Abnormal Development - Folic Acid and Neural Tube Defects

Introduction

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.

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.

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 | Neural System - Abnormalities | Axial Skeleton Abnormalities

Some Recent Findings

Disruption of the folate pathway in zebrafish causes developmental defects "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 Periconceptional bread intakes indicate New Zealand's proposed mandatory folic acid fortification program may be outdated "In September 2009, a folic acid fortification mandate (135 μg/100 g bread) was to be implemented in New Zealand.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 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." Australian Institute of Health and Welfare Mandatory folic acid and iodine fortification in Australia and New Zealand: baseline report for monitoring "This report presents key baseline data for monitoring mandatory folic acid and iodine fortification in Australia and New Zealand. Data are presented for each component of the fortification monitoring frameworks as follows: food composition; folic acid and iodine intake; folic acid and iodine status of the populations; and health outcomes." Reports Prevalence of neural tube defects in Australia prior to mandatory fortification of bread-making flour with folic acid."The birth prevalence of NTDs from 1998-2005, was 5/10,000 births. The total prevalence including terminations of pregnancy was 13/10,000 births. A 26% declining trend in total prevalence was seen from 1992-2005, but the main decline occurred prior to 1998. Women who were Indigenous, socially disadvantaged, young, living in remote areas and had multiple gestations were more likely to give birth to babies with NTDs." Low folic acid supplement intake rate among women in northern China with a high-prevalence of neural tube defects, 2008."In 2008, we conducted a cross-sectional survey to investigate awareness and intake rates of folic acid supplementation among women of childbearing age from 293 counties (all national-level poverty counties) in northern China that had a high prevalence of NTDs ( about 16.0/10,000 births of at least 28 weeks gestation in 2008)." Association of folate receptor (folr1, folr2, folr3) and reduced folate carrier (slc19a1) genes with meningomyelocele. "This study involved the analyses of selected single nucleotide polymorphisms across the folate receptor genes and the folate carrier gene in a large population sample. It provided evidence that the rare alleles of specific single nucleotide polymorphisms within these genes appear to be statistically significant for association to meningomyelocele in the patient population that was tested." High intake of folic acid disrupts embryonic development in mice. "Mthfr +/+ or +/- pregnant mice on a control diet (CD; recommended intake of folic acid for rodents) or folic acid-supplemented diet (FASD; 20-fold higher than the recommended intake) were examined for embryonic loss, delay, and defects at 10.5 and 14.5 days post coitum (dpc); 10.5-dpc placenta, and 14.5-dpc embryo hearts were studied histologically. ...Our study suggests that high folate intake may have adverse effects on fetal mouse development and that maternal MTHFR deficiency may improve or rescue some of the adverse outcomes. These findings underscore the need for additional studies on the potential negative impact of high folate intake during pregnancy.

Neural Tube Defect Classification

Neural tube defects comprise three distinct conditions: anencephaly, spina bifida and encephalocele.

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.
• ICD codes: ICD-9-BPA codes: 740.00–740.29 or ICD-10-AM codes: Q00.0–Q00.2.

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

• 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.

(Data excerpt from NHMRC Publication)

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.

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.

Data CDC Report

Folic Acid

Formula: C19H19N7O6

Alternate Names: Folic acid, Folate, Pteroylglutamic acid

(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.

Australian NHMRC

The Australian NHMRC (1988) recommends neonates be assessed for follow-up care under the following conditions.

(see the NHMRC WWW Page)

• Birthweight less than 1500g or gestational age less than 32 weeks
• Small-for-gestational-age neonates
• Perinatal asphyxia
• Apgar score less than 3 at 5 minutes
• clinical evidence of neurological dysfunction
• delay in onset of spontaneous respiration for more than 5 minutes and requiring mechanical ventilation
• Clinical evidence of central nervous system abnormalities ie., seizures, hypotonia
• Hyperbilirubinaemia of greater than 350umol/l in full term neonates
• Genetic, dysmorphic or metabolic disorders or a family history of serious genetic disorder
• Perinatal or serious neonatal infection including children of mothers who are HIV positive
• Psychosocial problems eg., infants of drug-addicted or alcoholic mothers.

References

Reviews

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Articles

<pubmed>11887752</pubmed> <pubmed>7474275</pubmed> <pubmed>68194</pubmed> <pubmed>1015847</pubmed>

Search PubMed

Search Bookshelf: Folic Acid and Neural Tube Defects | Folic Acid

• Folic Acid Supplementation for the Prevention of Neural Tube Defects An Update of the Evidence for the U.S. Preventive Services Task Force
• Screening for Neural Tube Defects— Including Folic Acid/Folate Prophylaxis Guide to Clinical Preventive Services, 2nd Edition: 1996

Search Pubmed: Folic Acid and Neural Tube Defects | Folic Acid

External Links

External Links Notice - The dynamic nature of the internet may mean that some of these listed links may no longer function. If the link no longer works search the web with the link text or name. Links to any external commercial sites are provided for information purposes only and should never be considered an endorsement. UNSW Embryology is provided as an educational resource with no clinical information or commercial affiliation.

• Australia Department of Health Nutrition and Healthy Eating Trends in Neural Tube Defects in Australia
• See also the NHMRC Publication Dietary Folic Acid and Neural Tube Defects
• National Perinatal Statistics Unit
• Australian Journal of Nutrition and Dietetics
• Australian Nutrition Foundation
• CSIRO Human Nutrition
• Food, Nutrition & Health Information - Centre for Advanced Food Research
• Office of Dietary Supplements, National Institutes of Health (USA)Dietary Supplement Fact Sheet: Folate
• Foodwatch
• Healthy Eating, Healthy Living
• AIS Sport Nutrition - information from the Australian Institute of Sport. Supplies nutrition research, a question-and-answer section, publications, and other resources.
• America's Eating Habits - a report from the U.S. Department of Agriculture's economic research service. Covers dietary recommendations, health claims in food advertising, reality about cholesterol, and various other topics. 
• British Nutrition Foundation - an organization that works with academic, private, and public groups on nutrition. Includes nutrition education, facts, news, and publications. 
• Center for Food Safety & Applied Nutrition - a repository of links relevant to all manner of food issues, including food safety. Emphasizes FDA regulations and related research programs. 
• Nutrition.gov - a collection of information and links to other sites on food safety, food programs, and federally funded research centers.
• Nutrition.org - site of the American Society for Nutritional Sciences. Features an encyclopedia that summarizes food sources, diet recommendations, and deficiencies for a number of macro- and micronutrients.
• Nutrition Navigator - a guide to nutrition websites reviewed and rated by Tufts University nutritionists. Supplies news and sections arranged by topic.
  • Antioxidants Research Laboratory
  • Genetics Laboratory
  • Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging
• U.S. Department of Agriculture
  • Beltsville Human Nutrition Research Center
  • Food Surveys Research Group
  • The Food Guide Pyramid: A Guide to Daily Food Choices
• Children's Nutrition Research Center
• Facts about the DASH Diet
• Healthfinder Kids
  • Nutrition
• Interactive Healthy Eating Index
• National Dairy Council
• Nutrition Explorations
  • The Food Guide Pyramid

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Cite this page: Hill, M.A. (2024, April 23) Embryology Abnormal Development - Folic Acid and Neural Tube Defects. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Abnormal_Development_-_Folic_Acid_and_Neural_Tube_Defects

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