Abnormal Development - Folic Acid and Neural Tube Defects

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Introduction

Neural groove closing to neural tube, early week 4, embryo stage 10, Gestational Age GA week 6).

In 2001, the Australian estimated birth prevalence of neural tube defects was 0.5 per 1,000 births (National Perinatal Statistics Unit). Low maternal dietary folic acid (folate) has been shown to be associated with the development of neural tube defects. In September 2009, mandatory folic acid fortification of bread flour was introduced in Australia.

Research over the last 20 years had suggested a relationship between maternal diet and the birth of an affected infant. Recent evidence has confirmed that folic acid, a water soluble vitamin (vitamin B9) found in many fruits (particularly oranges, berries and bananas), leafy green vegetables, cereals and legumes, may prevent the majority of neural tube defects.

Folatefruit.jpg
Folate.jpg
Fruits
Folic Acid

In the U.S.A., the Food and Drug Administration in 1996 authorized that all enriched cereal grain products be fortified with folic acid, with optional fortification beginning in March 1996 and mandatory fortification in January 1998.


In Australia, from 2009 the mandatory folic acid fortification standard required addition of folic acid to all wheat flour for bread making, with the exception of organic bread, within the prescribed range of 200–300 μg per 100 g of flour.


The March of Dimes Folic Acid Campaign (a major US charity group) has as one of its major objectives to reduce neural tube defects by 30% by 2001 using community programs, professional education, and mass media information.


Links: Nutrition | Folate Deficiency | Iodine Deficiency | Neural System - Abnormalities | Axial Skeleton Abnormalities


Environmental Links: Introduction | Low Folic Acid | Iodine Deficiency | Nutrition | Drugs | Australian Drug Categories | USA Drug Categories | Thalidomide | Herbal Drugs | Illegal Drugs | Smoking | Fetal Alcohol Syndrome | TORCH Infections | Viral Infection | Bacterial Infection | Zoonotic Infection | Toxoplasmosis | Malaria | Maternal Diabetes | Maternal Hypertension | Maternal Hyperthermia | Maternal Inflammation | Maternal Obesity | Hypoxia | Biological Toxins | Chemicals | Heavy Metals | Radiation | Prenatal Diagnosis | Neonatal Diagnosis | International Classification of Diseases | Fetal Origins Hypothesis

Some Recent Findings

AIHW Report - Folic acid and iodine fortification (2016)
Folic acid and iodine fortification (2016)
  • Australia - Decrease in neural tube defects since folic acid added to bread[1]"Mandatory fortification of bread with folic acid (in Australia) and iodine (in Australia and New Zealand) was introduced in 2009 to address two important public health issues: to reduce the prevalence of neural tube defects (serious birth defects such as spina bifida) in Australia and to deal with the re-emergence of iodine deficiency in both Australia and New Zealand. There was a significant (14.4%) overall decrease in the rate of neural tube defects (NTDs) in Australia following mandatory folic acid fortification. However among teenagers, the rate of NTDs decreased even more, by almost 55%, and for Aboriginal and Torres Strait Islander women, the rate of NTDs decreased by 74%."
  • Preconception folic acid supplementation and risk for chromosome 21 nondisjunction: a report from the US National Down Syndrome Project[2] "Both a lack of maternal folic acid supplementation and the presence of genetic variants that reduce enzyme activity in folate pathway genes have been linked to meiotic nondisjunction of chromosome 21; however, the findings in this area of research have been inconsistent. To better understand these inconsistencies, we asked whether maternal use of a folic acid-containing supplement before conception reduces risk for chromosome 21 nondisjunction. ...These data suggest that lack of folic acid supplementation may be associated specifically with MII errors in the aging oocyte. If confirmed, these results could account for inconsistencies among previous studies, as each study sample may vary by maternal age structure and proportion of meiotic errors." Trisomy 21
  • Association between maternal use of folic acid supplements and risk of autism spectrum disorders in children[3] "To examine the association between maternal use of prenatal folic acid supplements and subsequent risk of autism spectrum disorders (ASDs) (autistic disorder, Asperger syndrome, pervasive developmental disorder-not otherwise specified [PDD-NOS]) in children. The study sample of 85,176 children was derived from the population-based, prospective Norwegian Mother and Child Cohort Study (MoBa). The children were born in 2002-2008; by the end of follow-up on March 31, 2012, the age range was 3.3 through 10.2 years (mean, 6.4 years). The exposure of primary interest was use of folic acid from 4 weeks before to 8 weeks after the start of pregnancy, defined as the first day of the last menstrual period before conception. Relative risks of ASDs were estimated by odds ratios (ORs) with 95% CIs in a logistic regression analysis. Analyses were adjusted for maternal education level, year of birth, and parity. ...Use of prenatal folic acid supplements around the time of conception was associated with a lower risk of autistic disorder in the MoBa cohort. Although these findings cannot establish causality, they do support prenatal folic acid supplementation."
  • Disruption of the folate pathway in zebrafish causes developmental defects[4] "Our studies demonstrate that human and zebrafish utilize similar one-carbon pathways. Our data indicate that folate metabolism is essential for early zebrafish development. Zebrafish studies of the folate pathway and its deficiencies could provide insight into the underlying etiology of human birth defects and the natural role of folate in development."
  • Periconceptional bread intakes indicate New Zealand's proposed mandatory folic acid fortification program may be outdated[5] "In September 2009, a folic acid fortification mandate (135 μg/100 g bread) was to be implemented in New Zealand. However, due to political and manufacturer objection, fortification was deferred until May 2012. Based on estimates of bread consumption derived from a 1997 nationally representative survey, this program was intended to deliver a mean additional intake of 140 μg folic acid/d to women of childbearing age. ...This study provides insight on the ability of a fortification policy to benefit the groups at highest risk of poor folate intakes in a population. However, bread consumption among the target group of childbearing women appears to have declined since the data used in previous dietary modeling were collected. Thus, it seems prudent to re-model dietary folic acid intakes based on more recent national survey data prior to the implementation of a mandatory folic acid fortification policy."
  • Australian Institute of Health and Welfare Neural tube defects in Australia: prevalence before mandatory folic acid fortification [6] 19 Dec 2011 "The purpose of compiling this national report is to provide baseline prevalence of NTD, before implementation of mandatory folic acid fortification of bread flour in September 2009."
More recent papers  
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This table shows an automated computer PubMed search using the listed sub-heading term.

  • Therefore the list of references do not reflect any editorial selection of material based on content or relevance.
  • References appear in this list based upon the date of the actual page viewing.

References listed on the rest of the content page and the associated discussion page (listed under the publication year sub-headings) do include some editorial selection based upon both relevance and availability.

Links: References | Discussion Page | Pubmed Most Recent | Journal Searches


Search term: Neural Tube Defect

Meselech Ambaw Dessie, Ejigu Gebeye Zeleke, Shimelash Bitew Workie, Ayanaw Worku Berihun Folic acid usage and associated factors in the prevention of neural tube defects among pregnant women in Ethiopia: cross-sectional study. BMC Pregnancy Childbirth: 2017, 17(1);313 PubMed 28934941

Malwina Pietrzykowska-Kuncman, Dorota Zasina-Olaszek, Kuncman Łukasz, Marta Niedźwiecka, Krzysztof Szaflik, Iwona Maroszyńska Intake of folic acid by Polish women with higher education - a survey research: can we do more? Ginekol. Pol.: 2017, 88(8);428-433 PubMed 28930369

Shujaul Haq, Adeel Nasrullah, Iftikhar Ahmed, Haider Ghazanfar, Abu Baker Sheikh, Aisha Akhtar Hindgut Duplication: A Unique Case of Six Perineal Openings. Cureus: 2017, 9(7);e1433 PubMed 28924521

Andrew Campion, Clement Lee, Nan Bao, Jorge Lazareff A parental perspective concerning barriers to care for neural tube defects in China. Surg Neurol Int: 2017, 8;195 PubMed 28904822

David G Belair, Cynthia J Wolf, Carmen Wood, Hongzu Ren, Rachel Grindstaff, William Padgett, Adam Swank, Denise MacMillan, Anna Fisher, Witold Winnik, Barbara D Abbott Engineering human cell spheroids to model embryonic tissue fusion in vitro. PLoS ONE: 2017, 12(9);e0184155 PubMed 28898253

Neural Tube Closure

This cartoon movie shows a dorsolateral view (from the back left side) of the early embryo.


The process of the neural groove closing to form the early neural tube is shown. This process occurs during week 4 (Gestational Age GA week 6) in human development. The same process occurs in all vertebrate animals, but at different times (days) in their early development.


Failure of the neural tube to close anywhere along its length results in a "neural tube defect".

Neural Tube Defect Classification

Neural tube defects comprise three distinct conditions: anencephaly, spina bifida and encephalocele. Note that the current ICD10 classification system is being updated to ICD11 that is currently in beta testing status. The data on this page, other than the information table below, is from ICD10 classification.

International Classification of Diseases ICD-11 Beta Draft - 20 Developmental anomalies  
ICD-11 Beta Draft - NOT FINAL, updated on a daily basis, It is not approved by WHO, NOT TO BE USED for CODING except for agreed FIELD TRIALS.

Chapter 20 Developmental anomalies, only a few examples of the draft ICD-11 Beta coding and tree structure for "structural developmental anomalies" within this section are shown in the table below.

Mortality and Morbidity Statistics - 20 Developmental Anomalies  
Structural Developmental Anomalies  
  • Structural developmental anomalies of the nervous system  
    • LA00 Anencephaly or similar anomalies
    • LA01 Cephalocele
    • LA02 Spina bifida
    • LA03 Arnold-Chiari malformation type II
    • LA04 Congenital hydrocephalus
    • LA05 Cerebral structural developmental anomalies
    • LA06 Cerebellar structural developmental anomalies
    • LA07 Structural developmental anomalies of the neurenteric canal, spinal cord or vertebral column
    • LA0Y Other specified structural developmental anomalies of the nervous system
    • LA0Z Structural developmental anomalies of the nervous system, unspecified
  • Structural developmental anomalies of the eye, eyelid or lacrimal apparatus
    • LA10 Structural developmental anomalies of ocular globes
    • LA11 Structural developmental anomalies of the anterior segment of eye
    • LA30 Structural developmental anomalies of lens or zonula
    • LA31 Structural developmental anomalies of the posterior segment of eye
    • LA32 Structural developmental anomalies of eyelid, lacrimal apparatus or orbit
    • LA3Y Other specified structural developmental anomalies of the eye, eyelid or lacrimal apparatus
    • LA3Z Structural developmental anomalies of the eye, eyelid or lacrimal apparatus, unspecified
  • Structural developmental anomalies of the ear  
    • LA40 Structural anomaly of eustachian apparatus
    • LA41 Minor anomalies of pinnae
    • LA42 Structural developmental anomalies of ear causing hearing impairment
    • LA43 Otocephaly
    • LA44 Accessory auricle
    • LA4Y Other specified structural developmental anomalies of the ear
    • LA4Z Structural developmental anomalies of the ear, unspecified
  • Structural developmental anomalies of the face, mouth or teeth
    • LA50 Structural developmental anomalies of teeth and periodontal tissues
    • LA51 Structural developmental anomalies of mouth or tongue
    • Clefts of lip, alveolus or palate
    • LA70 Congenital velopharyngeal incompetence
    • LA71 Facial clefts
    • LA72 Facial asymmetry
    • LA73 Macrocheilia
    • LA74 Microcheilia
    • LA75 Compression facies
    • LA76 Pierre Robin syndrome
    • LC20 Dermoid cyst
    • LA7Y Other specified structural developmental anomalies of the face, mouth or teeth
    • LA7Z Structural developmental anomalies of the face, mouth or teeth, unspecified
  • Structural developmental anomalies of the neck  
  • Structural developmental anomalies of the respiratory system  
  • Structural developmental anomalies of the circulatory system  
    • Structural developmental anomaly of heart and great vessels
      • LB00 Congenital heart or great vessel related acquired abnormality
      • LB01 Congenital anomaly of atrioventricular or ventriculo-arterial connections
      • LB02 Congenital anomaly of the mediastinal veins Congenital anomaly of atria or atrial septum
      • LB20 Congenital anomaly of atrioventricular valves or septum
      • LB21 Congenital anomaly of ventricles and ventricular septum
      • LB22 Functionally univentricular heart
      • LB23 Congenital anomaly of ventriculo-arterial valves and adjacent regions
      • LB24 Congenital anomaly of great arteries including arterial duct
      • LB25 Anomalous position-orientation of heart
      • LB26 Total mirror imagery
      • LB27 Left isomerism
      • LB28 Congenital anomaly of coronary arteries
      • LB29 Structural developmental anomalies of the pericardium
      • LB2Y Other specified structural developmental anomaly of heart and great vessels
      • LB2Z Structural developmental anomaly of heart and great vessels, unspecified
    • LB30 Structural developmental anomalies of the peripheral vascular system
      • LB30.1 Capillary malformations
      • LB30.2 Lymphatic malformations
        • LB30.21 Macrocystic lymphatic malformation
        • LB30.22 Microcystic lymphatic malformation
        • LB30.23 Cystic hygroma in fetus
        • BD23.1 Primary lymphoedema
            • EK91 Yellow nail syndrome
            • LC5F.26 Noonan syndrome
        • LB30.2Y Other specified lymphatic malformations
        • LB30.2Z Lymphatic malformations, unspecified
      • LB30.3 Peripheral venous malformations
      • LB30.4 Peripheral arteriovenous malformations
      • LB30.5 Peripheral arterial malformations
      • LB30.6 Pulmonary arteriovenous fistula
      • LB30.Y Other specified structural developmental anomalies of the peripheral vascular system
      • LB30.Z Structural developmental anomalies of the peripheral vascular system, unspecified
    • LB3Y Other specified structural developmental anomalies of the circulatory system
    • LB3Z Structural developmental anomalies of the circulatory system, unspecified
  • Structural developmental anomalies of the diaphragm, abdominal wall or umbilical cord  
  • Structural developmental anomalies of the digestive tract  
  • Structural developmental anomalies of the liver, biliary tract, pancreas or spleen  
  • Structural developmental anomalies of the urinary system  
  • Structural developmental anomalies of the female genital system  
  • Structural developmental anomalies of the male genital system  
  • Structural developmental anomalies of the breast  
  • Structural developmental anomalies of the skeleton  
  • Structural developmental anomalies of the skin  
  • Structural developmental anomalies of the adrenal glands  
Multiple developmental anomalies or syndromes
Chromosomal anomalies, excluding gene mutations
Conditions with disorders of intellectual development as a relevant clinical feature
LD6Y Other specified developmental anomalies

LD6Z Developmental anomalies, unspecified

CD-11 Beta Draft - NOT FINAL, updated on a daily basis, It is not approved by WHO, NOT TO BE USED for CODING except for agreed FIELD TRIALS.


See also International Classification of Diseases

ICD-10 Links: XVII Congenital Malformations | System Tables | XVI Perinatal Period | XV Pregnancy Childbirth | Abnormal Development | Reports

Anencephaly

  • A congenital anomaly characterised by the total or partial absence of the cranial vault, the covering skin and the brain.
  • Remaining brain tissue may be very much reduced in size.
  • Craniorachischisis and iniencephaly are included.
  • Acephaly, the absence of the head observed in amorphous acardiac twins, is excluded.
International Classification of Diseases (ICD-10) - Anencephaly

ICD-10 codes: Q00 Anencephaly and similar malformations

  • Q00.0 Anencephaly, Acephaly, Acrania, Amyelencephaly, Hemianencephaly, Hemicephaly
  • Q00.1 Craniorachischisis
  • Q00.2 Iniencephaly

Spina bifida

  • A congenital anomaly characterised by a failure in the closure of the spinal column.
  • Characterised by herniation or exposure of the spinal cord and/or meninges through the incompletely closed spine.
  • This excludes spina bifida occulta and sacrococcygeal teratoma without dysraphism.
  • ICD codes: ICD-9-BPA codes: 741.00–741.99 or ICD-10-AM codes: Q05.0–Q05.9.


Encephalocele

  • A congenital anomaly characterised by herniation of the brain and/or meninges through a defect in the skull.
  • ICD codes: ICD-9-BPA codes: 742.00–742.09 or ICD-10-AM codes: Q01.0–Q01.2, Q01.8, Q01.9.

Australian Statistics

Folic acid and iodine fortification (2016)

From 13 September 2009, the mandatory folic acid fortification standard requires the addition of folic acid to all wheat flour for bread making, with the exception of organic bread, within the prescribed range of 200–300 μg per 100 g of flour.

A recent 2016 study[1] has shown since fortification:

  • Overall decrease in the rate of neural tube defects (NTDs) by 14.4%
  • Teenagers the rate of NTDs decreased by almost 55%
  • Aboriginal and Torres Strait Islander women the rate of NTDs decreased by 74%



An earlier 2011 study[6] looking at the prevalence of neural tube defects before mandatory fortification.

  • Women who have one infant with a neural tube defect have a significantly increased risk of recurrence
    • 40-50 per thousand compared with 2 per thousand for all births.
  • A randomised controlled trial conducted by the Medical Research Council of the United Kingdom demonstrated a 72% reduction in risk of recurrence by periconceptional (ie before and after conception) folic acid supplementation (4mg daily).
  • Other epidemiological research, including work done in Australia, suggests that primary occurrences of neural tube defects may also be prevented by folic acid either as a supplement or in the diet.
  • This has been confirmed in a randomised controlled trial from Hungary, which found that a multivitamin supplement containing 0.8mg folic acid was effective in reducing the occurrence of neural tube defects in first births.

Before mandatory folic acid fortification was introduced:

  • mean dietary folic acid intakes for women aged 16–44 years (the target population) in Australia was 108 micrograms (μg) of folic acid per day and in New Zealand was 62 μg of folic acid per day, well below the recommended 400 μg per day.
  • there were 149 pregnancies affected by NTDs in 2005 in Australia (rate of 13.3 per 10,000 births) in the three states that provide the most accurate baseline of NTD incidence (South Australia, Western Australia and Victoria), and 63 pregnancies affected by NTDs in 2003 in New Zealand (rate of 11.2 per 10,000 births).

Before mandatory iodine fortification was introduced:

  • large proportions of the Australian and New Zealand population had inadequate iodine intakes.
  • national surveys measuring median urinary iodine concentration (MUIC) in schoolchildren, an indicator of overall population status, confirmed mild iodine deficiency in both countries.
    • The concentration was 96 μg per litre in Australia, and 66 μg per litre in New Zealand, less than the 100–200 μg per litre considered optimal.
Links: Folic Acid and Neural Tube Defects | Iodine Deficiency | Australian Statistics | AIHW - folic acid and iodine

USA Statistics

In the U.S.A. the Food and Drug Administration in 1996 authorized that all enriched cereal grain products be fortified with folic acid, with optional fortification beginning in March 1996 and mandatory fortification in January 1998. The data below shows the subsequent changes in anencephaly and spina bifida rate over that period.

USA spina bifida rates.jpg

USA anencephaly rates.jpg

Data CDC Report[7]

Folic Acid

Formula: C19H19N7O6

Alternate Names: Folic acid, Folate, Pteroylglutamic acid


Folate Biosynthesis.jpg

(Data from KEGG)

Folate Biosynthesis(click image for full size or get original Map)

Folate Supplementation and Other Abnormalities

A recent study of periconceptional folate supplementation using the Cochrane Pregnancy and Childbirth Group's Trials Register (July 2010) identified no statistically significant evidence of any effects on prevention of cleft palate, cleft lip, congenital cardiovascular defects, miscarriages or any other birth defects.[8]


Surgery for Spina Bifida

Fetal Surgery

The neural tube remaining open during fetal development can lead to neural damage through exposure to amniotic fluid and mechanical effects. There are experimental fetal surgical techniques in some countries that allow prenatal repair and perhaps prevent further neurological damage. There are though fetal and maternal risks associated with this surgical procedure.[9] A recent 2014 Cochrane Database study[10] identified that "insufficient evidence to recommend drawing firm conclusions on the benefits or harms of prenatal repair as an intervention for fetuses with spina bifida."

Neonatal Surgery

The surgical repair after birth is a more common procedure.


References

  1. 1.0 1.1 AIHW 2016. Monitoring the health impacts of mandatory folic acid and iodine fortification 2016. Cat. no. PHE 208. Canberra: AIHW. PDF
  2. NaTasha D Hollis, Emily G Allen, Tiffany Renee Oliver, Stuart W Tinker, Charlotte Druschel, Charlotte A Hobbs, Leslie A O'Leary, Paul A Romitti, Marjorie H Royle, Claudine P Torfs, Sallie B Freeman, Stephanie L Sherman, Lora J H Bean Preconception folic acid supplementation and risk for chromosome 21 nondisjunction: a report from the National Down Syndrome Project. Am. J. Med. Genet. A: 2013, 161A(3);438-44 PubMed 23401135
  3. Pål Surén, Christine Roth, Michaeline Bresnahan, Margaretha Haugen, Mady Hornig, Deborah Hirtz, Kari Kveim Lie, W Ian Lipkin, Per Magnus, Ted Reichborn-Kjennerud, Synnve Schjølberg, George Davey Smith, Anne-Siri Øyen, Ezra Susser, Camilla Stoltenberg Association between maternal use of folic acid supplements and risk of autism spectrum disorders in children. JAMA: 2013, 309(6);570-7 PubMed 23403681 | JAMA
  4. Marina S Lee, Jenna R Bonner, David J Bernard, Erica L Sanchez, Eric T Sause, R Reid Prentice, Shawn M Burgess, Lawrence C Brody Disruption of the folate pathway in zebrafish causes developmental defects. BMC Dev. Biol.: 2012, 12;12 PubMed 22480165
  5. Simonette R Mallard, Andrew R Gray, Lisa A Houghton Periconceptional bread intakes indicate New Zealand's proposed mandatory folic acid fortification program may be outdated: results from a postpartum survey. BMC Pregnancy Childbirth: 2012, 12;8 PubMed 22333513
  6. 6.0 6.1 Macaldowie, A. and Hilder, L. (2011) Neural tube defects in Australia: prevalence before mandatory folic acid fortification. Cat. no. PER 53. Canberra: AIHW.
  7. CDC Trends in Spina Bifida and Anencephalus in the United States, 1991-2005
  8. Luz Maria De-Regil, Ana C Fernández-Gaxiola, Therese Dowswell, Juan Pablo Peña-Rosas Effects and safety of periconceptional folate supplementation for preventing birth defects. Cochrane Database Syst Rev: 2010, (10);CD007950 PubMed 20927767
  9. N Scott Adzick Fetal surgery for spina bifida: past, present, future. Semin. Pediatr. Surg.: 2013, 22(1);10-7 PubMed 23395140
  10. Rosalie M Grivell, Chad Andersen, Jodie M Dodd Prenatal versus postnatal repair procedures for spina bifida for improving infant and maternal outcomes. Cochrane Database Syst Rev: 2014, 10;CD008825 PubMed 25348498

Reviews

Paul W Veenboer, J L H Ruud Bosch, Floris W A van Asbeck, Laetitia M O de Kort Upper and lower urinary tract outcomes in adult myelomeningocele patients: a systematic review. PLoS ONE: 2012, 7(10);e48399 PubMed 23119003

Monika Eichholzer, Otmar Tönz, Roland Zimmermann Folic acid: a public-health challenge. Lancet: 2006, 367(9519);1352-61 PubMed 16631914

Tsunenobu Tamura, Mary Frances Picciano Folate and human reproduction. Am. J. Clin. Nutr.: 2006, 83(5);993-1016 PubMed 16685040

Shi Wu Wen, Mark Walker An exploration of health effects of folic acid in pregnancy beyond reducing neural tube defects. J Obstet Gynaecol Can: 2005, 27(1);13-9 PubMed 15937577


Articles

Anne M Molloy Folate bioavailability and health. Int J Vitam Nutr Res: 2002, 72(1);46-52 PubMed 11887752

L E Daly, P N Kirke, A Molloy, D G Weir, J M Scott Folate levels and neural tube defects. Implications for prevention. JAMA: 1995, 274(21);1698-702 PubMed 7474275

I Leck Folates and the fetus. Lancet: 1977, 1(8021);1099-100 PubMed 68194

R W Smithells, S Sheppard, C J Schorah Vitamin dificiencies and neural tube defects. Arch. Dis. Child.: 1976, 51(12);944-50 PubMed 1015847


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Cite this page: Hill, M.A. 2017 Embryology Abnormal Development - Folic Acid and Neural Tube Defects. Retrieved September 26, 2017, from https://embryology.med.unsw.edu.au/embryology/index.php/Abnormal_Development_-_Folic_Acid_and_Neural_Tube_Defects

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