Incidence Of Neural Tube Defects Research Articles

Chromium levels in placental tissue and neural tube defects: Association and mechanistic study

Human exposure to chromium (Cr) is common but little is known about its adverse effects on pregnancy outcomes. This study aimed to explore the association between Cr exposure and the risk of neural tube defects (NTDs) and the underlying mechanisms of Cr-induced NTDs. 593 controls and 408 NTD cases with placentas were included in this study. Chromium trichloride (Cr(III)) and potassium dichromate (Cr(VI)) were intragastrically administered to pregnant mice and the number of NTDs was recorded. The odds ratio for total NTDs in the highest exposure group in placenta was 4.18 (95% confidence interval (CI), 1.97–8.84). The incidence of fetal NTDs in mice administered with Cr(III) showed a dose-response relationship. Cr(VI) didn't show teratogenicity of NTDs whereas increased the stillbirth rate. Prenatal exposure to Cr(III) increased levels of oxidative stress and apoptosis in fetal mice. RNA-sequencing results indicated significant enrichment of the MAPK pathway. RT-qPCR and Western blot analysis revealed that Cr(III) induced increased expression of p-JNK, p-P38, and Casp3. Toxicological effects can be partly antagonized by antioxidant supplementation. High chromium exposure was associated with increased human NTD risks. Excessive Cr(III) exposure can induce NTDs in fetal mice by increasing apoptosis through upgrading oxidative stress and then activating JNK/P38 MAPK signaling pathway.

Incidence of neural tube defects and associated anomalies in a tertiary care hospital

Abstract Background: Neural tube defects (NTDs) are the second most common congenital malformations after cardiac anomalies. The rate of associated malformation is reported to be 17%–80%. NTDs could also be a component of syndromic process. Objective: The objective of the study was to study the incidence of NTDs and associated anomalies. Methods: A hospital-based observational study was carried out among 6934 pregnant women referred for ultrasound. Pregnant women with NTDs were included. Detailed maternal history and clinical data were recorded. All ultrasound examinations were performed transabdominally by a radiologist using a 1–5 MHz convex array transducer (Voluson S8). Results: During this period of study, a total of 6934 pregnant women were screened and 47 cases of NTDs were detected and included, giving an incidence of 6.7 in 1000 conceptions (95% confidence interval = 5.02–8.92). NTDs were more common in mothers of age group 20–30 years. Spina bifida was the most common type of NTD in 53% of the cases. The most common type of spina bifida was meningomyelocele in 56%. The most common associated central nervous system (CNS) anomaly was Chiari II malformation. Conclusion: The most common NTD was spina bifida. CNS anomalies are more commonly associated with NTDs, followed by extremity defects.

A CASE REPORT OF MYELOMENIGOCELE WITH ARNOLD CHIARI MALFORMATIN II-HIGHLIGHTING THE IMPORTANCE OF ANEMIA MUKTH BHARATH PROGRAMME

Introduction:Neural tube defects are common complex congenital malformations resulting from failure of neural tube closure during embryogenesis, which usually completes by 28 days post conception. Myelomeningocele is almost always associated with Arnold Chiari Malformation II (CM II)and vice versa. Aims &Objectives : As most of the neural tube defects can be prevented by pre-conceptional folate supplements, we would like to high light the importance of proper implementation and utilization of Anemia Mukhth Bharath Programme. Background: Neural tube defects (NTDs) are caused by a combination of multiple genes and multiple environmental factors like folic acid deficiency, insulin dependent diabetes, obesity and certain medications which interfere with folate metabolism.One of the beneficiaries under the Anemia Mukth Bharath programme are women in the reproductive age group in the pre-conception period and up to the first trimester of the pregnancy. They are advised to have400 mcg of Folic Acid tablets, daily, to reduce the incidence of neural tube defects in the fetus. Case report :We present a case of Chiari malformation associated with megaloblastic anemia with an attempt to highlight the importance of proper utilization of national program for prevention of iron and folate deficiency in women of reproductive age group. Clinical relevance : Neural tube defects are largely preventable anomalies by simple and effective management of folate deficiency preconceptionally. Conclusion :Proper utilization of the Anemia Mukth Bharath program which is available to the beneficiaries at their doorstep can not only prevent maternal anemia but also prevent fetal loss due to NTD.

Retrospective Investigation of the Incidence of Patients with Neural Tube Defects During the Pandemic Period, Single Center Study

Objective: Our aim in this study is as a result of the measures taken during the Covid 19 epidemic period; investigate whether factors related to immobilization due to the ban on going outdoors, carbon dioxide retention due to the use of masks, inability to perform appropriate pregnancy vizits on time and stress-related factors on pregnant women during the disease period increase the incidence of neural tube defects in both Turkish society and Syrian refugees living in Turkey. Materials and Methods: The data in the study were obtained from the archive of the single-center Şanlıurfa Research and Training Hospital. In this study, live births in the hospital archive between 01.01.2018-31.12.2019 and 01.01.2020-31.12.2021 and patients who were operated for neural tube defects were examined. Results: In the Turkish population, the incidence of neural tube defects in 2018, 2019, 2020 and 2021 was found to be 0.077%, 0.186%, 0.298% and 0.436%, respectively. There was a statistically significant difference between these years (p<0.001) (2018 and other years). The incidence of neural tube defects in refugees of Syrian origin in 2018, 2019, 2020 and 2021 was found to be 0.148%, 0.145%, 0.483% and 0.603%, respectively. There was a statistically significant difference between the years specified in refugees of Syrian origin (p<0.001) (2019 vs 2020 and 2019 vs. 2021). In 2020, the incidence of neural tube defects in refugees of Syrian origin (0.483%) was found to be significantly higher than the incidence of neural tube defects in the Turkish population (0.298%) (p=0.039). Conclusion: We detected an increase in neural tube defects due to the restrictions brought by the pandemic. The incidence increase between the sexes was similar. Incidence rates were similar in both Turks and Syrians in the years except 2020.

Inpp5e Regulated the Cilium-Related Genes Contributing to the Neural Tube Defects Under 5-Fluorouracil Exposure.

Primary cilia are crucial for neurogenesis, and cilium-related genes are involved in the closure of neural tubes. Inositol polyphosphate-5-phosphatase (Inpp5e) was enriched in primary cilia and closely related to the occurrence of neural tube defects (NTDs). However, the role of Inpp5e in the development of NTDs is not well-known. To investigate whether Inpp5e gene is associated with the neural tube closure, we established a mouse model of NTDs by 5-fluorouracil (5-FU) exposure at gestational day 7.5 (GD7.5). The Inpp5e knockdown (Inpp5e-/-) mouse embryonic stem cells (mESCs) were produced by CRISPR/Cas9 system. The expressions of Inpp5e and other cilium-related genes including intraflagellar transport 80 (Ift80), McKusick-Kaufman syndrome (Mkks), and Kirsten rat sarcoma viral oncogene homolog (Kras) were determined, utilizing quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR), western blot, PCR array, and immunofluorescence staining. The result showed that the incidence of NTDs was 37.10% (23 NTDs/62 total embryos) and significantly higher than that in the control group (P < 0.001). The neuroepithelial cells of neural tubes were obviously disarranged in NTD embryos. The mRNA and protein levels of Inpp5e, Ift80, Mkks, and Kras were significantly decreased in NTD embryonic brain tissues, compared to the control (P < 0.05). Knockdown of the Inpp5e (Inpp5e-/-) reduced the expressions of Ift80, Mkks, and Kras in mESCs. Furthermore, the levels of α-tubulin were significantly reduced in NTD embryonic neural tissue and Inpp5e-/- mESCs. These results suggested that maternal 5-FU exposure inhibited the expression of Inpp5e, which resulted in the downregulation of cilium-related genes (Ift80, Mkks, and Kras), leading to the impairment of primary cilium development, and ultimately disrupted the neural tube closure.

Maternal Smoking during Pregnancy and its effects on Neural Tube Defects.

Maternal smoking is a potent teratogen among congenital malformations, however its role in the development of Neural Tube Defects (NTDs) is still unclear. In this systematic review, we intend to further investigate the interaction of smoking during pregnancy and the incidence of NTDs. This article was written according to PRISMA criteria from February 2015 and August 2022. After examining the four stages of PRISMA criteria, we selected clinical articles. These articles were selected from PubMed, Scopus and Google scholar (for results follow-up) databases. We gathered NTDs effect and types, smoking type and habit of parents, from neonates. Eventually, 8 articles were included by two separated authors, Smoking was associated with an increase NTDs in the population of pregnant mothers and also among children whose fathers smoked. The main side effects that were considered to be the cause of NTDs besides smoking were alcohol and BMI (18.5-24.9). Smoking also affects the level of folic acid as a substance with an essential role that affects the closure of the neural tube. folic acid available to infants changing along with the level of other blood elements such as zinc, that necessary prevent for NTDs condition. Parental smoking can be considered as one of the strong teratogens in the occurrence of NTDs. Smoking, whether active or passive by the mother, or by the father, is associated with the occurrence of NTDs, In order to reduce the prevalence this disorder, we advise pregnant mothers and neonate's fathers to quit smoking.

Effect of sugammadex administration on neural tube development in 48-h chick embryos.

Sugammadex is a new generation drug that has led to significant changes in the practice of anesthesia. However, its effects on fetal development are not yet fully known. The aim of this study is to investigate the teratogenic effects of sugammadex on neural tube and embryonic development in early chick embryos. In this study, 50 0-day fertile specific non-pathogenic (SPF) eggs were used. Fifty eggs were divided into 5 different groups, each consisting of 10 pieces. While no substance was given to the control group at the 28th hour of the study, 4 different doses of sugammadex were administered to the experimental groups, respectively 2, 4, 8, 16 mg/kg. Cranio-caudal lengths of embryos, somite numbers, average number of argyrophilic nucleolar regulatory regions (AgNOR) per nucleus, total AgNOR area/total nuclear area (TAA/NA) ratios, Caspase-3 H-Score results, and presence of neural tube defect were compared among the groups. While the mean cranio-caudal lengths, somite counts, TAA/NA ratios and AgNOR counts of the embryos were found to be statistically significantly lower than the control group, Caspase-3 H-Score mean results were found to be significantly higher (p < .05). In addition, it was observed that there was an increase in neural tube patency and developmental delay. As a result, sugammadex crossing the placenta was revealed to increase the release of proapopitotic molecules and disrupt the developmental stages of embryos. Thus, it was determined that sugammadex in increased developmental delay and incidence of neural tube defects in early chick embryos with increased dose dependent. Despite these results, the effects of sugammadex on fetal development in in vivo and in vitro environments should be studied with further studies. RESEARCH HIGHLIGHTS: Sugammadex is a new generation drug that has led to significant changes in the practice of anesthesia. However, its effects on fetal development are not yet fully known. It has been observed that different doses of sugammadex increase the risk of neural tube defect development on chick embryos and slow the embryo development in a dose-dependent manner.

Wuzi Yanzong Pill protects neural tube defects by activating PI3K/Akt signaling pathway.

Neural tube defects (NTDs) are severe congenital malformations that can lead to lifelong disability. Wuzi Yanzong Pill (WYP) is an herbal formula of traditional Chinese medicine (TCM) that has been shown to have a protective effect against NTDs in a rodent model induced by all-trans retinoic acid (atRA), but the mechanism remains unclear. In this study, the neuroprotective effect and mechanism of WYP on NTDs were investigated in vivo using an atRA-induced mouse model and in vitro using cell injury model induced by atRA in Chinese hamster ovary (CHO) cells and Chinese hamster dihydrofolate reductase-deficient (CHO/dhFr) cells. Our findings suggest that WYP has an excellent preventive effect on atRA-induced NTDs in mouse embryos, which may be related to the activation of the PI3K/Akt signaling pathway, improved embryonic antioxidant capacity, and anti-apoptotic effects, and this effect is not dependent on folic acid (FA). Our results demonstrated that WYP significantly reduced the incidence of NTDs induced by atRA; increased the activity of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and content of glutathione (GSH); decreased the apoptosis of neural tube cells; up-regulated the expression of phosphatidylinositol 3 kinase (PI3K), phospho protein kinase B (p-Akt), nuclear factor erythroid-2 related factor (Nrf2), and b-cell lymphoma-2 (Bcl-2); and down-regulated the expression of bcl-2-associated X protein (Bax). Our in vitro studies suggested that the preventive effect of WYP on atRA-treated NTDs was independent of FA, which might be attributed to the herbal ingredients of WYP. The results suggest that WYP had an excellent prevention effect on atRA-induced NTDs mouse embryos, which may be independent of FA but related to the activation of the PI3K/Akt signaling pathway and improvement of embryonic antioxidant capacity and anti-apoptosis.

Global, regional, and national epidemiological trends in neural tube defects between 1990 and 2019: a summary.

Neural tube defects (NTD), such as spina bifida, are surgically treatable and primarily preventable non-communicable diseases. How incidence, mortality and disability-adjusted life year (DALYs) rates of NTD have modulated over time is not well defined. Correspondingly, the aim of this study was to quantitively define the global, regional, and national epidemiological trends in these. A retrospective review of data from the Global Burden of Disease Study 2019 Database was performed. Global, regional, and national outcomes for NTD were collected for incidence, mortality, and DALY rates and their age-standardized metrics analyzed. There were 7 regions at a regional level, and 204 countries and territories at a national level. Globally, the latest age-standardized rates of incidence, mortality, and DALYs of NTD were 2.1 per 100,000 population, 1.3 per 1000,000, and 117 per 100,000 respectively. All rates demonstrated decreases in the last two decades to now. Regionally, sub-Saharan Africa and North America demonstrated the highest and lowest age-standardized rates of incidence (4.0 vs 0.5 per 100,000), mortality (3.0 vs 0.4 per 100,000), and DALYs (266 vs 33 per 100,000), respectively. Similar to global trends, all regions demonstrated decrease in these rates over the last two decades. Nationally, the highest age-standardized rates were reported in African countries, Central African Republic, with highest incidence rate (7.6 per 100,000), and Burkina Faso with highest mortality rate (5.8 per 100,000) and DALY rate (518 per 100,000). India was the country with the highest number of new NTD cases (22,000 per country) in the most recent year of study. Between 1990 and 2019, 182/204 (89%), 188/204 (92%), and 188/204 (92%) countries and territories demonstrated a decrease in age-standardized incidence, mortality, and DALY rates respectively, with the greatest decreases seen in Saudi Arabia for all statistics. Between 1990 and 2019, overall trends in incidence, mortality, and DALY rates of NTD have been favorably downtrending globally. Regionally, these rates in the highest sub-Saharan Africa were 8 times greater compared to the lowest North America. Nationally, although the majority of countries showed decreases in these rates, a small number of countries demonstrated uptrending rates of NTD. Understanding the mechanics behind these trends will allow future public health endeavors for both prevention and neurosurgical treatment to be targeted appropriately.

Contribution of folic acid to human health and challenges of translating the science into effective policy: a call to action for the implementation of food fortification in Ireland

Over 30 years ago it was proven beyond doubt that folic acid supplementation of mothers in early pregnancy protects against neural tube defects (NTD) in their babies. Such conclusive scientific evidence led to clear recommendations for women worldwide to take 0⋅4 mg/d folic acid before conceiving and in early pregnancy, but implementing these into effective policy has been problematic. As a result, there has been no change in the incidence of NTD in Ireland, the UK or any other European country over the 25-year period that the current strategy, recommending periconceptional folic acid supplements to women, has been in place. Thus preventable NTD are not being prevented. Notably, in September 2021, the UK government announced that starch is to be fortified with folic acid on a mandatory basis. A similar decision is now urgently needed in Ireland, where rates of NTD are among the highest in the world. A policy of mandatory folic acid fortification of food would be highly effective in preventing NTD because it reaches all women, including those who have not planned their pregnancy. International evidence shows that wherever such a policy has been introduced, it has proved to be effective in reducing rates of NTD in that country. Apart from preventing NTD, the driver of policy in the area, other potential health benefits across the lifecycle can be anticipated from folic acid fortification. Urgent action is needed on implementation of mandatory food fortification with folic acid in Ireland so that mothers and their babies can benefit.

An optimal combination of five main monomer components in Wuzi Yanzong Pill that prevents neural tube defects and reduces apoptosis and oxidative stress

Ethnopharmacological relevanceWuzi Yanzong Pill (WYP) is a classic traditional Chinese medicine (TCM) formula that is used for reproductive system diseases. Previous studies showed that WYP had a preventive effect on the development of neural tube defects (NTDs) induced by all-trans retinoic acid (atRA) in mice. Aim of the studyThis study aimed to determine the optimal combination of main monomer components in WYP on preventing NTDs and to understand the underlying mechanism. Materials and methodsAn optimal combination was made from five representative components in WYP including hyperoside, acteoside, schizandrol A, kaempferide and ellagic acid by orthogonal design method. In a mouse model of NTDs induced by intraperitoneal injection of atRA, pathological changes of neural tube tissues were observed by Hematoxylin & Eosin (HE) staining, neural tube epithelial cells apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL), protein changes related to apoptosis, anti-apoptosis, and antioxidant factors were detected with Western blot. Potential targets and mechanisms of monomer compatibility group (MCG) acting on NTDs were analyzed by bioinformatics. ResultsTreatment with different combinations of WYP bioactive ingredients resulted in varying decreases in the incidence of NTDs in mice embryos. The combination of MCG15 (200 mg/kg of hyperoside, 100 mg/kg of acteoside, 10 mg/kg of schizandrol A, 100 mg/kg of kaempferide and 1 mg/kg of ellagic acid) showed the most significant reduction in NTD incidence. Mechanistically, MCG15 inhibited apoptosis and oxidative stress, as evidenced by reduced TUNEL-positive cells, downregulation of caspase-9, cleaved caspase-3, Bad, and Bax, and upregulation of Bcl-2, as well as decreased MDA and increased SOD, CAT, GSH, HO-1, and GPX1 levels. Bioinformatics analysis showed that MCG15 acted on the PI3K/Akt signaling pathway, which was confirmed by Western blot analysis showing increased expression of p-PI3K, p-Akt/Akt, and Nrf2 related indicators. ConclusionWe have identified an optimal combination of five bioactive components in WYP (MCG15) that prevented NTDs in mice embryos induced by atRA by activating the PI3K/Akt signaling pathway and inhibiting apoptosis and oxidative stress.

Neural Tube Defects and Folate Deficiency: Is DNA Repair Defective?

Neural tube defects (NTDs) are complex congenital malformations resulting from failure of neural tube closure during embryogenesis, which is affected by the interaction of genetic and environmental factors. It is well known that folate deficiency increases the incidence of NTDs; however, the underlying mechanism remains unclear. Folate deficiency not only causes DNA hypomethylation, but also blocks the synthesis of 2'-deoxythymidine-5'-monophosphate (dTMP) and increases uracil misincorporation, resulting in genomic instabilities such as base mismatch, DNA breakage, and even chromosome aberration. DNA repair pathways are essential for ensuring normal DNA synthesis, genomic stability and integrity during embryonic neural development. Genomic instability or lack of DNA repair has been implicated in risk of development of NTDs. Here, we reviewed the relationship between folate deficiency, DNA repair pathways and NTDs so as to reveal the role and significance of DNA repair system in the pathogenesis of NTDs and better understand the pathogenesis of NTDs.

The Effect of Health Education on Knowledge, Attitude and Practice of Folic Acid Supplementation among Periconceptional Women at the Health Clinic in Kuala Lumpur

Background: Neural tube defects (NTDs) are congenital abnormalities of the central nervous system that can be prevented by consuming 400 µg of folic acid daily during conception until the twelfth week of pregnancy. Malaysia is experiencing an increase in NTD cases. Addressing women's knowledge, attitudes, and practices regarding folic acid- and folate-rich foods is crucial to reduce the incidence of NTDs. Objectives: This study aimed to evaluate the impact of a health education program on improving knowledge, attitudes, and practices related to folic acid supplementation among periconceptional women in a community clinic. Methods: A pre- and post-quasi-experimental study was conducted among 114 periconceptional women in two groups. The intervention group received structured Folic Acid supplementation education, while the control group received routine antenatal care. Results: Regarding knowledge, the intervention significantly improved the scores of the intervention group, increasing from 13.40 to 15.39. This improvement was statistically significant, with a mean difference of 1.98 (p &lt; 0.001), large effect size of 0.16, and strong statistical power of 0.89. Meanwhile for attitude, the intervention group experienced a more significant increase in scores, from 25.72 to 27.46. Statistically significant effects were observed (p = 0.031), along with a large effect size 0.26 and relatively high statistical power 0.99. In terms of practice, the intervention group showed a significant improvement, with scores increasing from 27.68 33.16. The findings were significant, with a mean difference of 5.47 (p &lt; 0.001), extreme effect size of 0.74, and strong statistical power of 1.00. Conclusion: A comprehensive health education program for pregnant women can significantly improve their understanding, attitude, and adherence to folic acid supplementation. In addition, it is essential to promote the consumption of folic acid-fortified foods.

Genetic Effects of ITPK1 Polymorphisms on the Risk of Neural Tube Defects: a Population-Based Study.

Inositol is closely related to the occurrence of neural tube defects (NTDs). Inositol 1, 3, 4-trisphosphate 5/6-kinase (ITPK1) gene encoded an essential regulatory enzyme ITPK1, which is involved in inositol metabolism and has a critical role in the development of neural tube and axial mesoderm. It had been reported that some polymorphisms of critical genes in inositol pathways, including ITPK1, were associated with NTDs in Chinese pregnant women; however, the association between fetus ITPK1 polymorphisms and NTDs had not been reported. In a high incidence of NTDs region of China, a case-control study was performed to evaluate the association between fetal ITPK1 polymorphisms and NTDs. The ITPK1 polymorphisms were genotyped by iPLEX® Gold assay. Inositol levels in fetus brain tissues were analyzed. Three genetic polymorphisms of fetus ITPK1's, including rs3818175, rs2295394, and rs4586354, were statistically associated with spina bifida (NTD subtypes). A higher risk of spina bifida was associated with genotype GG of rs3818175, genotype CC of rs4586354, and genotype TT of rs2295394 (OR = 2.66, 95% CI [1.17-6.05], P = 0.017; OR = 2.22, 95% CI [1.02-4.80], P = 0.041; and OR = 2.33, 95% CI [1.00-5.48], P = 0.047), when compared with the other wild-type genotypes CC, TT, and CC, respectively. Decreased brain inositol level was found in NTDs fetuses, compared to normal controls. Inositol levels were found to significantly decrease with rs2295394 (CC genotype), rs4586354 (TT genotype), and rs3818175 (GC genotype) (P < 0.05). The polymorphisms of fetus ITPK1 were associated with the incidence of NTDs and might be a genetic risk factor for spina bifida.

An exploratory study of the level of folic acid in food staples in Ireland in 2021

Abstract Background Ireland previously had widespread voluntary fortification but there has been a major decline in the number of food staples fortified with folic acid in Irish supermarkets in the past 15 years. In this research we set out to examine the level of folic acid in food staples in supermarkets with the leading market share in the Republic of Ireland. Methods The food labels of food staples (breads, spreads, milk, cereals, cereal bars, yoghurt/yoghurt drinks) were photographed in supermarkets with the leading market share in the Republic of Ireland (Tesco's, Dunnes, SuperValu, Lidl, Aldi, and M&amp;S) between 2017 and 2021.The data was extracted and collated in an excel spreadsheet. The data was analysed to examine the level of folic acid in each product. We compared the levels captured at the current times with the levels previously captured in 2017. Results Preliminary analysis suggests that folic acid level in food staples in Ireland continues to decline. Folic acid was not found in any breads (except a number of gluten free breads), milks, spreads but was found in several cereals marketed mainly at children. Conclusions This study reports on the declining levels of folic acid in the food chain in Ireland. The number of food staples fortified with folic acid continues to decline demonstrating that voluntary fortification in Ireland is no longer an effective measure for passively augmenting the folic acid levels of consumers. This is of concern due to the incidence of neural tube defects in Ireland largely preventable by folic acid. Key messages

Inhibition of retinoic acid signaling impairs cranial and spinal neural tube closure in mice lacking the Grainyhead-like 3 transcription factor

Neural tube closure is a dynamic morphogenic event in early embryonic development. Perturbations of this process through either environmental or genetic factors induce the severe congenital malformations known collectively as neural tube defects (NTDs). Deficiencies in maternal folate intake have long been associated with NTDs, as have mutations in critical neurulation genes that include the Grainyhead-like 3 (Grhl3) gene. Mice lacking this gene exhibit fully penetrant thoraco-lumbo-sacral spina bifida and a low incidence of exencephaly. Previous studies have shown that exposure of pregnant mice carrying hypomorphic Grhl3 alleles to exogenous retinoic acid (RA) increases the incidence and severity of NTDs in their offspring. Here, we demonstrate that inhibition of RA signaling using a high affinity pan-RA receptor antagonist administered to pregnant mice at E7.5 induces fully penetrant exencephaly and more severe spina bifida in Grhl3-null mice. Later administration, although prior to neural tube closure has no effect. Similarly, blockade of RA in the context of reduced expression of Grhl2, a related gene known to induce NTDs, has no effect. Taken together, these findings provide new insights into the complexities of the interplay between RA signaling and Grhl3-induced neurulation.

The effect of long and short-term use of folate supplementation on shunt revision and spina bifida in demographically matched pregnant women: A cross-sectional clinical study

IntroductionNewborn defects are one of the leading causes of admission to the pediatric service. The incidence of neural tube defects (NTD) increases with folate deficiency in pregnant women. This study focuses on folate supplementation and its postpartum effects. Materials and methodsThis cross-sectional study was designed to assess neural tube defect-related risks in data-matched pregnancies in terms of Folate supplementation. ResultsFolate supplementation at ≥3 months pregnancy had a 10 times higher protectivity against Tethered Cord Syndrome (TCS) than pregnancies without folate supplementation (p = 0,028; Odds ratios [OR] = 10.2). However, folate supplementation provided between 0 and 2 months of pregnancy did not differ from pregnant women who did not receive folate supplementation (p = 0,887). Compared to pregnant women without folate supplementation, pregnant women with folate supplementation at ≥3 months did not have higher protectivity against Spina Bifida, yet pregnant women with folate supplementation between 0 and 2 months did provide 19 times more protection against Spina Bifida (p = 0,023; OR = 19,444). Although there was no difference between not using folate supplementation during pregnancy or using it for less than 3 months (p = 0,491) in the protection against shunt revisions, the risk of shunt revisions increased 4 times if it was used for greater than 3 months during pregnancy (p = 0,018; OR = 4,03). ConclusionThe probability of shunt revision increased 4 times if folate was used for more than 3 months during pregnancy. Folate supplementation for only short periods of time protects against Spina bifida while long-term folate supplementation provides highly effective protection for TCS.

High Dietary Folic Acid Intake Is Associated with Genomic Instability in Peripheral Lymphocytes of Healthy Adults.

Mandatory fortification of food with synthetic folic acid (FA) was instituted in 1998 to reduce the incidence of neural tube defects. Adequate folate status is correlated with numerous health benefits. However, elevated consumption of FA is controversially associated with deleterious effects on health. We previously reported that excess FA mimicked folate depletion in a lymphoblastoid cell line. To explore the impact of FA intake from fortified food, we conducted an observational human study on 33 healthy participants aged 18–40 not taking any supplements. Food intake, anthropomorphic measurements, and blood samples were collected and analyzed. Our results show that individuals belonging to the highest tertile of folic acid intake, as well as ones with the highest folic acid to total folate intake ratio (FAR), display a significantly greater incidence of lymphocyte genomic damage. A decrease in global DNA methylation is observed in the highest tertile of FAR compared to the lowest (p = 0.055). A downward trend in the overall gene expression of select DNA repair and one carbon cycle genes (MGMT, MLH1, UNG, MTHFR, MTR) is noted with increased folate status and FA intake. These results provide supporting evidence that high consumption of FA from fortified foods can precipitate genomic instability in peripheral lymphocyte in vivo.

High Folate, Perturbed One-Carbon Metabolism and Gestational Diabetes Mellitus.

Folate is a dietary micronutrient essential to one-carbon metabolism. The World Health Organisation recommends folic acid (FA) supplementation pre-conception and in early pregnancy to reduce the risk of fetal neural tube defects (NTDs). Subsequently, many countries (~92) have mandatory FA fortification policies, as well as recommendations for periconceptional FA supplementation. Mandatory fortification initiatives have been largely successful in reducing the incidence of NTDs. However, humans have limited capacity to incorporate FA into the one-carbon metabolic pathway, resulting in the increasingly ubiquitous presence of circulating unmetabolised folic acid (uFA). Excess FA intake has emerged as a risk factor in gestational diabetes mellitus (GDM). Several other one-carbon metabolism components (vitamin B12, homocysteine and choline-derived betaine) are also closely entwined with GDM risk, suggesting a role for one-carbon metabolism in GDM pathogenesis. There is growing evidence from in vitro and animal studies suggesting a role for excess FA in dysregulation of one-carbon metabolism. Specifically, high levels of FA reduce methylenetetrahydrofolate reductase (MTHFR) activity, dysregulate the balance of thymidylate synthase (TS) and methionine synthase (MTR) activity, and elevate homocysteine. High homocysteine is associated with increased oxidative stress and trophoblast apoptosis and reduced human chorionic gonadotrophin (hCG) secretion and pancreatic β-cell function. While the relationship between high FA, perturbed one-carbon metabolism and GDM pathogenesis is not yet fully understood, here we summarise the current state of knowledge. Given rising rates of GDM, now estimated to be 14% globally, and widespread FA food fortification, further research is urgently needed to elucidate the mechanisms which underpin GDM pathogenesis.

Prevalence and trend analysis of severe multiple disabling birth defects in Chongqing City from 2007 to 2020

Objective: To explore the prevalence and change trend of severe multiple disabling birth defects in Chongqing City from 2007 to 2020, and to provide a basis for comprehensive prevention and control measures of severe multiple disabling birth defects. Methods: Based on hospital monitoring data, 1 103 children with severe multiple disabling birth defects monitored by all birth defects monitoring institutions in Chongqing City from January 2007 to December 2020 were included in the study. They were grouped by year, perinatal gender, maternal permanent residence (urban/rural), maternal age, different regions and other categories. Chi-square test was used to analyze the differences in the incidence of severe multiple disabling birth defects in different categories, and linear trend test was used to analyze the change trend. Results: From 2007 to 2020, a total of 1 022 314 perinatal births and 1 103 severe multiple disabling birth defects were monitored in Chongqing City, with an incidence of 10.79/10 000, including 11.47/10 000 in urban areas and 9.48/10 000 in rural areas, with an incidence higher in urban areas than in rural areas(χ2=8.424,P=0.004). Male was 10.47/10 000, female was 10.97/10 000, there was no significant difference between male and female(χ2=0.606,P=0.436). The incidence of maternal in different age groups was u-shaped, and there was statistical difference in incidence among different age groups (χ2=59.465, P<0.001). The incidence of maternal in<20 years old and ≥35 years old was higher, and in 25-29 years old was lower. The incidence rate was 17.96/10 000 in 2007 and 7.18/10 000 in 2020, which decreased by 60.02% in 2007-2020. The incidence of neural tube defect, chromosome syndrome, limb shortening and abdominal wall defect decreased by 78.12%, 77.38%, 80.55% and 91.30%, respectively. Severe Congenital heart disease rose by 456.16%. From 2007 to 2020, the overall incidence of the disease showed a decreasing trend (χ2trend =117.046, P<0.001), except for the rise of severe congenital heart disease, (χ2trend=8.744, P=0.003), the other four types of diseases were on the decline (neural tube defects χ2trend =48.618, P<0.001; chromosome syndrome χ2trend=50.999, P<0.001; limb shortening χ2trend=73.464, P<0.001; abdominal wall defect χ2trend=79.863, P<0.001). Conclusion: From 2007 to 2020, the incidence of severe disabling birth defects in Chongqing City showed a downward trend, and there were regional and age differences. The incidence of severe congenital heart disease is on the rise.