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 Man-Made

Folic Acid (Pteroyl-monoglutamic acid) Pteridine       p-Aminobenzoic acid Folic Acid contains ONE glutamic acid Folate contains 2-7 glutamic acids 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. ½ cup boiled spinach contains 130 mcg ·1/2 cup of cooked lentils contains 179 micrograms of folate. ·1/2 cup of pinto beans contains 147 micrograms of folate. ·1/3 cup of roasted peanuts provides only 109 micrograms of folate (peanuts are loaded with fat). ·6oz OJ from concentrate contains 82 mcg 1 medium orange contains 47 micrograms of 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. It requires the action of an enzyme in the GI tract to break it down to the folic acid form for absorption (in the proximal jejunum via active and passive transport)

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.

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. Enriched means adding back nutrients that were lost during food processing (for example, natural B vitamins). Fortified means adding nutrients that weren’t present originally (for example, man-made folic acid). These foods were chosen for fortification with folic acid because they are staple products for most of the U.S. population, Since fortification began there has been a 31% decrease in spina bifida and a 16% decrease in anencephaly.

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: 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. Look for 100% next to folic acid on the nutrition label.

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). Folic acid is not toxic, even in high amounts, and excess folic acid in the body is excreted through urine. However, with the exception of women who have had a prior NTD-affected pregnancy, it is recommended that women consume no more than 1,000 micrograms of folic acid daily. NOTE: Very large amounts of folic acid may hide the ability to quickly diagnose a vitamin B-12 deficiency, a sign of pernicious anemia. This disease can lead to serious brain and nerve damage if not treated with vitamin B-12. Pernicious anemia is rare in young and middle-aged people. Today, doctors can use a definitive test to check individuals for a B-12 deficiency, even when large amounts of folic acid are present.

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.

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. NTDs occur at a rate of about 1 per 1000 pregnancies in the U.S. Ninety percent of women with NTD-affected pregnancies have no personal or family history of NTDs. If a woman can get pregnant, the pregnancy can be affected by an NTD.

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. Often a woman doesn’t even know she is pregnant at this time.

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. As development progresses, a groove occurs, and tissue begins to fold over into a tube.

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. Closure will normally be complete within a week. The lower end becomes the spine and the upper end, the brain.

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 Birth defects that happen when the neural tube does not fully close at the top.  Anencephaly occurs when the skull and brain do not form properly.  Babies with anencephaly die before or shortly after birth.  Encephalocele is a rarer form of neural tube defect. It occurs when the skull does not form properly, allowing part of the baby’s brain to be outside the skull

What are Neural Tube Defects? Spina Bifida A birth defect that occurs when the neural tube does not fully close at the bottom…. Therefore, a sac protrudes from the back and contains part of the spinal cord, spinal nerves, and spinal fluid. The spine is usually repaired (the hole is closed) shortly after birth. However, damage has already been done to the spinal cord and nerves by then.

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. The physical impact of spina bifida varies depending on the location and severity of the lesion. Many children must have multiple surgeries, and most require a shunt, (which is a tube that drains fluid from the brain to the abdomen or the heart). If the fluid builds up in the brain, it can cause seizures, brain damage, and even death.

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). **** Randomized trials showed, more than a decade ago (1992), that FA can reduce the occurrence of NTD’s by 50% or more.

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.  Dietary folate is insufficient protection against NTDs. Only folic acid supplementation, along with a healthy diet, has been proven to reduce NTD risk.

Additional Birth Defects Researchers are studying other potential benefits of multivitamins containing folic acid. Heart Defects Cleft Lip/Cleft Palate Limb Defects Urinary Defects For cardiovascular some studies suggest a possible 25-50% overall risk reduction, For orofacial clefts, studies suggest an apparent reduced risk, which varies by cleft type and perhaps, according to some investigators, by pill dosage. For limb deficiencies, studies estimated approximately a 50% reduced risk. For urinary tract defects, studies reported reduced risks

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. Folic acid is essential for cell duplication because DNA can not be produced without sufficient folic acid because it is essential to make the critical base pairs needed by DNA molecules

What are the metabolic roles of folic acid?

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

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). Homocysteine is an aa in the blood… too much is related to a higher risk of CHD, stroke, PVD (Works with B-12) Methylation: a biochemical rxn resulting in the addition of a methyl group (CH3) to another molecule

Metabolic Role Amino acid metabolism 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. CVD remains the leading killer of women in the US. CHD accounts for most of the CVD deaths in women. Because CHD is often fatal, and because nearly 2/3 of women who die suddenly have no previous symptoms, it is important to prevent CVD. High risk= Established CHD, Carotid Artery Disease (with > 50% stenosis), Peripheral Artery Disease, Abdominal Aortic aneurysm, DM, chronic kidney dz Problem is that screening for homocysteine isn’t widely available and may cost $85-200, which is not covered by insurance

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. An estimated 31,000 stroke related deaths and 17,000 ischemic heart dz deaths may have been prevented each year since fortification was implemented (1998) The decline in stroke mortality was associated with a consistent pattern that ran across all genders and racial groups

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. To see whether there was a link between folate intake and blood pressure, the authors evaluated detailed dietary and health information for more than 150,000 women over eight years. One group included 62,260 women aged 43 to 70 from the Nurses' Health Study, a prospective study of the risk factors for major chronic disease in women. The other group included 93,803 women, aged 27 to 44, from the Nurses' Health Study II, which involves younger women.

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. Among women who did not use supplements, folate from foods alone did not lower their risk of high blood pressure, the study found.

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. Molecular effects of FA depletion: Alterations of gene expression and Increased DNA damage-disruption of DNA repair/integrity (enhance carcinogenesis)

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%. Several case control and cohort studies report an inverse relationship between folic acid intake and risk for colorectal cancer

Colon Cancer Nurse’s 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.

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. Low levels of folic acid result in increased rates of colorectal cancer

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. Researchers suspect that folate, a B vitamin, may play an ongoing role of protecting the brain throughout our lifetimes. In a recent study study of Catholic nuns, women with the lowest levels of folate in their blood were more likely to have Alzheimer's-type brain lesions when they died. It is still unclear how folate levels affect the development of brain wasting or Alzheimer's

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: Genetics Interactions with medications 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 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.

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). Est. ¼ of NTD’s are attributed to C677T

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 In a recent article by Shelly Rothenberg in the NEJM, it appears as if a vast preponderance of women who gave birth to kids with spina bifida have circulating auto antibodies to the folate receptor.

Rothenberg Study Basically, these are the 12 case mothers who had NTD affected pregnancies. 9 of the 12 had significant levels of autoantibodies to FR as determined by their assay.

Rothenberg Study In comparison, with the control subjects only two mothers were producing this autoantibody.

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 auto-antibodies to the folate receptor. Problems with uptake and metabolism of folic acid are overcome by increased intake of synthetic folic acid.

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. Prescription drugs that interfere with folic acid : phenobarbital, phenytoin (Dilantin), carbamazapine (Tegretol), and primidone (Mysoline), used primarily to prevent seizures; the antibiotic combination of trimethoprim and a sulfonamide (Bactrim, Septra), commonly used for urinary tract infections; triamterene (Dyrenium), a diuretic used for high blood pressure; and sulfasalazine (Azulfidine), used for ulcerative colitis and other inflammatory conditions. Other widely-prescribed medications that are reported to interfere with folic acid are: the anticonvulsant valproic acid (Depakene); cimetidine (Tagamet), used to treat heartburn and reflux; beta-blockers and calcium-channel blockers, used for high blood pressure and certain heart disorders; and cholestyramine (Locholest, Questran), used to lower cholesterol levels. If pt. capable of having a baby, or if she's pregnant, it may be necessary to increase the daily supplement of folic acid above 400 micrograms, as well as to monitor blood levels carefully. This should be taken as folic acid alone, not in a multivitamin, due to risk of excessive intake of other vitamins.

Folic Acid Knowledge MOD Gallup Poll 2004

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

Folic Acid Behavior Although awareness is high, intake still remains low Healthy People 2010 goal: Increase to 80% nonpregnant women aged 15 to 44 years who consume at least 400 μg of folic acid each day from fortified foods or dietary supplements Those least likely to consume a vitamin containing folic acid: 18-24y Not attended college Income under $25,000 Non-white 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. 51% said they would be VERY likely 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. It is important to remember that it is easier to change behavior when a change is linked to an already established habit Counsel patients to make it part of your routine – take folic acid when you get up in the morning, or when you brush your teeth, or when eat a meal. We will not reduce the rate of neural tube defects unless women of childbearing age change their behavior and begin incorporating 400 micrograms of folic acid into their diet every day.

Patrice Christoffersen pchristo@isdh.state.in.us 317-234-2976 Thank you! Questions? Patrice Christoffersen pchristo@isdh.state.in.us 317-234-2976 RBC folate = reflects folate stored in the body (more reflective of folate status) <140 ng/mL is def. Serum folate = reflects folic acid available to cells Incr MCV >100 micro m3