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European Journal of Obstetrics,... Oct 2020Folate (vitamin B9) is widely accepted to protect against fetal neural tube defects. The main sources of dietary folate are folic acid-fortified foods and folic... (Review)
Review
Folate (vitamin B9) is widely accepted to protect against fetal neural tube defects. The main sources of dietary folate are folic acid-fortified foods and folic acid-containing dietary supplements. However, folic acid is inactive in the human body and must be converted by the liver into the active molecule 5-methyltetrahydrofolate (5-MTHF). 5-MTHF functions as a methyl donor in many metabolic reactions, including the conversion of homocysteine into methionine, the biosynthesis of glycine from serine, and the biosynthesis of DNA precursor molecules. Therefore, folate is fundamental for growth, especially in the embryonic and fetal stages. Prescription of folic acid to women in the preconception period and during pregnancy is a consolidated practice. However, it can pose health risks in certain conditions, such as megaloblastic anemia, where it will conceal megaloblastic anemia due to vitamin B12 deficiency and in cases of reduced hepatic transformation of folic acid (e.g. due to genetic variants or during some pharmacotherapies). Some of these risks can be avoided by supplementation with 5-MTHF rather than folic acid. Because 5-MTHF does not require activation, it is immediately available to mother and fetus and does not accumulate in blood like folic acid does in cases of reduced hepatic transformation. This paper reviews the advantages and disadvantages of folate supplementation with folic acid versus 5-MTHF, with a focus on maternal and fetal health.
Topics: Dietary Supplements; Female; Folic Acid; Humans; Neural Tube Defects; Pregnancy; Tetrahydrofolates
PubMed: 32868164
DOI: 10.1016/j.ejogrb.2020.06.012 -
Birth Defects Research Nov 2019Neural tube defects (NTDs) are the second most common congenital malformations in humans affecting the development of the central nervous system. Although NTD... (Review)
Review
Neural tube defects (NTDs) are the second most common congenital malformations in humans affecting the development of the central nervous system. Although NTD pathogenesis has not yet been fully elucidated, many risk factors, both genetic and environmental, have been extensively reported. Classically divided in two main sub-groups (open and closed defects) NTDs present extremely variable prognosis mainly depending on the site of the lesion. Herein, we review the literature on the histological and pathological features, epidemiology, prenatal diagnosis, and prognosis, based on the type of defect, with the aim of providing important information based on NTDs classification for clinicians and scientists.
Topics: Anencephaly; Female; Humans; Neural Tube Defects; Pregnancy; Prenatal Diagnosis; Risk Factors
PubMed: 30421543
DOI: 10.1002/bdr2.1380 -
Cell May 2023Neural tube (NT) defects arise from abnormal neurulation and result in the most common birth defects worldwide. Yet, mechanisms of primate neurulation remain largely...
Neural tube (NT) defects arise from abnormal neurulation and result in the most common birth defects worldwide. Yet, mechanisms of primate neurulation remain largely unknown due to prohibitions on human embryo research and limitations of available model systems. Here, we establish a three-dimensional (3D) prolonged in vitro culture (pIVC) system supporting cynomolgus monkey embryo development from 7 to 25 days post-fertilization. Through single-cell multi-omics analyses, we demonstrate that pIVC embryos form three germ layers, including primordial germ cells, and establish proper DNA methylation and chromatin accessibility through advanced gastrulation stages. In addition, pIVC embryo immunofluorescence confirms neural crest formation, NT closure, and neural progenitor regionalization. Finally, we demonstrate that the transcriptional profiles and morphogenetics of pIVC embryos resemble key features of similarly staged in vivo cynomolgus and human embryos. This work therefore describes a system to study non-human primate embryogenesis through advanced gastrulation and early neurulation.
Topics: Animals; Humans; Blastocyst; Embryo, Mammalian; Embryonic Development; Macaca fascicularis; Neural Tube Defects; Neurulation; Tissue Culture Techniques
PubMed: 37172562
DOI: 10.1016/j.cell.2023.04.019 -
Child's Nervous System : ChNS :... Jul 2023Neural tube defects (NTDs) are common birth defects and contribute to life-long disabilities, high medical care costs, and perinatal and child mortality. This review is... (Review)
Review
Neural tube defects (NTDs) are common birth defects and contribute to life-long disabilities, high medical care costs, and perinatal and child mortality. This review is a primer on prevalence, causes, and evidence-based prevention strategies for NTDs. The estimated average global prevalence of NTDs is two cases per 1000 births, amounting to approximately 214,000-322,000 affected pregnancies worldwide annually. Prevalence and associated adverse outcomes are disproportionately high in developing countries. NTDs have multiple risk factors including genetic and non-genetic (i.e., maternal nutritional status, pre-pregnancy diabetes, early pregnancy exposure to valproic acid (anti-epileptic medication), and a previous pregnancy affected by a NTD) factors. Maternal folate insufficiency before and during early pregnancy is the most common risk factor and is preventable. Folic acid (vitamin B9) is required for formation of the neural tube early in pregnancy, around 28 days after conception, when most women are unaware of their pregnancies. Current guidelines recommend that all women planning or capable of pregnancy take a daily supplement containing 400-800 μg of folic acid. Mandatory folic acid fortification of staple foods (e.g., wheat flour, maize flour, rice) is safe, economical, and the effective intervention for primary prevention of NTDs. Currently, about 60 countries are implementing mandatory folic acid fortification of staple foods, preventing just a quarter of all preventable NTD cases worldwide. There is an urgent need for active champions, including neurosurgeons and other healthcare providers, to generate political will and promote effective mandatory food fortification with folic acid, and reach equitable primary prevention of NTDs in all countries.
Topics: Pregnancy; Child; Female; Humans; Flour; Prevalence; Food, Fortified; Triticum; Neural Tube Defects; Folic Acid; Primary Prevention
PubMed: 36882610
DOI: 10.1007/s00381-023-05910-7 -
Annual Review of Nutrition Aug 2022For three decades, the US Public Health Service has recommended that all persons capable of becoming pregnant consume 400 μg/day of folic acid (FA) to prevent neural... (Review)
Review
For three decades, the US Public Health Service has recommended that all persons capable of becoming pregnant consume 400 μg/day of folic acid (FA) to prevent neural tube defects (NTDs). The neural tube forms by 28 days after conception. Fortification can be an effective NTD prevention strategy in populations with limited access to folic acid foods and/or supplements. This review describes the status of mandatory FA fortification among countries that fortify ( = 71) and the research describing the impact of those programs on NTD rates (up to 78% reduction), blood folate concentrations [red blood cell folate concentrations increased ∼1.47-fold (95% CI, 1.27, 1.70) following fortification], and other health outcomes. Across settings, high-quality studies such as those with randomized exposures (e.g., randomized controlled trials, Mendelian randomization studies) are needed to elucidate interactions of FA with vitamin B as well as expanded biomarker testing.
Topics: Dietary Supplements; Female; Folic Acid; Food, Fortified; Humans; Neural Tube Defects; Pregnancy; Vitamin B 12
PubMed: 35995050
DOI: 10.1146/annurev-nutr-043020-091647 -
Trends in Neurosciences Jul 2020Neural tube defects (NTDs) represent a failure of the neural plate to complete the developmental transition to a neural tube. NTDs are the most common birth anomaly of... (Review)
Review
Neural tube defects (NTDs) represent a failure of the neural plate to complete the developmental transition to a neural tube. NTDs are the most common birth anomaly of the CNS. Following mandatory folic acid fortification of dietary grains, a dramatic reduction in the incidence of NTDs was observed in areas where the policy was implemented, yet the genetic drivers of NTDs in humans, and the mechanisms by which folic acid prevents disease, remain disputed. Here, we discuss current understanding of human NTD genetics, recent advances regarding potential mechanisms by which folic acid might modify risk through effects on the epigenome and transcriptome, and new approaches to study refined phenotypes for a greater appreciation of the developmental and genetic causes of NTDs.
Topics: Folic Acid; Humans; Neural Tube Defects
PubMed: 32423763
DOI: 10.1016/j.tins.2020.04.009 -
Nature Nov 2021Understanding human organ formation is a scientific challenge with far-reaching medical implications. Three-dimensional stem-cell cultures have provided insights into...
Understanding human organ formation is a scientific challenge with far-reaching medical implications. Three-dimensional stem-cell cultures have provided insights into human cell differentiation. However, current approaches use scaffold-free stem-cell aggregates, which develop non-reproducible tissue shapes and variable cell-fate patterns. This limits their capacity to recapitulate organ formation. Here we present a chip-based culture system that enables self-organization of micropatterned stem cells into precise three-dimensional cell-fate patterns and organ shapes. We use this system to recreate neural tube folding from human stem cells in a dish. Upon neural induction, neural ectoderm folds into a millimetre-long neural tube covered with non-neural ectoderm. Folding occurs at 90% fidelity, and anatomically resembles the developing human neural tube. We find that neural and non-neural ectoderm are necessary and sufficient for folding morphogenesis. We identify two mechanisms drive folding: (1) apical contraction of neural ectoderm, and (2) basal adhesion mediated via extracellular matrix synthesis by non-neural ectoderm. Targeting these two mechanisms using drugs leads to morphological defects similar to neural tube defects. Finally, we show that neural tissue width determines neural tube shape, suggesting that morphology along the anterior-posterior axis depends on neural ectoderm geometry in addition to molecular gradients. Our approach provides a new route to the study of human organ morphogenesis in health and disease.
Topics: Ectoderm; Humans; Models, Biological; Morphogenesis; Neural Plate; Neural Tube; Neural Tube Defects; Organ Culture Techniques; Regeneration; Stem Cells
PubMed: 34707290
DOI: 10.1038/s41586-021-04026-9 -
Journal of Obstetrics and Gynaecology... Jan 2021This revised guideline is intended to provide an update on the genetic aspects, prevention, screening, diagnosis, and management of fetal neural tube defects.
OBJECTIVE
This revised guideline is intended to provide an update on the genetic aspects, prevention, screening, diagnosis, and management of fetal neural tube defects.
TARGET POPULATION
Women who are pregnant or may become pregnant. Neural tube defect screening should be offered to all pregnant women.
OPTIONS
For prevention: a folate-rich diet, and folic acid and vitamin B supplementation, with dosage depending on risk level. For screening: second-trimester anatomical sonography; first-trimester sonographic screening; maternal serum alpha fetoprotein; prenatal magnetic resonance imaging. For genetic testing: diagnostic amniocentesis with chromosomal microarray and amniotic fluid alpha fetoprotein and acetylcholinesterase; fetal exome sequencing. For pregnancy management: prenatal surgical repair; postnatal surgical repair; pregnancy termination with autopsy. For subsequent pregnancies: prevention and screening options and counselling.
OUTCOMES
The research on and implementation of fetal surgery for prenatally diagnosed myelomeningocele has added a significant treatment option to the previous options (postnatal repair or pregnancy termination), but this new option carries an increased risk of maternal morbidity. Significant improvements in health and quality of life, both for the mother and the infant, have been shown to result from the prevention, screening, diagnosis, and treatment of fetal neural tube defects.
BENEFITS, HARMS, AND COSTS
The benefits for patient autonomy and decision-making are provided in the guideline. Harms include an unexpected fetal diagnosis and the subsequent management decisions. Harm can also result if the patient declines routine sonographic scans or if counselling and access to care for neural tube defects are delayed. Cost analysis (personal, family, health care) is not within the scope of this clinical practice guideline.
EVIDENCE
A directed and focused literature review was conducted using the search terms spina bifida, neural tube defect, myelomeningocele, prenatal diagnosis, fetal surgery, neural tube defect prevention, neural tube defect screening, neural tube defect diagnosis, and neural tube defect management in order to update and revise this guideline. A peer review process was used for content validation and clarity, with appropriate ethical considerations.
VALIDATION METHODS
The authors rated the quality of evidence and strength of recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. See online Appendix A (Tables A1 for definitions and A2 for interpretations of strong and weak recommendations).
INTENDED AUDIENCE
Maternity care professionals who provide any part of pre-conception, antenatal, delivery, and neonatal care. This guideline is also appropriate for patient education. RECOMMENDATIONS (GRADE RATINGS IN PARENTHESES).
Topics: Female; Genetic Testing; Humans; Maternal Health Services; Neural Tube Defects; Pregnancy; Prenatal Care; Prenatal Diagnosis; Quality of Life; Societies, Medical
PubMed: 33212246
DOI: 10.1016/j.jogc.2020.11.003 -
Cellular and Molecular Life Sciences :... Nov 2022Gastrulation and neurulation are successive morphogenetic processes that play key roles in shaping the basic embryonic body plan. Importantly, they operate through... (Review)
Review
Gastrulation and neurulation are successive morphogenetic processes that play key roles in shaping the basic embryonic body plan. Importantly, they operate through common cellular and molecular mechanisms to set up the three spatially organized germ layers and to close the neural tube. During gastrulation and neurulation, convergent extension movements driven by cell intercalation and oriented cell division generate major forces to narrow the germ layers along the mediolateral axis and elongate the embryo in the anteroposterior direction. Apical constriction also makes an important contribution to promote the formation of the blastopore and the bending of the neural plate. Planar cell polarity proteins are major regulators of asymmetric cell behaviors and critically involved in a wide variety of developmental processes, from gastrulation and neurulation to organogenesis. Mutations of planar cell polarity genes can lead to general defects in the morphogenesis of different organs and the co-existence of distinct congenital diseases, such as spina bifida, hearing deficits, kidney diseases, and limb elongation defects. This review outlines our current understanding of non-canonical Wnt signaling, commonly known as Wnt/planar cell polarity signaling, in regulating morphogenetic movements of gastrulation and neural tube closure during development and disease. It also attempts to identify unanswered questions that deserve further investigations.
Topics: Humans; Neurulation; Gastrulation; Cell Polarity; Wnt Signaling Pathway; Neural Tube; Morphogenesis; Neural Tube Defects
PubMed: 36369349
DOI: 10.1007/s00018-022-04620-8 -
Journal of Obstetrics and Gynaecology... Jun 2022To provide updated guidance on pre-conception folic acid and multivitamin supplementation for primary and secondary (recurrence) prevention of neural tube defects and...
OBJECTIVE
To provide updated guidance on pre-conception folic acid and multivitamin supplementation for primary and secondary (recurrence) prevention of neural tube defects and other folate-sensitive congenital anomalies.
TARGET POPULATION
Women aged 12-45 years who could become pregnant should be aware of the risk of serious birth defects without adequate pre-conception and first-trimester folic acid supplementation.
OPTIONS
Optimizing folic acid supplementation is complex and depends on factors including dosage; type of supplement; bioavailability of folate from food, timing of initiating supplementation; and metabolic and genetic factors. For all women who could become pregnant, a low daily dosage of folic acid is recommended before conception and throughout pregnancy and breastfeeding. High-dosage folic acid supplementation is recommended only for women who can become pregnant and have had a previous pregnancy affected by a neural tube defect or other folate-sensitive congenital anomaly. Directed personalized approaches could be considered and adopted for women who can become pregnant and have complex risks (genetic, medical, or surgical risk factors), using new knowledge of co-factor metabolism and synergy, as well as red blood cell or serum folate testing. Such approaches would require changes to current provincial health care maternal serum folate screening/testing.
OUTCOMES
New approaches to oral folic acid supplementation, including triage tools, need to be considered to optimize the benefits of decreasing risk of neural tube defects and folate-sensitive congenital anomalies.
BENEFITS, HARMS, AND COSTS
Oral folic acid supplementation, or dietary folate intake combined with a multivitamin/micronutrient supplement, is associated with lower rates of neural tube defects, other folate-sensitive birth defects, and obstetrical complications. The costs are those attributable to daily vitamin supplementation and a healthy, folate-rich diet.
EVIDENCE
A literature search was designed and carried in PubMed and the Cochrane Library databases from 1990 to 2021 using following MeSH terms and keywords (and variants): folic acid supplementation; folate food fortification; primary neural tube defect prevention; prevention of recurrence of neural tube defects; folate-sensitive birth defects; folate supplementation benefit; folate supplementation risk; folate pregnant woman physiology; pregnant woman RBC folate level; pregnant woman serum folate levels; folate and epilepsy; folate and obesity. This guideline was based upon expert guidelines or opinions, systematic reviews, randomized controlled clinical trials, and observational case-control studies and case series retrieved, published in English from 1990 to 2021.
VALIDATION METHODS
The authors rated the quality of evidence and strength of recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. See online Appendix A (Tables A1 for definitions and A2 for interpretations of strong and weak recommendations).
INTENDED AUDIENCE
Maternity health care providers (physicians, midwives, nurses) and other providers of pregnancy-related wellness and health counselling.
SUMMARY STATEMENTS
RECOMMENDATIONS.
Topics: Dietary Supplements; Female; Folic Acid; Humans; Neural Tube Defects; Pregnancy; Vitamins
PubMed: 35691683
DOI: 10.1016/j.jogc.2022.04.004