Folic Acid Implications in Birth Defects and Chronic

Folic Acid: Implications in Birth Defects and Chronic Disease Patrice Christoffersen, RD

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

What is Folic Acid? Folate = Natural Form Folic Acid = Synthetic Form

Folic Acid (Pteroyl-monoglutamic acid) Pteridine p-Aminobenzoic acid L-Glutamic acid

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.

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.

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

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. n 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.

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).

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.

Where can you get folic acid? Good sources of folic acid include: n n n 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 with 100% DV of folic acid per serving.

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.

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).

What does folic acid do? Although the underlying biologic mechanism is unknown, researchers have found strong evidence that the Bvitamin, folic acid, can prevent 50 -70% of neural tube defects (NTD) like anencephaly and spina bifida.

How common are NTD’s? § 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.

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 17 th and the 28 th day after conception.

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.

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.

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.

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.

What are Neural Tube Defects? Anencephaly Encephalocele

What are Neural Tube Defects? Spina Bifida

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.

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 341: 1485 -1490, 1999).

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.

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

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.

What are the metabolic roles of folic acid?

Metabolic Role The roles of folic acid n n 1) nucleic acid metabolism 2) amino acid metabolism Its role in nucleic acid metabolism involves two pathways…

Metabolic Role n n 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).

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

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.

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.

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.

March 5, 2004 Researchers reported… Folic acid fortification of enriched grain products in the late 1990’s 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.

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. 2005; 293: 320 -329.

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.

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.

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

Colon Cancer Nurse’s Health Study and Health Professionals Follow-up Study. w A 30 -40% decreased risk for colorectal adenomas was found with total folate intakes greater than 700 mcg/d.

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.

Alzheimer’s 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.

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.

Folic Acid Status May be affected by: n Genetics n Interactions with medications n Inadequate intake or absorption

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 C 677 T MTHFR. w Approximately 10% of the US population possess the homozygous polymorphism. Without the enzyme, homocysteine cannot be converted to methionine. w As a result, homocysteine builds up in the bloodstream and methionine is depleted.

MTHFR The C 677 T 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).

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. 350: 134 -142, 2004

Rothenberg Study

Rothenberg Study

Summary of Rothenberg Study 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 autoantibodies to the folate receptor.

Inadequate Intake or Absorption Malabsorption syndromes, including Crohn’s disease, tropical sprue, and gluten sensitive enteropathy can result in deficiency secondary to inadequate absorption. Alcoholism leads to impaired absorption and poor diet.

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.

Folic Acid Knowledge

Folic Acid Knowledge March of Dimes Folic Acid Survey conducted by The Gallup Organization, August 2003

Folic Acid Behavior March of Dimes Folic Acid Survey conducted by The Gallup Organization, August 2003

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.

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

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.

Thank you! Questions? Patrice Christoffersen pchristo@isdh. state. in. us 317 -234 -2976