Folic Acid: Implications in Birth Defects and Chronic Disease

1
Folic Acid Implications in Birth Defects and
Chronic Disease

• Patrice Christoffersen, RD

2
What is the Recommended Daily Value?

• Adults (14-years and older) 400 mcg/d
• Pregnancy (all ages) 600 mcg/d
• Breastfeeding (all ages) 500 mcg/d
• Previously affected pregnancy 4000 mcg/d

3
What is Folic Acid?

• Folate Natural Form
• Folic Acid Synthetic Form

4
Folic Acid (Pteroyl-monoglutamic acid)
Pteridine
     
 
 
p-Aminobenzoic acid
L-Glutamic acid
5
What is Folic Acid?

• Folate is the natural (complex) form found in
  foods such as dark-green leafy vegetables,
  broccoli, asparagus, lentils, beans, peanuts,
  strawberries, kiwi, orange juice, liver.
• Folate in foods can be lost through processing
  and cooking, reducing the amount of available
  folate.

6
What is Folic Acid?

• A diet rich in folate is important, however the
  average daily intake of folate from foods is
  about 200 micrograms.
• Efficacy of folate absorption is estimated at
  50.
• So, of the 200 micrograms that are eaten, only
  about 100 micrograms are actually used by the
  body.

7
What is Folic Acid?

• Folic acid is the synthetic (simple) form of
  folate.
• Used in nutritional supplements and food
  fortification.
• Only form that can be transported across
  membranes.
• Most oxidized and stable form of folate.

8
What is Folic Acid?

• The FDA ruled that starting January 1, 1998, all
  cereal and grain products labeled enriched must
  be fortified with folic acid.
• 140 mcg FA per 100 grams of flour.
• This translates to about 10 of the recommended
  daily value for a slice of enriched bread or 25
  of the recommended daily value for a 1 cup
  serving of cooked pasta.
• Some cereals are fortified with 100 DV (400 mcg)
  folic acid per serving.

9
Bioavailability

• The structural difference between folic acid and
  food folate accounts for differences in
  bioavailability, with folic acid being more
  readily absorbed.
• To take into account this difference in
  bioavailability the Institute of Medicine
  introduced the Dietary Folate Equivalent (DFE).

10
Dietary Folate Equivalent (DFE)

• 1 mcg of food folate provides 1 mcg of DFE.
• 1 mcg of folic acid taken on an empty stomach
  provides 2 mcg of DFE.
• 1 mcg of folic acid taken with food or as
  fortified food provides 1.7 mcg of DFE.

11
Where can you get folic acid?

• Good sources of folic acid include
• Multivitamins Most sold in the US have all the
  folic acid you need (400 mcg).
• Folic acid supplements These are a smaller
  vitamin pills that contain only folic acid.
• Cereals with100 DV of folic acid per serving.

12
Who needs folic acid?

• Just about everyone can benefit from taking folic
  acid!
• It is an important vitamin that is recommended
  for all men and women.
• Folic acid is most important for any female who
  could possibly become pregnant.

13
Institute of Medicine

• Recommends all women of reproductive age (capable
  of becoming pregnant) consume 400 mcg/d of folic
  acid from supplements or fortified foods, in
  addition to a diet rich in food folate.
• For women who have had a previous affected
  pregnancy, folic acid supplementation of 4 mg/d
  is recommended (under physician supervision).

14
What does folic acid do?

• Although the underlying biologic mechanism is
  unknown, researchers have found strong evidence
  that the B-vitamin, folic acid, can prevent
  50-70 of neural tube defects (NTD) like
  anencephaly and spina bifida.

15
How common are NTDs?

• Estimated 4,000 affected pregnancies yearly.
• About 2,500 babies born yearly.
• 1,500 babies born with spina bifida.
• 1,000 babies born with anencephaly.
• About 1,500 fetuses are miscarried or terminated
  after diagnosis.

16
What are Neural Tube Defects?

• Neural Tube Defects (NTDs) are birth defects of
  the brain and the spinal cord.
• They occur when the neural tube, which later
  becomes the brain and the spine, fails to close
  properly.
• This happens very early in pregnancy, between the
  17th and the 28th day after conception.

17
What does folic acid do?

• Half of all pregnancies are unplanned, so it is
  important for women (14 45 yr) to get in the
  habit of taking folic acid so that their body has
  it when it is needed most.

18
What are Neural Tube Defects?
After the egg and the sperm unite, cells divide
and multiply to form an elongated structure as
seen in day 22.
19
What are Neural Tube Defects?

• A zippering effect closes the groove or the
  tube beginning in the center and going both up
  and down as seen in day 23.

20
What are Neural Tube Defects?

• A defect may occur in the upper or lower portion
  of the neural tube.
• If the tube fails to close properly on the upper
  portion of the neural tube, a brain defect called
  anencephaly or another called encephalocele
  occurs.
• If it fails to close properly along the lower
  portion of the neural tube, a spinal defect
  called spina bifida occurs.

21
What are Neural Tube Defects?
Anencephaly
Encephalocele
22
What are Neural Tube Defects?

• Spina Bifida

23
Spina Bifida

• The damage that occurs may lead to muscle
  weakness, paralysis, and loss of bowel and
  bladder control.
• Hydrocephalus also occurs frequently in these
  babies.

24
China Folic Acid Community Intervention

• NTD/Folic acid support is corroborated by the
  recently published results of an interventional
  study conducted by the CDC in two areas of China,
  one with high prevalence and the other with low
  prevalence of NTDs (N Engl J Med 3411485-1490,
  1999).

25
China Folic Acid Community Intervention

• The investigators found that among women who took
  400 mcg/d of folic acid from the time of their
  premarital examination until the end of the first
  trimester of pregnancy, the risk of NTDs was
  reduced by 85 in the region with high risk for
  NTDs and by 40 in the low risk region. 

26
Additional Birth Defects

• Researchers are studying other potential benefits
  of multivitamins containing folic acid.
• Heart Defects
• Cleft Lip/Cleft Palate
• Limb Defects
• Urinary Defects

27
What else does folic acid do?

• Folic acid and other B vitamins are needed to
  produce red blood cells.
• Folic acid is also necessary for the production
  and maintenance of DNA and RNA, the building
  blocks of cells.
• It may reduce your risk of heart disease, stroke
  and certain cancers.

28
What are the metabolic roles of folic acid?
29
Metabolic Role

• The roles of folic acid
• 1) nucleic acid metabolism
• 2) amino acid metabolism
• Its role in nucleic acid metabolism involves two
  pathways

30
Metabolic Role

• The first pathway involves purine and pyrimidine
  synthesis which makes folic acid essential for
  cell division and DNA and RNA synthesis.
• The second pathway includes synthesis of the
  methyl donor S-adenosylmethionine (SAM), used in
  hundreds of methylation reactions, including
  methylation of DNA (which plays a key role in
  gene expression).

31
Metabolic Role

• Amino acid metabolism
• Folic acid derivatives are needed for the
  conversion of the amino acid homocysteine to
  methionine.

32
Cardiovascular Disease

• Homocysteine is an amino acid in the blood, too
  much of it is related to a higher risk of
  coronary heart disease, stroke and peripheral
  vascular disease.
• Evidence suggests that homocysteine may promote
  atherosclerosis by damaging the inner lining of
  arteries and promoting blood clots.
• Folic acid and other B vitamins help break down
  homocysteine in the body.

33
New Evidenced-Based Guidelines for CVD Prevention
in Women (AHA 2004)

• Last year recommendations were published for CVD
  preventive care in all women age 20 years and
  older.
• One of these is that folic acid supplementation
  should be considered in high risk women if a
  higher than normal level of homocysteine has been
  detected.

34
Cardiovascular Disease

• Several studies have found that higher blood
  levels of folic acid and B vitamins are related
  to lower concentrations of homocysteine.
• Other evidence shows that low blood levels of
  folic acid are linked with a higher risk of fatal
  CHD and stroke.

35
March 5, 2004 Researchers reported

• Folic acid fortification of enriched grain
  products in the late 1990s appears to have
  resulted in a decline in stroke and ischemic
  heart disease deaths.
• There has been evidence of three-fold
  acceleration in the decline of stroke related
  mortality that has been temporarily related to
  folic acid fortification.

36
Folic acid may prevent hypertension

• Researchers from Brigham and Women's Hospital in
  Boston found that women who consumed high levels
  of the B vitamin from food and supplements
  significantly reduced their risk of developing
  hypertension.
• JAMA. 2005293320-329.

37
Folic acid may prevent hypertension

• Among younger women who consumed at least 1,000
  micrograms per day of folate from dietary and
  supplemental sources, there was a 46 percent
  reduction in risk of hypertension compared to
  women whose folate intake was less than 200
  micrograms per day.
• Older women had an 18 percent reduction in risk
  of hypertension.

38
Cancer

• Since folic acid is involved in the synthesis,
  repair and functioning of DNA (our genetic map),
  a deficiency may result in damage to DNA that
  leads to cancer.
• A relationship between folic acid and several
  types of cancers has been observed in several
  population-based studies but is most clearly
  defined for colorectal cancer and colorectal
  adenomas.

39
Colon Cancer

• Nurses Health Study cohort
• After 14 years of follow-up, women consuming at
  least 400 mcg/d of total folate had a 31
  decreased risk of colon cancer.
• After 15 years of taking a vitamin supplement
  with folic acid, relative risk of colon cancer
  was decreased by 75.

40
Colon Cancer

• Nurses Health Study and Health Professionals
  Follow-up Study.
• A 30-40 decreased risk for colorectal adenomas
  was found with total folate intakes greater than
  700 mcg/d.

41
Cancer

• Epidemiologic studies provide support for the
  hypothesis that decreased methyl group
  availability may contribute to cancer risk.
• Risks were exacerbated by methyl deplete diets
  high alcohol, low folate, low methionine.

42
Alzheimers Disease

• Recent research suggests that folate deficiency
  and a high homocysteine level may increase the
  risk for development of Alzheimer's disease and
  vascular dementia.
• More clinical trials are needed.

43
Folic Acid Deficiency

• Folic acid deficiency can lead to impairment of
  cell division, accumulation of possibly toxic
  metabolites such as homocysteine, and impairment
  of methylation reactions involved in the
  regulation of gene expression.

44
Folic Acid Status

• May be affected by
• Genetics
• Interactions with medications
• Inadequate intake or absorption

45
Genetic Variation

• The MTHFR enzyme is important for hemical
  reactions involving folate.
• A common polymorphism is found in the gene for
  the enzyme MTHFR (methylene tetrahydrofolate
  reductase), known as C677T MTHFR.
• Approximately 10 of the US population possess
  the homozygous polymorphism.
• Without the enzyme, homocysteine cannot be
  converted to methionine.
• As a result, homocysteine builds up in the
  bloodstream and methionine is depleted.

46
MTHFR

• The C677T variant has been associated with an
  increased risk of cardiovascular disease
  including coronary heart disease and stroke in
  adults.
• Research suggests that the variant may be a risk
  factor for birth defects that occur during the
  development of the brain and spinal cord (neural
  tube defects).

47
Auto-Antibodies to Folate Receptor in Maternal
Serum Samples-Case Mothers

• Women produce auto antibodies against the folate
  receptors preventing the binding and transport of
  folic acid to cellular components during critical
  periods of embryonic development. Supplemental
  folic acid competes with the auto antibodies and
  restores cellular folate concentrations.
• Rothenberg et al., N. Engl. J. Med. 350134-142,
  2004

48
Rothenberg Study
49
Rothenberg Study
50
Summary of RothenbergStudy

• 9 out of 12 (75) mothers who previously had a
  child with an NTD had auto-antibodies to the
  folate receptor.
• 2 out of 20 (10) mothers who previously gave
  birth to non-affected infants had auto-antibodies
  to the folate receptor.

51
Inadequate Intake or Absorption

• Malabsorption syndromes, including Crohns
  disease, tropical sprue, and gluten sensitive
  enteropathy can result in deficiency secondary to
  inadequate absorption.
• Alcoholism leads to impaired absorption and poor
  diet.

52
Drugs that interfere with Folic Acid

• Phenobarbital, phenytoin (Dilantin),
  carbamazapine (Tegretol) and primidone
  (Mysoline) are used to primarily prevent
  seizures.
• Antibiotic combination of trimethoprim and a
  sulfonamide (Bactrim, Septra) are commonly used
  for urinary tract infections.
• Triamterene (Dyrenium) is a diuretic used for
  high blood pressure.
• Sulfasalazine (Azulfidine) is used for
  ulcerative colitis and other inflammatory
  conditions.
• Anticonvulsant valproic acid (Depakene)
• Cimetidine (Tagamet) is used to treat heartburn
  and reflux.
• Beta-blockers and calcium-channel blockers are
  used for high blood pressure and certain heart
  disorders.
• Cholestyramine (Locholest, Questran) is used to
  lower cholesterol levels.

53
Folic Acid Knowledge
54
Folic Acid Knowledge
March of Dimes Folic Acid Survey conducted by The
Gallup Organization, August 2003
55
Folic Acid Behavior
March of Dimes Folic Acid Survey conducted by The
Gallup Organization, August 2003
56
Healthy People 2010

• To increase at least by 80, the proportion of
  women of childbearing age who take a vitamin with
  the recommended 400 mcg per day.

57
Health Care Implications

• The majority (89) of women surveyed, who do not
  currently take a vitamin supplement on a daily
  basis, say they would be likely to take one if
  advised to do so by their physician or other
  health care provider.

March of Dimes Folic Acid Survey conducted by The
Gallup Organization, August 2003
58
Health Care Implications

• Your patients listen to what you tell them.
• Regardless of whether or not patients planning a
  pregnancy, discuss the importance of folic acid
  with all women of childbearing age.
• Make folic acid a routine and standard part of
  the delivery of preventative healthcare
  services.

59
Thank you! Questions?

• Patrice Christoffersen
• pchristo_at_isdh.state.in.us
• 317-234-2976