significant decrease in the level of vitamin B12 in mothers with NTD neonates and in the affected neonates was noted. A negative correlation was found between homocysteine and vitamin B12 levels in case and control mothers. CONCLUSION: A correlation of an increase in serum homocysteine with a decrease in vitamin B12 was seen in mothers of neonates with NTD. A similar observation as made in the neonates with NTDs. It may be suggested that maternal decrease in vitamin B12, in mothers who have normal folic acid may be associated with NTD in their children.

Formate: The Neglected Member of One-Carbon Metabolism.

Formate, the only non-tetrahydrofolate (THF)-linked intermediate in one-carbon metabolism, is produced in mammals from a variety of metabolic sources. It occurs in serum of adults at a concentration of approximately 30 µM. Its principal function lies as a source of one-carbon groups for the synthesis of 10-formyl-THF and other one-carbon intermediates; these are primarily used for purine synthesis, thymidylate synthesis, and the provision of methyl groups for synthetic, regulatory, and epigenetic methylation reactions. Although formate is largely produced in mitochondria, these functions mostly occur in the cytoplasm and nucleus. Formate plays a significant role in embryonic development, as evidenced by the effectiveness of formate in the pregnant dam's drinking water on the incidence of neural tube defects in some genetic models. High formate concentrations in fetal lambs may indicate a role in fetal development and suggest that extracellular formate may play a role in the interorgan distribution of one-carbon groups.

Autoantibodies against homocysteinylated protein in a mouse model of folate deficiency-induced neural tube defects.

BACKGROUND: Periconceptional supplementation with folic acid results in a significant reduction in the incidence of neural tube defects (NTDs). Nonetheless, NTDs remain a leading cause of perinatal morbidity and mortality worldwide, and the mechanism(s) by which folate exerts its protective effects are unknown. Homocysteine is an amino acid that accumulates under conditions of folate-deficiency, and is suggested as a risk factor for NTDs. One proposed mechanism of homocysteine toxicity is its accumulation into proteins in a process termed homocysteinylation. METHODS & RESULTS: Herein, we used a folate-deficient diet in pregnant mice to demonstrate that there is: (i) a significant inverse correlation between maternal serum folate levels and serum homocysteine; (ii) a significant positive correlation between serum homocysteine levels and titers of autoantibodies against homocysteinylated protein; and (iii) a significant increase in congenital malformations and NTDs in mice deficient in serum folate. Furthermore, in mice administered the folate-deplete diet before conception, supplementation with folic acid during the gestational period completely rescued the embryos from congenital defects, and resulted in homocysteinylated protein titers at term that are comparable to that of mice administered a folate-replete diet throughout both the pre- and postconception period. These results demonstrate that a low-folate diet that induces NTDs also increases protein homocysteinylation and the subsequent generation of autoantibodies against homocysteinylated proteins. CONCLUSION: These data support the hypotheses that homocysteinylation results in neo-self antigen formation under conditions of maternal folate deficiency, and that this process is reversible with folic acid supplementation.

Inositol for the prevention of neural tube defects: a pilot randomised controlled trial.

Although peri-conceptional folic acid (FA) supplementation can prevent a proportion of neural tube defects (NTD), there is increasing evidence that many NTD are FA non-responsive. The vitamin-like molecule inositol may offer a novel approach to preventing FA-non-responsive NTD. Inositol prevented NTD in a genetic mouse model, and was well tolerated by women in a small study of NTD recurrence. In the present study, we report the Prevention of Neural Tube Defects by Inositol (PONTI) pilot study designed to gain further experience of inositol usage in human pregnancy as a preliminary trial to a future large-scale controlled trial to evaluate efficacy of inositol in NTD prevention. Study subjects were UK women with a previous NTD pregnancy who planned to become pregnant again. Of 117 women who made contact, ninety-nine proved eligible and forty-seven agreed to be randomised (double-blind) to peri-conceptional supplementation with inositol plus FA or placebo plus FA. In total, thirty-three randomised pregnancies produced one NTD recurrence in the placebo plus FA group (n 19) and no recurrences in the inositol plus FA group (n 14). Of fifty-two women who declined randomisation, the peri-conceptional supplementation regimen and outcomes of twenty-two further pregnancies were documented. Two NTD recurred, both in women who took only FA in their next pregnancy. No adverse pregnancy events were associated with inositol supplementation. The findings of the PONTI pilot study encourage a large-scale controlled trial of inositol for NTD prevention, but indicate the need for a careful study design in view of the unwillingness of many high-risk women to be randomised.

Identification of Biomarkers by Proteomics for Prenatal Screening for Neural Tube Defects.

Neural tube defect (NTD) is a serious congenital defect, but current methods for identifying NTD are limited. We used proteomic analysis of maternal serum to identify NTD-specific proteins whose levels differed between women with NTD fetuses (n = 50) and those with healthy fetuses (n = 40). Three NTD-specific protein peaks (8,130.6, 15,941.7, and 3,960.3 m/z) were identified using MALDI-TOF-mass spectrophotemetry, and were included in a diagnostic model developed using Biomarker Patterns software. The model used cut-offs for the relative intensity of the three peaks to indicate if a case had or did not have NTD. The model identified 48 of the 50 NTD cases and 36 of the 40 control cases correctly, resulting in the sensitivity of 96.0% (48/50) and the specificity of 90.0% (36/40). The diagnostic model was also tested on 105 clinical cases at high risk for NTD, as determined by having high alpha-fetoprotein levels, resulting in the sensitivity of 100% (101/101) and the specificity of 75.0% (3/4). Using the International Protein Index database, we identified proteins with a molecular mass of 8,130.6 Da as ADP-ribosylation factor 1 and a protein similar to cold agglutinin FS-1 antibody light-chain. The 15,941.7-Da peak corresponded to vitamin K3 protein, and the identity of the 3,960.3-Da protein was unclear. Thus, this study developed a diagnostic model consisting of the three peaks which may be indicators of NTD. This new assay may be at least as accurate for diagnosing NTD compared with the commonly used clinical test that assesses alpha-fetoprotein levels.

Lack of association between the methylenetetrahydropholate reductase gene A1298C polymorphism and neural tube defects in a Turkish study group.

The etiology underlying neural tube defects (NTDs) is not fully understood and is believed to involve a complex milieu of genetic and environmental factors. The A1298C polymorphism in the methylenetetrahydropholate reductase gene (MTHFR) has been associated with mild risk for NTDs. In this study, the genotype distribution of the MTHFR gene A1298C polymorphism and the levels of serum homocysteine, vitamin B12, and folate were evaluated in 33 children with NTDs, their mothers, and 46 healthy controls. Genotyping of the A1298C polymorphism was performed by real-time polymerase chain reaction. The A and C allele frequencies in children with NTDs and their mothers were similar to controls (P = 0.160). The 1298AA and 1298CC genotype frequencies (P = 0.551 and 0.062, respectively) in children with NTDs and their mothers did not differ from controls. On the other hand, the 1298AC genotype frequencies in children with NTDs and their mothers were significantly different from controls (P = 0.025). The genotype frequency of 1298AC was lower in children with NTDs than in controls. There was no significant association between clinical distribution of NTDs and 1298AA/AC/CC genotypes (P > 0.05). Serum vitamin B12 levels were higher in children with NTDs than their mothers and controls (P = 0.001). There were no differences among serum homocysteine and folate levels in all groups (P = 0.494 and 0.141, respectively). Both genetic and nutritional factors are important in the etiology of NTDs. Thus, the A1298C polymorphism cannot be regarded as a major risk factor for NTDs.

Diagnostic value of CA 19-9 in pregnancies complicated by spinal neural tube defects: a preliminary study.

OBJECTIVES: Various physiological and pathological conditions can induce significant variations in plasma concentrations of tumor markers, such as CA 19-9, which is present in the serum and amniotic fluid of pregnant women. Herein, we aimed to determine the clinical importance of maternal serum CA 19-9 levels in the diagnosis of neural tube defects (NTDs). MATERIAL AND METHODS: A total of 100 women were included in this controlled cross-sectional study. Thirty-three patients whose pregnancies were complicated by isolated meningocele or meningomyelocele constituted the study group, whereas 33 normal, healthy pregnant women constituted the control group, and 34 age- and body mass index (BMI)-matched non-pregnant women were chosen for the validation group. RESULTS: The mean maternal serum CA 19-9 levels were 17.2 ± 17.0 IU/mL, 7.1 ± 5.9 IU/mL, and 4.7 ± 3.6 IU/mL in the study, control, and validation groups, respectively (p < 0.001). ROC analyses showed that elevated CA 19-9 values may predict NTDs (p < 0.001). The cut-off value for CA 19-9 was found to be 9.6 IU/mL at 70% (51%-84%, 95% CI) sensitivity and 84% (74%-92%, 95% CI) specificity. CONCLUSIONS: CA 19-9 may be a promising noninvasive marker for NTDs. Further studies are needed to reveal the clinical applicability and diagnostic potential of maternal serum CA 19-9 levels in the identification of NTDs.

Tea consumption is not associated with reduced plasma folate concentration among Chinese pregnant women.

BACKGROUND: The aim of this study was to evaluate the relationship between tea consumption and plasma folate concentration in populations with high and low prevalence of neural tube defects (NTDs) in China. METHODS: Cross-sectional survey was conducted in three cities/counties in China, in which 1724 pregnant women during early second trimester were recruited and interviewed about tea consumption and folic acid use in 2011 to 2012. A total of 5-ml nonfasting blood sample was collected and plasma folate concentration was determined by microbiological assay. RESULTS: Approximately 16.2% of the women reported that they had ever drank tea during and before the current pregnancy, women with higher educational level, and those who resided in urban were more likely to drink tea. Most of them prefer green tea (55.2%); 13.6% of women drank tea ">6 times/week," and 29.0% of them drank "less than once a week." The median of plasma folate concentration was 48.7 nmol/L in women who drank tea while it is 45.2 nmol/L in women who did not drink tea, with no statistical difference. The results showed there was no association between tea drinking and plasma folate concentration in Chinese pregnant women stratified by folic acid supplementation and other selected characteristics. CONCLUSION: Low level of tea drinking is not associated with decreased plasma folate concentration in the Chinese populations with high and low prevalence of NTDs.

Levels of polycyclic aromatic hydrocarbons in maternal serum and risk of neural tube defects in offspring.

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental pollutants, and have been reported to be a risk factor for human neural tube defects (NTDs). We investigated the relationship between PAH concentrations in maternal serum and NTD risk in offspring using a case-control study design, and explored the link between PAH concentrations to household energy usage characteristics and life styles. One hundred and seventeen women who had NTD-affected pregnancies (cases) and 121 women who delivered healthy infants (controls) were recruited in Northern China. Maternal blood samples were collected at pregnancy termination or at delivery. Twenty-seven PAHs were measured by gas chromatography-mass spectrometry. The concentrations of 13 individual PAHs detected were significantly higher in the cases than in the controls. Clear dose-response relationships between concentrations of most individual PAHs and the risk of total NTDs or subtypes were observed, even when potential covariates were adjusted for. High-molecular-weight PAHs (H-PAHs) showed higher risk than low-molecular-weight PAHs (L-PAHs). No associations between PAH concentrations and indoor life styles and energy usage characteristics were observed. It was concluded that maternal exposure to PAHs was associated with an increased risk of NTDs, and H-PAHs overall posed a higher risk for NTDs than L-PAHs.

Is MSAFP still a useful test for detecting open neural tube defects and ventral wall defects in the era of first-trimester and early second-trimester fetal anatomical ultrasounds?

INTRODUCTION: To evaluate whether maternal serum α-fetoprotein (MSAFP) improves the detection rate for open neural tube defects (ONTDs) and ventral wall defects (VWD) in patients undergoing first-trimester and early second-trimester fetal anatomical survey. MATERIAL AND METHODS: A cohort of women undergoing screening between 2005 and 2012 was identified. All patients were offered an ultrasound at between 11 weeks and 13 weeks and 6 days of gestational age for nuchal translucency/fetal anatomy followed by an early second-trimester ultrasound at between 15 weeks and 17 weeks and 6 days of gestational age for fetal anatomy and MSAFP screening. All cases of ONTD and VWD were identified via query of billing and reporting software. Sensitivity and specificity for detection of ONTD/VWD were calculated, and groups were compared using the Fisher exact test, with p < 0.05 as significance. RESULTS: A total of 23,790 women met the criteria for inclusion. Overall, 15 cases of ONTD and 17 cases of VWD were identified; 100% of cases were diagnosed by ultrasound prior to 18 weeks' gestation; none were diagnosed via MSAFP screening (p < 0.001). First-trimester and early second-trimester ultrasound had 100% sensitivity and 100% specificity for diagnosing ONTD/VWD. DISCUSSION: Ultrasound for fetal anatomy during the first and early second trimester detected 100% of ONTD/VWD in our population. MSAFP is not useful as a screening tool for ONTD and VWD in the setting of this ultrasound screening protocol.

Association between the MTHFR (rs1801133) gene variation and serum trace elements levels (Copper and Zinc) in individuals diagnosed with neural tube defects.

BACKGROUND AND AIMS: Neural tube defects (NTDs) occur when the neural tube fails to close within 28 days of human embryonic development. This results in central nervous system disorders like anencephaly, spina bifida, and encephalocele. Early diagnosis and treatment are crucial to minimize their impact on an individual's health and well-being. The present study aims to define the association between prenatal exposure to trace elements (Cu and Zn) and the single nucleotide polymorphism (SNP) of the MTHFR gene involved in folate metabolism pathways in neural tube defects in children and their mothers. MATERIAL AND METHODS: A cross-sectional study involving 331 participants (90 NTD cases, 88 healthy mothers, 85 NTD children, and 68 healthy children) from antenatal check-ups in Obstetrics and Gynaecology and Pediatric Surgery for Neural Tube Defects in the Outpatient Department (OPD) and Inpatient Department (IPD). Assessed Cu and Zn concentrations and their associations. Genomic DNA was extracted, and real-time PCR was used to determine genotypes. Atomic absorption spectrophotometry measured trace elements. Statistical analyses included Chi-Square tests, odds ratios, and Mann-Whitney U tests. RESULTS: Significant associations were found between MTHFR C677T genotypes and NTD risk in mothers (p = 0.0491) and children (p = 0.0297). Allelic frequency analysis indicated a T allele association with NTD risk in children (p = 0.0107). Recessive models showed significant associations in mothers (p = 0.0169) and children (p = 0.1678). Cu levels differed significantly between NTD cases and controls (p < 0.0001), with MTHFR genotypes influencing Cu levels. Zinc levels also varied significantly (p < 0.0001). CONCLUSION: This study reveals complex associations between MTHFR C677T genotypes, trace element concentrations, and NTD risk in mothers and children. This targeted approach allows healthcare providers to identify at-risk pregnancies early, enabling personalised interventions like folic acid supplementation and counselling to moderate neural tube defect (NTD) risk in a future pregnancy.

Fatty acids profile in pregnancies affected by neural tube defects.

This study aimed to determine if maternal fatty acids (FA) levels during pregnancy are associated with the occurrence of neural tube defects (NTDs) and to explore the correlation between FA and maternal vitamin D, homocysteine, vitamin B12, and folate in cases. Plasma FA composition was assessed using capillary gas chromatography. Comparisons between cases and controls were performed by independent samples t-test for continuous variables. Cases had significantly higher levels of heptadecanoic acid, linolelaidic acid, and arachidonic acid (ARA):(eicosapentaenoic acid+docosahexaenoic acid) ratio than controls (p < 0.05). Nervonic acid, ARA, adrenic acid, eicosapentaenoic acid, docosahexaenoic acid, and omega-3 polyunsaturated fatty acids (n-3 PUFA) levels were significantly lower in cases (p < 0.05). Maternal 25-hydroxyvitamin D (25(OH)D) levels were positively correlated with maternal polyunsaturated fatty acids and omega-6 polyunsaturated fatty acids. RBC folate levels were negatively correlated with n-3 PUFA.Further research is required to clarify the association of FA metabolism with NTDs.

The diagnostic utility of folate receptor autoantibodies in blood.

Folate supplementation reduces the risk of neural tube defect (NTD) pregnancy, and folinic acid has been used to correct cerebral folate deficiency (CFD) in children with developmental disorders. In the absence of systemic folate deficiency, the discovery of autoantibodies (AuAbs) to folate receptor α (FRα) that block the uptake of folate offers one mechanism to explain the response to folate in these disorders. The association of FRα AuAbs with pregnancy-related complications, CFD syndrome, and autism spectrum disorders and response to folate therapy is highly suggestive of the involvement of these AuAbs in the disruption of brain development and function via folate pathways. The two types of antibodies identified in the serum of patients are blocking antibody and binding antibody. The two antibodies can be measured by the specific assays described and exert their pathological effects either by functional blocking of folate transport as previously shown or hypothetically by disrupting the FR by an antigen-antibody-mediated inflammatory response. We have identified both IgG and IgM AuAbs in these conditions. The predominant antibodies in women with NTD pregnancy belong to the IgG1 and IgG2 isotype and in CFD children, the IgG1 and IgG4 isotype. This review describes the methods used to measure these AuAbs, their binding characteristics, affinity, cross-reactivity, and potential mechanisms by which folate therapy could work. Because these AuAbs are associated with various pathologies during fetal and neonatal development, early detection and intervention could prevent or reverse the consequences of exposure to these AuAbs.

Is 5-methyltetrahydrofolate an alternative to folic acid for the prevention of neural tube defects?

Women have higher requirements for folate during pregnancy. An optimal folate status must be achieved before conception and in the first trimester when the neural tube closes. Low maternal folate status is causally related to neural tube defects (NTDs). Many NTDs can be prevented by increasing maternal folate intake in the preconceptional period. Dietary folate is protective, but recommending increasing folate intake is ineffective on a population level particularly during periods of high demands. This is because the recommendations are often not followed or because the bioavailability of food folate is variable. Supplemental folate [folic acid (FA) or 5-methyltetrahydrofolate (5-methylTHF)] can effectively increase folate concentrations to the level that is considered to be protective. FA is a synthetic compound that has no biological functions unless it is reduced to dihydrofolate and tetrahydrofolate. Unmetabolized FA appears in the circulation at doses of >200 µg. Individuals show wide variations in their ability to reduce FA. Carriers of certain polymorphisms in genes related to folate metabolism or absorption can better benefit from 5-methylTHF instead of FA. 5-MethylTHF [also known as (6S)-5-methylTHF] is the predominant natural form that is readily available for transport and metabolism. In contrast to FA, 5-methylTHF has no tolerable upper intake level and does not mask vitamin B12 deficiency. Supplementation of the natural form, 5-methylTHF, is a better alternative to supplementation of FA, especially in countries not applying a fortification program. Supplemental 5-methylTHF can effectively improve folate biomarkers in young women in early pregnancy in order to prevent NTDs.

A GCH1 haplotype and risk of neural tube defects in the National Birth Defects Prevention Study.

Tetrahydrobiopterin (BH(4)) is an essential cofactor and an important cellular antioxidant. BH(4) deficiency has been associated with diseases whose etiologies stem from excessive oxidative stress. GTP cyclohydrolase I (GCH1) catalyzes the first and rate-limiting step of de novo BH(4) synthesis. A 3-SNP haplotype in GCH1 (rs8007267, rs3783641, and rs10483639) is known to modulate GCH1 gene expression levels and has been suggested as a major determinant of plasma BH(4) bioavailability. As plasma BH(4) bioavailability has been suggested as a mechanism of neural tube defect (NTD) teratogenesis, we evaluated the association between this GCH1 haplotype and the risk of NTDs. Samples were obtained from 760 NTD case-parent triads included in the National Birth Defects Prevention Study (NBDPS). The three SNPs were genotyped using TaqMan® SNP assays. An extension of the log-linear model was used to assess the association between NTDs and both offspring and maternal haplotypes. Offspring carrying two copies of haplotype C-T-C had a significantly increased NTD risk (risk ratio [RR]=3.40, 95% confidence interval [CI]: 1.02-11.50), after adjusting for the effect of the maternal haplotype. Additionally, mothers carrying two copies of haplotype C-T-C had a significantly increased risk of having an NTD-affected offspring (RR=3.46, 95% CI: 1.05-11.00), after adjusting for the effect of the offspring haplotype. These results suggest offspring and maternal variation in the GCH1 gene and altered BH(4) biosynthesis may contribute to NTD risk.