Folate

 

Folate (Folic acid)

Folate is the name used for any compound which has vitamin-like activity similar to that of folic acid, the form of this vitamin most commonly used in supplements and fortified foods. Folic acid takes its name from the Latin word for foliage as it was originally isolated from leafy green vegetables. The terms folic acid and folate are generally used to refer to the same substance.

Genetic material

Folic acid is essential for the synthesis of DNA and RNA, the genetic material of cells. It plays a vital role in the growth and reproduction of all body cells, maintaining the genetic code, regulating cell division and transferring inherited characteristics from one cell to another.

Metabolism

Folic acid is essential for protein metabolism. As part of its role in protein metabolism, folate converts the amino acid known as homocysteine to methionine. High levels of homocysteine have been linked to an increased risk of cardiovascular disease.

Blood

The formation of healthy red and white blood cells requires folic acid.

Brain and nervous system

Folic acid is involved in the production of neurotransmitters such as serotonin and dopamine, which regulate brain functions including mood, sleep and appetite. Folic acid is essential for the development of the brain, spinal cord and skeleton in the fetus.

Absorption and metabolism

Folic acid is absorbed from the small intestine. The amount of folic acid absorbed from food depends on the source but the average is around 50 per cent. Research shows that synthetic forms of folic acid are absorbed better than natural food forms with around 85 per cent of supplemental folic acid being absorbed if it is taken with a small amount of food.1

Around 50 per cent of body stores are in the liver. The amount stored may last for about four months before symptoms of deficiency develop.

Deficiency

Folate deficiency is the most common nutritional deficiency in the world. Diets low in vegetables, frequent alcohol and prescription drug use and the sensitivity of folate to light and heat contribute to this widespread deficiency. The elderly, alcoholics, psychiatric patients, people taking certain medications and women taking the contraceptive pill may be at greatest risk of folate deficiency. Prolonged stress, viral infections and chronic liver disease are also risk factors.

When folate intake is inadequate, levels in serum fall, levels in red blood cells also fall, homocysteine concentration rises and finally, changes in the blood cell-producing bone marrow and other rapidly dividing cells occur. Ultimately, folate acid deficiency affects the growth and repair of all the cells and tissues of the body.

Because red blood cells have a lifespan of 120 days, folate levels in the blood can be lowered for many weeks before symptoms of anemia become apparent. Tests which rely on anemia to diagnose folate deficiency may therefore not be appropriate.

As many as 5 to 15 per cent of people may have a particular type of genetic mutation in the DNA which codes for an enzyme involved in homocysteine metabolism. This leads to higher homocysteine concentrations and therefore an increased risk of heart disease; and in women, of having babies with neural tube defects. Such people have higher folate requirements than those who do not have this type of genetic mutation, and may need supplements.2

Elderly people

Many elderly people are at risk of folate deficiency. In a study published in 1996, Canadian researchers investigated folate and vitamin B12 intakes and body levels in 28 men and 30 women aged over 65 years. The results showed that 57 per cent of men and 67 per cent of women were at risk of deficiency.3

Folate deficiency may cause or worsen the mental difficulties which older people often experience. In a 1996 study, Spanish researchers analyzed the relationship between mental and functional capacities and folate status in a group of 177 elderly people. In this study, almost 50 per cent of the people had folate intakes below recommended values. Those with poor test results had significantly lower folate levels.4

Blood

Folic acid deficiency causes macrocytic anemia in which the red blood cells are fewer in number, larger in size and contain less oxygen-carrying hemoglobin than normal cells. The symptoms of anemia are lethargy, apathy, breathlessness, poor body temperature regulation, pallor, forgetfulness, irritability and stomach disorders.

Cardiovascular disease

Many studies have shown that low folic acid levels are linked to an increased risk of atherosclerosis and heart disease. Folic acid may exert its protective effects on the cardiovascular system by reducing the levels of homocysteine in the blood. Homocysteine is a product of protein breakdown which can damage the cells which line the arteries and promote the clumping together of platelets which increases clot formation. Homocysteine levels are influenced by dietary intakes of folate, vitamin B6 and vitamin B12. They also vary according to race, gender, age and certain disease conditions.

Evidence from the Framingham Heart Study, an ongoing analysis of the risk factors for heart disease which began almost 50 years ago and involves over 1000 men and women, supports the links between folate, homocysteine and heart disease. During the study, researchers examined the relationship between intake of folate from foods and supplements with blood plasma folate and homocysteine concentrations among 885 elderly people. The results showed that plasma folate was significantly greater and homocysteine lower in women than in men. Users of supplements, breakfast cereals, or green leafy vegetables had significantly greater plasma folate and lower homocysteine levels than non-users. Plasma folate concentration was also greater in those who drank orange juice.5

In a study published in 1998, researchers at the Cleveland Clinic conducted a study to investigate the relationships between homocysteine, B vitamins, and vascular diseases. The study involved 750 patients with documented vascular disease and 800 control patients matched for age and sex. The results showed that those in the top 20 per cent for homocysteine concentrations had a greater risk of vascular disease. Those in the lowest 10 per cent of folate intakes also had an increased risk of disease.6

A 1996 Canadian study of the relationship between fatal coronary heart disease and folic acid levels in 5000 men and women found that the risk of coronary heart disease increased as folic acid levels decreased. Those in the lowest intake group were 69 per cent more likely to die of heart disease than those with the highest intakes.7

Low blood folic acid levels also seem to increase heart attack risk in young women. In a 1997 study, researchers at the University of Washington measured the homocysteine, folic acid and vitamin B12 levels in 79 heart attack survivors under 45 and compared these with levels in 386 healthy control subjects. Those with the highest homocysteine levels had 2.3 times the risk of heart attack compared to those with the lowest levels. Those with the highest levels of folic acid had around half the risk of heart attack compared with those with the lowest levels.8

Results from the US Physicians Health Study published in 1996 found a small link between low folate levels and risk of heart attack, but this was not statistically significant.9

Nervous system

Folic acid deficiency causes mood disorders with symptoms of irritability, forgetfulness and hostility. Low levels may play a role in depression, possibly due to a reduction in neurotransmitter levels.

In a study published in 1996, USDA researchers investigated the relationships between plasma concentrations of homocysteine and vitamins B12 and B6 and folate, and cognitive test scores in 70 men, aged 54 to 81 years old. Lower concentrations of vitamin B12 and folate and higher concentrations of homocysteine were associated with poorer results on the tests.10

Folate deficiency may also be linked to depression. Borderline low or deficient folate levels have been detected in as many as 38 per cent of adults diagnosed with depressive disorders.11 Low folate levels have also been linked to poorer response to the antidepressant drug Prozac. In a study published in 1997, researchers examined the relationships between levels of folate, vitamin B12, and homocysteine in 213 depressed patients taking Prozac. The results showed that people with low folate levels were more likely to have melancholic depression and were significantly less likely to respond to the drug.12

Gastrointestinal system

Symptoms of folic acid deficiency also include loss of appetite, inflamed tongue, gastrointestinal problems and diarrhea. Folic acid deficiency can damage the lining of the gut and reduce absorption of other nutrients which can lead to malnutrition.

Neural tube defects

Folic acid deficiency may affect up to a third of all pregnant women and is associated with birth defects. Pregnant women who are folic acid-deficient risk having babies with neural tube defects, such as anencephaly (failure of the brain to develop) and spina bifida (failure of the spinal column to close). The risk of neural tube defects in the US is around one per 1000 pregnancies. The high risk period for folate deficiency-related birth defects is around one month before conception until around one month after. Many women are unaware that they are pregnant during this time so maintaining adequate folic acid levels is vital for any woman who might become pregnant. 

Cancer

Folate deficiency may play a role in cancer development, particularly cancers of the cervix, lung and colon. It may be that folate deficiency itself is not carcinogenic but may contribute to an increased risk of cancer as deficiency may affect the repair of DNA and increase chromosome fragility. It may also diminish the ability of the immune system to fight cancer cells and viruses. Deficiency has been shown to affect a gene involved in suppressing tumor formation.13

Colorectal cancer

In a study published in 1996, researchers examined the relationship between folate status and colorectal cancer in male smokers aged 50 to 69 involved in the Alpha-Tocopherol Beta carotene (ATBC) Study. The researchers measured folate levels in 144 cases of colorectal cancer and 276 healthy people. Those with higher dietary folate intakes had a reduced risk of colon cancer. Men with a high-alcohol, low-folate, low-protein diet were at higher risk for colon cancer than men who consumed a low-alcohol, high-folate, high-protein diet.14

Cervical dysplasia

Low blood levels of folic acid may increase the risk of cervical dysplasia (precancerous changes in the cells lining the cervix), possibly by enhancing the effect of other risk factors. Researchers from the University of Alabama in Birmingham investigated the links between folate deficiency and cervical dysplasia in 294 young women with the disorder and 170 healthy women. They also assessed the impact of factors such as smoking, oral contraceptive use, human papillomavirus (HPV) infection, and number of sexual partners. The results showed that at low folate levels the risk of dysplasia caused by HPV infection was increased.15

Other symptoms

Low folic acid may also contribute to rheumatoid arthritis and osteoporosis, constipation, cataracts, headaches and infertility.

Sources

The best sources of folate are liver, brewer’s yeast and dark green leafy vegetables such as spinach and kale. Dried beans, green vegetables, oranges, avocados and whole wheat products are also good sources.

Food processing such as boiling and heating can destroy folic acid. It can also be destroyed by being stored unprotected at room temperature for long periods.

Food fortification with folic acid

Since January, 1998, commercial grain products in the USA have been enriched with 140 mcg of folic acid per 100 g of grain product. It is estimated that this will deliver an average increase in intake of 100 mcg per day. Breakfast cereals may contain up to a daily dose of folic acid.

There has been concern that fortifying foods with folic acid would increase the risk of permanent damage from vitamin B12 deficiency due to the fact that high folic acid intakes can mask this deficiency. However, a study published in the Journal of the American Medical Association in 1996 suggests that the benefits of folic acid fortification, which include reduced risk of stroke and heart disease, outweigh the risk of masked vitamin B12 deficiency. Researchers at Tufts University, Boston, looked at the food intakes and blood folate and homocysteine concentrations of almost 750 people aged 67 to 96 years. From these results they predicted the value of adding folic acid to grain products and the effect on cardiovascular disease and vitamin B12-related disorders. Their results suggest that fortification at a level of 140 mcg per 100 g of grain product would reduce the risk of coronary artery disease by 5 per cent.16

A 1998 study reported in the New England Journal of Medicine provides further support for the possibility of reducing homocysteine levels by fortifying foods with folic acid. Researchers assessed the effects of breakfast cereals fortified with three levels of folic acid in a randomized, double-blind, placebo-controlled, crossover trial in 75 men and women with coronary artery disease. The results showed that folic acid increased and plasma homocysteine decreased in proportion to the folic acid content of the cereal. Cereal providing 127 mcg of folic acid daily, (which is about the amount that would result from the FDA’s enrichment policy) decreased plasma homocysteine by only 3.7 per cent. However, cereals providing 499 and 665 mcg of folic acid daily decreased plasma homocysteine by 11 per cent and 14 per cent respectively. These results suggest that folic acid fortification at levels higher than that recommended by the FDA may be necessary to effectively reduce homocysteine levels and reduce the risk of cardiovascular disease.17

Recommended dietary allowances

In 1989, the government lowered the RDAs from 400 mcg to 200 mcg for men and 180 mcg for women. Increasing awareness of the importance of folic acid in preventing birth defects and cardiovascular disease led in 1998 to the raising of RDAs to 400 mcg. The tolerable upper intake level has been set at 1000 mcg per day.

The RDA for pregnant women doubles due to the role of folic acid in cell growth in the baby and for increased blood volume and expanding tissues in the mother. Folic acid is the vitamin most closely related to pregnancy outcome.

Supplements

Folic acid is the type of folate usually found in supplements and fortified foods, as it is the most stable. Some supplements contain folinic acid, the most active form of folate.

Pregnant women, the elderly, and those with absorption difficulties are likely to benefit from supplements. Any condition that increases metabolic rate, such as infection and hyperthyroidism; and any condition that increases cell turnover, such as rapid tissue growth or hemolytic anemia, increases folate requirements. Anyone taking medications that increase folate requirements may also benefit from supplements.

Surveys show that for the last 25 years, around a quarter of Americans have regularly taken a multivitamin containing 400 mcg of folic acid. It is becoming clear that those who do so have a reduced risk of disease, particularly cardiovascular disease. A woman who takes a folate supplement reduces the risk that her child will be born with a birth defect. However, research shows that only one third of women of childbearing age consume a supplement containing the recommended amount of folic acid daily.18

According to a 1996 study of prescription multivitamins reported in the Journal of The American Pharmaceutical Association, US researchers found that several brands did not deliver the expected amount of folic acid because the tablets did not dissolve quickly enough. The researchers examined nine multivitamin products to see if they released 75 per cent of the folic acid within one hour, as required by the United States Pharmacopoeia Convention’s dissolution standard. Only three of the products did so and most of the products missed the standard by a wide margin. Folic acid is best absorbed in the area of the intestine that lies just beyond the stomach. If the multivitamins do not dissolve within about an hour, the folic acid may pass this area and the amount available for optimal absorption is not adequate.19

Toxic effects of excess intake

Toxicity is considered rare. Symptoms are gastrointestinal disturbances, sleep problems and possible allergic skin reactions. These effects can occur at doses above 15 mg.

Therapeutic effects of supplements

Pregnancy

In 1992, the US Public Health Service issued a recommendation that all women capable of becoming pregnant should consume 400 mcg of folic acid daily in order to avoid the risk of neural tube defects in their babies. Around 50 per cent of neural tube defects may be preventable by increasing folate intakes. Eating foods naturally high in folic acid, eating fortified foods and taking supplements are good ways of increasing folic acid intake to recommended levels. Adequate consumption of folic acid should begin before and continue during at least the first four weeks after conception when the fetal neural tube is being formed.

Research suggests that in women who have previously had a child with a neural tube defect, folic acid in doses of up to 4 mg daily can reduce the risk of recurrence by about 70 per cent. This is something to be discussed with a doctor as such large amounts of folic acid are only available on prescription.

Studies suggest that the levels of folate necessary to prevent neural tube defects are more easily derived from fortified foods or supplements than from natural food sources alone. In an editorial in the New England Journal of Medicine, Godfrey Oakley MD of the Centers for Disease Control in Atlanta commented that "anyone who chooses to counsel a woman to consume 400 mcg of food-derived folate rather than 400 mcg of supplemental folic acid will be recommending a strategy that has not been proved to prevent birth defects and that leads to lower blood folate concentrations." Many experts recommend folic acid supplements and a diet rich in folates for women who are hoping to become pregnant.

In a study published in The Lancet in 1996, Irish researchers tested the effectiveness of different ways of raising folic acid levels. Participants in the three month trial included 62 women randomly assigned to one of the following five groups: folic acid supplement (400 mcg per day); folic-acid-fortified foods (an additional 400 mcg per day); dietary folate (an additional 400 mcg per day); dietary advice, and control. The results showed that red blood cell folate concentrations increased significantly in the groups taking folic acid supplements or food fortified with folic acid. The researchers concluded that advice to women to consume folate-rich foods as the only way to boost folate levels is misleading.20

In another study also published in The Lancet, researchers studied blood folic acid levels in 95 women in order to determine the minimum effective dose of folic acid for food fortification necessary to prevent neural tube defects. The women in the study were divided into four groups. One group received no folic acid while the other groups got doses of 100, 200 and 400 mcg daily. After six months, the researchers found that women taking 100 mcg daily had blood folic acid levels sufficient to prevent 22 per cent of neural tube defects. Those taking 200 mcg had a 41 prevention level and 400 mcg gave a 47 per cent prevention level. The researchers felt that as between 50 and 70 per cent of neural tube defects are thought to be preventable by folic acid, the reduction achieved by an additional 100 mcg per day would be substantial.21

A trial of the effects of vitamin supplements containing folate supplements on the incidence of neural tube defects involving over 4700 women was carried out in Hungary. In the women who did not receive folic acid there were six babies born with neural tube defects. In the group receiving the supplements, there were none.22

Cardiovascular disease

Folic acid supplements may reduce the risk of coronary heart disease by reducing homocysteine levels. In a paper published in the British Medical Journal in 1998, researchers analyzed the results of randomized controlled trials that assessed the effects of folic acid-based supplements on blood homocysteine concentrations. The data included that from 1114 people in 12 trials. They found that 0.5 to 5 mg folic acid daily reduced blood homocysteine concentrations by 25 per cent.23

In 1998, researchers at the Harvard School of Public Health published data from the Nurses Health Study which showed that intake of folate and vitamin B6 above the current recommended dietary allowance is important in the prevention of coronary heart disease among women. The study involved
80 082 women with no cardiovascular disease, cancer, high cholesterol or diabetes on entry to the study. During a 14 year period there were 658 cases of non-fatal heart attack and 281 cases of fatal coronary heart disease. Women in the highest folate intake group had around a 30 per cent reduced risk of disease. The risk of coronary heart disease was reduced by about 25 per cent in women who regularly used multiple vitamins.24

Those with the highest homocysteine levels may respond best to increases in folic acid intake, and above a certain level of intake, increasing folic acid may not affect homocysteine levels. In a 1997 Irish study, researchers assessed the effects of various doses of supplements on homocysteine levels. Of the three folic acid doses, 200 mcg appeared to be as effective as 400 mcg, while 100 did not lower levels sufficiently.25

Cancer

Several studies suggest that folic acid supplements can help to reduce the risk of cancerous changes in several areas such as the cervix, lung and gastrointestinal tract.

Colorectal cancer

In a study published in 1997, researchers at the Cleveland Clinic investigated the links between folate and cancerous changes in 98 patients with ulcerative colitis. Patients taking folic acid supplements had a 30 per cent lower risk of developing cancerous changes in the bowel. The lower the folate levels, the more advanced the degree of cancerous changes in the cells.26 In a 1997 Italian study, researchers also studied the effects of folate supplements on pre-cancerous cell changes in ulcerative colitis. The results showed that folate reduced these changes.27 Folic acid may also help to prevent the pre-cancerous changes in lung tissue caused by smoking.28

Cervical dysplasia

Folic acid supplementation may protect abnormal cells from becoming cancerous and may reverse cervical dysplasia in some cases. A 1996 study done at the University of Alabama at Birmingham suggests that supplements may be useful in preventing the initial changes but do not appear to affect the progress of established disease.29 Some researchers have found a higher risk of abnormalities in cervical tissue in women using oral contraceptives and suggest that folic acid supplements are beneficial in preventing cervical dysplasia in these women.30

Anemia

Folic acid is used to treat folic acid deficiency anemia and for supplementation in those suffering from sickle cell disease.

Mental function

Many psychiatric patients show folic acid deficiency, especially those suffering from depression. Supplements may be particularly beneficial in elderly people suffering from impaired mental function. This may be due to effects on neurotransmitters such as serotonin and dopamine.

Other uses

Folic acid supplements are given to those taking the drug, methotrexate, to prevent toxic side effects.31 Folic acid may be of value in the treatment of gout and may also shorten the recovery time from hepatitis. Supplements may be useful in the treatment of osteoporosis as increased homocysteine levels may lead to defective bone formation. Folic acid may also be useful in improving skin condition in vitiligo.32 Folic acid mouthwash may be useful in the treatment of periodontal disease and gum inflammation.

Interactions with other nutrients

Folic acid requires vitamin B12, niacin and vitamin C to be converted to its biologically active form. Vitamin C helps to reduce folic acid excretion. High folic acid intakes may reduce zinc absorption, although the effect is likely to be a subtle one.

Interactions with drugs

NSAIDs such as aspirin, ibuprofen and acetaminophen can increase folate requirements if taken for long periods. Anticonvulsant drugs such as phenytoin and phenobarbital also raise folate requirements which may be of particular concern as these drugs are often taken for long periods. Methotrexate increases requirements and it is recommended that people taking this drug for long periods also take folic acid supplements. Cholestyramine, chloramphenicol, estrogen, colchicine, antacids, antituberculosis drugs, trimethoprim, sulfasalazine, corticosteroid drugs and tobacco can raise folic acid requirements. Chronic alcohol use leads to folic acid deficiency.

Cautions

Large amounts of folic acid can mask anemia caused by vitamin B12 deficiency. Although this is rare, in some cases it may lead to permanent nerve damage. Amounts greater than 400 mcg per day should not be taken by anyone with anemia unless a diagnosis of pernicious anemia is ruled out.

Folic acid can interfere with the effectiveness of anticonvulsant drugs such as phenytoin and can result in an increase in seizure activity if large doses are taken.

1 Pfeiffer CM; Rogers LM; Bailey LB; Gregory JF 3rd Absorption of folate from fortified cereal-grain products and of supplemental folate consumed with or without food determined by using a dual-label stable-isotope protocol. Am J Clin Nutr, 1997 Dec, 66:6, 1388-97

2 Jacques PF; Bostom AG; Williams RR; Ellison RC; Eckfeldt JH; Rosenberg IH; Selhub J; Rozen R. Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation, 1996 Jan, 93:1, 7-9

3 Quinn K; Basu TK. Folate and vitamin B12 status of the elderly. Eur J Clin Nutr, 1996 Jun, 50:6, 340-2

4 Ortega RM; Mañas LR; Andrés P; Gaspar MJ; Agudo FR; Jiménez A; Pascual T Functional and psychic deterioration in elderly people may be aggravated by folate deficiency. J Nutr, 1996 Aug, 126:8, 1992-9

5 Tucker KL; Selhub J; Wilson PW; Rosenberg IH Dietary intake pattern relates to plasma folate and homocysteine concentrations in the Framingham Heart Study. J Nutr, 1996 Dec, 126:12, 3025-31

6 Robinson K; Arheart K; Refsum H; Brattström L; Boers G; Ueland P; Rubba P; Palma Reis R; Meleady R; Daly L; Witteman J; Graham I Low circulating folate and vitamin B6 concentrations: risk factors for stroke, peripheral vascular disease, and coronary artery disease. European COMAC Group. Circulation, 1998 Feb, 97:5, 437-43

7 Morrison HI; Schaubel D; Desmeules M; Wigle DT Serum folate and risk of fatal coronary heart disease. JAMA, 1996 Jun, 275:24, 1893-6

8 Schwartz SM et al. Myocardial infarction in young women in relation to plasma total homocysteine, folate, and a common variant in the methylenetetrahydrofolate reductase gene. Circulation, 1997 Jul, 96:2, 412-7

9 Chasan-Taber L, Selhub J, Rosenberg IH, Malinow MR, Terry P, Tishler PV, Willett W, Hennekens CH, Stampfer MJ. A prospective study of folate and vitamin B6 and risk of myocardial infarction in US physicians. J Am Coll Nutr 1996 Apr;15(2):136-143

10 Riggs KM; Spiro A 3rd; Tucker K; Rush D Relations of vitamin B-12, vitamin B-6, folate, and homocysteine to cognitive performance in the Normative Aging Study. Am J Clin Nutr, 1996 Mar, 63:3, 306-14

11 Alpert JE; Fava M Nutrition and depression: the role of folate. Nutr Rev, 1997 May, 55:5, 145-9

12 Fava M; Borus JS; Alpert JE; Nierenberg AA; Rosenbaum JF; Bottiglieri T Folate, vitamin B12, and homocysteine in major depressive disorder. Am J Psychiatry, 1997 Mar, 154:3, 426-8

13 Kim YI; Pogribny IP; Basnakian AG; Miller JW; Selhub J; James SJ; Mason JB Folate deficiency in rats induces DNA strand breaks and hypomethylation within the p53 tumor suppressor gene. Am J Clin Nutr, 1997 Jan, 65:1, 46-52

14 Glynn SA; Albanes D; Pietinen P; Brown CC; Rautalahti M; Tangrea JA; Gunter EW; Barrett MJ; Virtamo J; Taylor PR. Colorectal cancer and folate status: a nested case-control study among male smokers. Cancer Epidemiol Biomarkers Prev, 1996 Jul, 5:7, 487-94

15 Butterworth CE Jr; Hatch KD; Macaluso M; Cole P; Sauberlich HE; Soong SJ; Borst M; Baker VV. Folate deficiency and cervical dysplasia. JAMA, 1992 Jan 22-29, 267:4, 528-33

16 Tucker KL; Mahnken B; Wilson PW; Jacques P; Selhub J. Folic acid fortification of the food supply. Potential benefits and risks for the elderly population. JAMA, 1996 Dec, 276:23, 1879-85 1996;276:1879-85

17 Malinow MR; Duell PB; Hess DL; Anderson PH; Kruger WD; Phillipson BE; Gluckman RA; Block PC; Upson BM. Reduction of plasma homocyst(e)ine levels by breakfast cereal fortified with folic acid in patients with coronary heart disease. N Engl J Med, 1998 Apr, 338:15, 1009-15

18 Use of folic acid-containing supplements among women of childbearing age—United States, 1997. MMWR Morb Mortal Wkly Rep, 1998 Feb, 47:7, 131-4

19 Hoag SW; Ramachandruni H; Shangraw RF. Failure of prescription prenatal vitamin products to meet USP standards for folic acid dissolution. J Am Pharm Assoc (Wash), 1997 Jul, NS37:4, 397-400

20 Cuskelly GJ; McNulty H; Scott JM. Effect of increasing dietary folate on red-cell folate: implications for prevention of neural tube defects Lancet, 1996 Mar, 347:9002, 657-9

21 Daly S; Mills JL; Molloy AM; Conley M; Lee YJ; Kirke PN; Weir DG; Scott JM. Minimum effective dose of folic acid for food for