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There appears to be a significant impairment of folic acid absorption in patients with HIV disease. The virus can cause an enteropathy in the absence of opportunistic infection. Folinic acid may also not be absorbed as well since it is absorbed by the same gut mechanisms as folic acid. Folate absorption is abnormal in early and late HIV disease. Some of the neurologic manifestations of children with AIDS disease are due to folate deficiency. Folic acid hypersupplementation and intravenous (rather than oral) folinic acid supplementation may be desirable in patients affected with human immunodeficiency virus.

Folic Acid Absorption in Patients Infected With Human Immunodeficiency Virus, Revell, P., et al, Journal of Internal Medicine, 1991;230:227-231.

Anencephaly, Spina Bifida

Anencephaly, Spina Bifida

One of the most exciting medical findings of the last part of the 20th century is that folic acid, a simple, widely available, water soluble volume, can prevent spina bifida and anencephaly. Thus begins an article by Doctor Godfrey P. Oakley. He notes that birth defects are the leading cause of infant mortality in the United States. According to the article, the incidence of birth defects have varied by geographic location, and by personal factors such as social class and race. Doses showing benefit of folic acid supplementation in the prevention of neural tube defects have been 0.4 mg, 0.8 mg and 4 mg. In November, an advisory committee to the Food and Drug Administration recommended developing a policy that would permit appropriate foods to be fortified with folic acid. Presently, females can take 0.4 mgs of folic acid in a vitamin pill, or eat a serving of food such as a breakfast cereal fortified with the USDA recommended daily allowance of folic acid per serving. Folic acid can also be increased by eating foods rich in folates such as leafy, dark green vegetables. The author states women should, except under a physician's direction, keep their consumption of folic acid below 1 mg per day, since this elevated dose may cause difficulties in diagnosing pernicious anemia. The author warns of using foods fortified with vitamin A or supplements which contain vitamin A, because an excess of vitamin A can cause birth defects. By increasing the consumption of folic acid, it is believed that the prevention of spina bifida and anencephaly may result worldwide among thousands of infants annually. With prevention programs, it is possible that reduction rates of these birth defects could occur within a single year.

Folic Acid-Preventable Spina Bifida and Anencephaly, JAMA, March 10, 1993;269(10):1292-1293.

The United States Public Health Service recommends 0.4 mg of folic acid per day, for the purpose of reducing the risk of neural tube defects or spina bifida. One should keep folic acid levels below 1 mg/day, so as not to obscure the diagnosis of vitamin B12 deficiency (pernicious anemia).

Recommendations for the Use of Folic Acid to Reduce Number of Spina Bifida Cases and Other Neural Tube Defects, JAMA, March 10, 1993;269(10):1233-1238/Morbidity and Mortality Weekly Report, 1992;41:RR-14.

Anemia, Alcohol Abuse and RedCell

Anemia, Alcohol Abuse and Red Cell Redistribution Width

An increase in red cell distribution width (RDW) may indicate alcoholism and iron deficiency anemia
Alcohol abuse may be seen when the red cell distribution width is high combined with the normal MCV. A high MCV and RDW may indicate an immune hemolytic anemia or Vitamin B12 or folic acid deficiency.

Red Cell Distribution Width in Alcohol Abuse and Iron Deficiency Anemia, Seppa, Kaija, M.D. and Sillanaukee, Pekka, M.S.c, JAMA, February 26, 1992;267(8):1070.

Cancer Lung, Bowel and Cervix

Cancer (Lung, Bowel and Cervix) and Inflammatory Bowel Disease

There is a belief that folic acid concentration may be higher in some tissues than others, thereby resulting in a localized deficiency in spite of normal blood levels.

Evidence for localized folic acid deficiency includes: (1) lower circulating folate levels in smokers compared with nonsmokers, (2) lower circulating levels in smokers with bronchial metaplasia, (3) lower folate levels in scrapings of buccal mucosa of smokers than nonsmokers, (4) improvement in bronchial atypical metaplasia in smokers supplemented with folic acid, (5) lower red blood cell folate levels and a higher incidence of cellular features compatible with folate deficiency in geographic areas and individuals in South Africa at high risk for esophageal cancer, and (6) a trend towards a lower prevalence of colonic dysplasia and ulcerative colitis in patients who use folic acid supplements.

These results suggest that a localized folate deficiency may be co-carcinogenic.

Localized Deficiencies of Folic Acid in Aerodigestive Tissues, Heimburger, Douglas C., M.D., Beyond Nutrition: New Views on the Functions and the Health Effects of Vitamins, New York Academy of Sciences, February 9-12, 1992;7.

Celiac Disease

Coeliac disease

Evaluated the prevalence of malnutrition in patients with untreated coeliac disease (CD) according to their pattern of presentation, and the effect of gluten-free diet (GFD) upon nutritional status.

The nutritional status was evaluated by anthropometric measurements (percentage of ideal body weight for height and sex, percentage of standard triceps skinfold thickness and percentage of ideal arm-muscle circumference).

The overall prevalence of malnutrition in our series of CD patients was 53%. Prevalence of malnutrition (actual body weight less than 90% of the ideal) was significantly higher in classical coeliacs (67%) than in subclinical ones (31%), in patients with DH (13%) and in healthy volunteers (13%).

Prevalence of malnutrition in CD is lower than was previously thought. CD patients with classical presentation may require a longer period of GFD to achieve a significant improvement of their nutritional status, with respect to those with subclinical presentation, probably because of a greater extent of intestinal damage.

Finally, a careful evaluation of dietary habits is usually sufficient to identify incomplete adherence to GFD as the reason for nonimprovement of the nutritional status in patients with CD.

Corazza GR et al., Subclinical coeliac disease: an anthropometric assessment. J Intern Med, 236:183-7, 1994 Aug.

Celiac Disease and Epilepsy

Celiac Disease and Epilepsy

Folic acid deficiency with neurologic abnormalities should be considered among atypical clinical presentations of patients with celiac disease.

Celiac Disease, Folic Acid Deficiency and Epilepsy With Cerebral Calcifications, Ventura, A., et al, ACTA Pediatrica Scandinavica, 1991;80:559-562.

Cervical Cancer

Cervical Cancer

Women infected with the human papilloma virus may be able to reduce their increased risk of cervical cancer by increasing daily folic acid intake.

Encourages an increase in the daily recommended allowance of folic acid back to 400 mcg/d, up from 180 mcg/d, in women, and 200 mcg/d in men. Liver, pinto beans, broccoli, spinach and orange juice are rich sources of folic acid. There is no evidence that increasing folic acid intake prevents cancer, but increasing amounts of the vitamin in the diet may prevent the initial cervical epithelial changes that are caused by the human papilloma virus. Thirty percent of sexually active women in their 20's have been exposed to HPV. It was noted by a spokesperson from the National Cancer Institute that other nutrient deficiencies may also play a role.

Folic Acid Lack and HPV Increase Cervical Cancer Risk, Medical Tribune, February 13, 1992;11.

The prevalence of human papilloma virus type 16 infection was initially 16% among subjects in the upper tertile of red blood cell folate, versus 37% of the lower tertile.

Folate deficiency may be involved as a cocarcinogen during the initiation of cervical dysplasia, but after a viral genome has been incorporated into the host, DNA folic acid supplements have little or no effect on the course of the infection.

Oral Folic Acid Supplementation for Cervical Dysplasia: A Clinical Intervention Trial, Butterworth, C.E., Jr., M.D., et al, American Journal of Obstetrics and Gynecology, March 1992;166(3):803-809.

Cognitive Impairment

Cognitive Impairment

Vitamin B12 contributed significantly to the variance in the Mini-Mental State examination (MMSE). There was no correlation between the MMSE and serum, red cell folate, or B12 in the other dementias or the cognitively impaired nondementia group, and no significant correlation between MMSE and other nutritional indices in any group.

Folate, Vitamin B12 and Cognitive Impairment in Patients With Alzheimer's Disease, Levitt, A.J., et al, ACTA Pshychiatr Scand, 1992;86:301-305.

Colon Cancer

Colorectal Adenomas

Colorectal Adenomas

High dietary folic acid was inversely related to the risk of colorectal adenoma in women and men. Those who consume more than 30 gms of alcohol daily (2 drinks) had an elevated risk of adenoma compared to nondrinkers. Methionine intake was inversely related to the risk of adenomas 1 cm or larger. Folate, alcohol and methionine might influence methyl group availability. A methyl-deficient diet may be a risk factor for the early stages of colorectal neoplasia. This supports efforts to increase folate in segments of the population having diets with low intakes of this nutrient.

Folate, Methionine, and Alcohol Intake and Risk of Colorectal Adenoma, Giovannucci, Edward, et al, Journal of the National Cancer Institute, June 2, 1993;85(11):875-881.

Crohn's Disease

Crohn's Disease

Dietary modification in Crohn's disease can lead to symptom reduction and relief of inflammation. Low folic acid levels due to sulphasalazine therapy suggests the need for folate supplementation.

Nutrition and Crohn's Disease, Lennard-Jones, J.E., M.D., Annals of The Royal College of Surgeons of England, 1990;72:152-154.

Patients with Crohn's disease have nutritional deficiencies from lack of food intake and/or malabsorption.

Red blood cell folic acid status was assessed. Patients were given 400 ug/d or 800 ug/d for 6-16 weeks. It was found that folate levels were low even after TPN with 400 ug/d and in those receiving 800 ug/g folate levels tended to increase but were not in the normal range. The authors recommend a dosage of 800 ug/d or greater in AMAFDA formulations for Crohn's disease patients on long-term TPN. Folate is important for intestinal mucosa turnover and healing.

Red Cell Folate Concentrations in Patients With Crohn's Disease on Parenteral Nutrition, Tominaga, Masaya, et al, Postgraduate Medical Journal, 1989;65:818-820.

Elderly Canadians

Elderly (Canadians)

The majority of nonsupplemented elderly had adequate folate levels. Low red cell folate levels (less than 140 ng/ml) were observed in 8% of free-living women, versus 11% of institutionalized women; and low levels were found in 14% of free-living men, versus 22% of institutionalized men. Sixteen per cent of elderly women and 12% of elderly men took folate supplements, and none had plasma red blood cell folate levels below 3.0 ng/ml and 140 ng/ml respectively.

Observations on the Folate Status of Self-Elected Group of Institutionalized and Free-Living Elderly Canadians, Hoppner, K., et al, Journal of the Canadian Dietetic Association, Summer 1991;52(2):93-96.

Epileptic Mothers

Epileptic Mothers

Serum folic acid levels in the epileptic mothers were significantly lower than controls.
Decreased serum folic acid concentrations are related to congenital malformations in the offspring of epileptic mothers. It is known that folic acid plays a major role in the metabolism of the developing fetus since it is crucial in DNA synthesis of growing cells. Folate supplements should be given to mothers on antiepileptic medications starting before conception and during pregnancy. The reduced form of folic acid, 5formyltetrahydrofolate is recommended; it has fewer neurotoxic effects than folic acid itself.

Serum Folic Acid Levels in Epileptic Mothers and Their Relationship to Congenital Malformations, Ogawa, Yoshihiro, et al, Epilepsy Research, 1991;8:75-78.



In the fall of l992, the Centers For Disease Control and Prevention recommended that all women of child bearing age consume at least .4 mg of folic acid each day to prevent birth defects. The FDA's task is to implement this advice by fortifying foods and encouraging the use of supplements. The diets of most U.S. women do not contain the U.S. recommended daily allowances, which is .4 mgs for pregnant females. The Committee recommended the fortifying of certain foods with folic acid, without mentioning the use of nutritional supplementation. A level of fortification or which foods to fortify was not recommended. It was stated that this Advisory Committee did not address the use of supplements straight on. In the meeting the Committee decided to focus on fortification, despite the concerns regarding over-fortification and the masking of pernicious anemia. The Committee stated that they would look into the use of supplements if there was good data. It is interesting to note that nearly all the studies regarding folic acid's effect on birth defects to date have been done with supplementation. A spokesperson for The Council For Responsible Nutrition states that, in the short term, supplements should be advised since they are readily available and don't require a lengthy process such as fortification. Even though the Committee did not endorse supplements, they did not come out with any statement against supplements. Dr. Simopolous, head of The Center of Genetics, Nutrition, and Health, stated that fortification is not the way to go. Supplementation affects a targeted population, whereas food fortification reaches the general population. Some individuals may be harmed by an excessive amount of folic acid intake.

FDA Committee Proposes Folic Acid Fortification, Nutrition Week, January 15, 1993;23(3):2-3.

Food Fortification

Food Fortification

This study evaluated the impact of folate fortification of food on folic intake in women of child-bearing age. Folic acid intake was measured by a 7-day weighed procedure over a 2-year period. Over this time period, there was an increasing number of cereals fortified with folic acid. The results showed a significant increase in the consumption of folic acid in these women. Folate fortification of staple foods such as white bread, could make an important contribution to achieving the experts' advisory recommendations for folate intake in women of child-bearing age. Fortification would have specific importance for those at risk for low levels of intake including smokers, young mothers, those in low socioeconomic status or families with 6 or more members.

Fortified Foods and Folate Intake in Women of Child-Bearing Age, Schorah, C.J. and Wild, J., The Lancet, May 29, 1993;341:1417.

Food Supply

Food Supply

The Food and Drug Administration has proposed that B-vitamin folic acid be added to flour, breads and other grain products to aid in the prevention of birth defects. The agency also proposed to allow manufacturers of folate supplements to label their products with a health claim.

Folic acid fortified foods would apply to flours, breads, rolls, grits and macaroni products already enriched with other nutrients. However, increased intakes of folic acid can mask the symptoms of pernicious anemia, a vitamin-B12 deficiency that could result in nerve damage.

FDA Proposes to Add Folic Acid to Food Supply, Nutrition Week, October 8, 1993;2.



Food fortification of staple foods is more likely to succeed than wholesale distribution of vitamin pills.

Multi-Vitamins For The Prevention of Neural Tube Defects: How Convincing is The Evidence?, Smithells, R.W., Drugs, 1989;38(6):849-854.

Guidelines England

Guidelines (England)

This trial was to determine whether folic acid supplement or a mixture of 7 other vitamins (A, D, B1, B2, B6, C and nicotinamide) around the time of conception prevented neural tube defects.
Over 1195 females completed their pregnancies, with 27 known to have delivered infants with neural tube defects, 6 in the folic acid group and 21 from 2 other groups. This was a 72% protective effect. The other vitamins showed no significant protective effect. There was no harm from the folic acid supplementation which was given in a 4 mg capsule. The vitamins contained vitamin A 4000 units, vitamin D 400 I.U., B1 1.5 mg, B2 1.5 mg, B6 1.0 mg, vitamin C 40 mg and nicotinamide 15 mg. In the controlled capsules there was dried ferrous sulfate 120 mgs and di-calcium phosphate 240 mgs. The authors conclude that folic acid supplementation that is started before pregnancy can now be definitely recommended for all women who have had an effected pregnancy. Public health measures should be taken to provide adequate amounts of folic acid to all pregnant females.

Some consideration should be given to extending fortification of staple foods with folic acid. Prevention of Neural Tube Defects: Results of the Medical Research Council Vitamin Study, The MRC Vitamin Study Research Group, The Lancet, July 20, 1991;338:131-137.

Recommends that women who have had a previously affected fetus should be given folic acid supplements if they intend to have another pregnancy, and therapy should begin before conception. This should take place at prenatal clinics and/or at the birth of infants with malformations. The dosage utilized was 4 mgs per day of folic acid and the question is whether a lesser dose could have as much benefit. Another question concerns the length of time that the supplement is needed preceding conception. Risk to folic acid supplementation needs to be assessed at the 2 different doses used, .36 mgs a day which was in the original multivitamin preparation, or 4 mgs per day in this most recent study.

Green leafy vegetables are a good source of folic aicd but cooking can reduce their folic acid content.

Folic Acid and Neural Tube Defects, The Lancet, July 20, 1991;338:153-154.

Reviews the recent suggestion by the British Medical Research Council Vitamin Study Group that daily supplementation with folic acid before conception and during early pregnancy substantially reduces the recurrence of neural tube defects (Lancet, 1991;338:131-7, 153-4).

Women in the United States who have had their pregnancy resulting in an infant or a fetus with a neural tube defect have a 2 to 3% risk for having another pregnancy result in neural tube defects. Approximately 4,000 infants with neural tube defects are born in the United States annually and worldwide the number is approximately 400,000. Because of these findings the CDC has recommended the use of folic acid supplementation of 4 mg/d for women who previously had an infant or fetus with spina bifida, anencephaly or encephalocele. It is noted that in an earlier study .36 mg/d of folic acid was associated with a substantial reduction in neural tube defects. Since the 4 mg dosage is a large dose, the Food and Drug Administration regards folic acid at this dose to require an approved new drug application. It is noted that 4 mg/d of folic acid may mask vitamin B12 deficiency while neurologic manifestations progress.

If there are no contraindications, 4 mg/d of folic acid should be taken from at least 4 weeks before conception through the first 3 months of pregnancy.

One mg folic acid tablets are available as a prescription item. Multi-vitamin and mineral preparations which contain folic acid should not be used to get the 4 mg/d dose since there will be harmful levels of vitamins A and D.

Use of Folic Acid For the Prevention of Spina Bifida and Other Neural Tube Defects - 1983-1991, Morbidity and Mortality Weekly Report, August 2, 1991;40(30):513-516.


Epidemiologic studies have identified hyperhomocysteinemia as a possible risk factor for atherosclerosis. We determined the risk of carotid-artery atherosclerosis in relation to both plasma homocysteine concentrations and nutritional determinants of hyperhomocysteinemia.

Elderly subjects (418 men and 623 women; age range, 67 to 96 years) from the Framingham Heart Study were examined for the relation between the maximal degree of stenosis of the extracranial carotid arteries (as assessed by ultrasonography) and plasma homocysteine concentrations, as well as plasma concentrations and intakes of vitamins involved in homocysteine metabolism, including folate, vitamin B12, and vitamin B6.

The prevalence of carotid stenosis was 43 percent in the men and 34 percent in the women.

High plasma homocysteine concentrations and low concentrations of folate and vitamin B6, through their role in homocysteine metabolism, are associated with an increased risk of extracranial carotid-artery stenosis in the elderly.

Selhub-J et al., Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis [see comments]. N-Engl-J-Med. 1995 Feb 2; 332(5): 286-91.

Hyperhomocysteine (I)

Hyperhomocysteine (I)

The addition of vitamin B-12 to folic acid supplements or enriched foods may enhance the reduction of homocysteine, thereby increasing the effectiveness of these supplements in the prevention of vascular disease and neural tube defects. Folic acid, in amounts 1-2 times the RDA, has been shown to lower plasma homocysteine levels. The study compared the homocysteine-lowering potential of a folic acid supplement with that of 2 supplements containing different doses of vitamin B-12 in addition to folic acid. Significant reductions in plasma homocysteine were observed in all groups receiving vitamin treatment. The effect observed with the combination of folic acid + vitamin B-12was significantly larger than that with a supplement containing folic acid alone.

Br?onstrup A; Hages M; Prinz-Langenohl R; Pietrzik KP: Effects of folic acid and combinations of folic acid and vitamin B-12 on plasma homocysteine concentrations in healthy, young women, Am J Clin Nutr, 1998 Nov; 68(5):1104-10

Folate Adequacy and Homocysteine Level

Folate Adequacy and Homocysteine Levels

Those with coronary artery disease had lower plasma folate levels and higher plasma homocysteine levels than controls. Folate was inversely associated with homocysteine levels for both cases and controls. There was a threshold for elevated homocysteine when folate levels were less than the World Health Organization recommended lower limit of 13.8 nmol/l. Plasma folate levels at the lower range of those considered to be normal in the United States (greater than 6.8 mmol/l) were inadequate to prevent elevations in homocysteine levels. Over 50% of the American population have folate values in the range associated with elevated homocysteine levels. The high prevalence of folate inadequacy addresses the need to reassess what levels of folate are needed to prevent disease and maintain health.

Plasma Folate Adequacy as Determined by Homocysteine Levels, Lewis, Charles A., M.D., M.P.H., et al, Beyond Deficiency: New Views on the Function and Health Effects of Vitamins, New York Academy of Sciences, February 9-12, 1992;15529.

Gastrointestinal Tract

Gastrointestinal Tract

It has been reported that there is increased pentane and carbon disulphide concentrations in the breath of schizophrenic patients. Alkanes in the breath may come from sites of cellular injury when oxygen free radicals peroxidate membrane lipids. Acute exposure to high concentrations of carbon disulphide can result in psychosis possibly by interfering with dopamine B-hydroxylase.

The greatest concentration of carbon disulphide in schizophrenic patients comes from the metabolic activity of the large-bowel flora.

Schizophrenia and the Gut, Again, The Lancet, November 6, 1993;342:1128-1129.



Hungarian researchers have stated that approximately 75% of all neural tube defects could be eliminated by giving folic acid supplements. The U.S. criteria is to wait for a first time neural tube defect before giving folic acid supplementation. The fact is that 95% of babies with a defect are born to women who have never had an affected pregnancy.

Folic Acid Could Cut 75% of All Neural Tube Defects, McKeown, L.A., Medical Tribune, June 11, 1992;21.

Infant Supplementation

Infant Supplementation

One mg of oral folic acid is routinely given to premature infants receiving enteral feedings. A
Since there was a lack of evidence for any physiologic effect of very high dose folic acid given to nonerythroblastic infants, it might be wise to limit oral folate supplementation in preterm infants to 50-200 ug per day.

High Folate Intakes Related to Zinc Status in Preterm Infants, Fuller, N.J., et al, European Journal of Pediatrics, 1992;151:51-53.

Preterm infants (#104) were evaluated for the effects of folic acid supplementation. These infants were given 1 mg oral supplement of folic acid in the form of pteroylglutamic acid once they began enteral feeding.

With the high folate levels attained by 1 mg per day supplementation along with evidence that high folate intakes may impair zinc absorption, their recommendations of folate supplementation remain at the ranges described previously (.05-.2 mg).

Plasma Folate Levels in Preterm Infants, With and Without A 1 Mg Daily Folate Supplement, Fuller, N.J., et al, European Journal of Pediatrics, 1992;151:48-50.

Lithium and Folic Acid

Lithium and Folic Acid

Bipolar patients on lithium therapy do not have a folate deficiency.

Serum and Red Cell Folate an Affective Morbidity in Lithium Prophylaxis, McKeon, P., et al, ACTA Psychiatr. Scand., 1991;83: 199-201.

Lithium Treatment

Lithium Treatment

Folate deficiency is uncommon among Chinese psychiatric patients but high folate levels enhance lithium's benefits.

Folate Concentration in Chinese Psychiatric Patients on Long Term Lithium Treatment, Lee, Sing, et al, Journal of Affective Disorders, 1992;24:265-270.

Liver Disease

Liver Disease

Heavy alcohol intake leads to inadequate food intake, malabsorption due to folic acid deficiency and/or maldigestion secondary to pancreatic insufficiency. These patients need energy requirements 25 kcal/kg/day, protein intake of 30-70g/d and fat calories less than 30% and the remainder can be carbohydrate. Urea production, the main mechanism for ammonia disposal, may be reduced in the alcoholic liver. Those with hepatic encephalopathy should increase calories from carbohydrate and decrease protein ingestion and also take 1.5 oz. of lactulose several times daily which will produce acidy stools decreasing colonic ammonia absorption.

Folic acid deficiency is common and can lead to intestinal malabsorption. Raw, leafy green vegetables, oranges, bananas are good sources. 5 mg folic acid may be taken once or twice weekly.

Nutrition and Liver Disease, Feinman, L., M.D. and Lieber, C.S., M.D., Hospital Medicine, April 1990;150-166.

Maternal Heat Exposure

Maternal Heat Exposure

A cohort of over 23,000 women who had serum alphafetoprotein screening and amniocentesis were evaluated for the risk of neural tube defects from heat exposure.

Heat exposure in the first trimester of pregnancy to hot tub, sauna, or fever resulted in an increased risk of neural tube defect. Hot tub exposure appeared to have the strongest effect of any single heat exposure.

Maternal Heat Exposure and Neural Tube Defects, Milunsky, Aubrey, MBBCh, et al, JAMA, August 19, 1992;268(7):882-885.

There was a definite increased risk to neural tube defects with elevated body temperature from taking hot baths during the first gestational month, as well as reported illness and the use of medications during pregnancy. There were significant dietary factors, which included the reduction in neural tube defects with a higher intake of vitamin A/beta-carotene rich fruits and vegetables.

Neural Tube Defect Etiology: New Evidence Concerning Maternal Hyperthermia, Health and Diet, Sandford, M.K., et al, Developmental Medicine and Child Neurology, 1992;34:661-665.

Maternal Vitamin Intake

Maternal Vitamin Intake

This study demonstrated no relationship between maternal serum folate, vitamin B12, or retinol levels and the risk of neural tube defects. Conclude that folate supplementation in high risk populations is warranted, but vitamin supplements may not be beneficial in general obstetric populations and low risk areas.

Maternal Vitamin Levels During Pregnancies Producing Infants with Neural Tube Defects, Mills, James L., M.D., MS, et al, Journal of Pediatrics, June 1992;120(6):863-871.

Maternal Zinc Levels

Maternal Zinc Levels

Women (#17) with neural tube defect offspring were evaluated for midtrimester maternal toenail zinc levels, utilizing neutron activation analysis. There was an overall increased risk for neural tube defect with increasing toenail zinc levels. Those with elevated zinc levels had a 3.1 odds ratio of developing neural tube defects, compared to those with normal toenail zinc levels.

Maternal Zinc and Fetal Neural Tube Defects, Milunsky, Aubrey, et al, Teratology, 1992;46:341-348.

Maternal serum folate and zinc concentrations were evaluated at 18 and 30 weeks gestation in 285 pregnant women. There was a weak linear relationship between maternal serum folate and zinc concentrations at 30 weeks gestation. Folic acid supplementation had favorable effects on birth weight and Apgar scores of newborns, and reduced prevalence of fetal growth retardation and maternal infections. There was no significant correlation found between serum zinc concentrations and birth weight of infants. The concept that folic acid supplementation has an inverse effect on maternal zinc nutriture and pregnancy outcome is not supported.

Maternal Serum Folate and Zinc Concentrations and Their Relationship to Pregnancy Outcome, Tamura, Tsunenobu, et al, American Journal of Clinical Nutrition, 1992;56:365-370.



Folic acid is a cofactor in the synthesis of cellular DNA, which is important in the production of tissues in the bone marrow, small intestines, and colon where there is a rapid turnover of cells.

Nutrients ingested, along with dietary polyglutamate, may have an effect on its obligatory intestinal surface digestion and subsequent assimilation. Legumes, tomatoes and oranges appear to inhibit human brush-border folate hydrolase, while cereal grain flours, milk, cabbage, cauliflower, and lettuce are not inhibitory. In miniature pigs which have high amounts of folate hydrolase, similar to those in humans, chronic alcohol ingestion inhibits folate hydrolase by 50% but it does not depress the monoglutamate transport process. Zinc does increase folate hydrolase activity, while paradoxically interfering with the final PteGlu transport. Polyglutamate hydrolase is a large macromolecule.

Dietary Folate - The Digestible Vitamin, Gray, Gary M.: Western Journal of Medicine, December 1991;155(6):660-662.



It was found that those who supplemented with folic acid had significantly lower toxicity from methotrexate without sacrificing efficacy.
Recommend 1 mg of folic acid daily during low dose therapy as a useful adjunct to reduced toxicity without altering efficacy.

The Effect of Folic Acid Supplementation on The Toxicity of LowDose Methotrexate in Patients With Rheumatoid Arthritis, Morgan, Sarah L., et al, Arthritis and Rheumatism, January 1990;33(1):9-18.

Folate depletion may be a cause of some of the undesirable side effects from methotrexate supplementation. This evidence tentatively recommends folate supplementation and/or using fewer toxic antifolate medications in the treatment of rheumatoid arthritis.

Rheumatology . Koopman, W. J. JAMA, June 1991;265 (23):3169-3170.

Mood disorders

Mood disorders

Evaluated patients at a mood disorder clinic for red cell folic acid, vitamin B12 and thyroid hormone levels. The patients were free of antidepressant medications for at least 2 months, and free of lithium for 3 months. They had no history of drug abuse.

There was a significant negative correlation between red cell folate, T4 and free thyroxine index persisting. Other than that, there were other relationships found. There was another significant negative correlation between thyroid hormones and both B12 and red cell folate levels. The correlation with red cell folate persisted after antidepressant treatment.

Folate, Vitamin B12 and Thyroid Function in Depression, Levitt, A.J. and Joffe, R.T., Biological Psychiatry, 1993;33:52-53.

Neural Tube Defects

Neural Tube Defects

Pregnant women should supplement with synthetic folic acid or fortified foods to prevent neural tube defects such as spina bifida or anencephaly, and those women with prior pregnancies may need a larger dose of folate to increase blood folate levels equivalent to the general population. The Public Health Service of the United States recommends that all women capable of childbearing consume 0.4 mg (400 microg) folic acid per day to decrease the risk neural tube defects.

Neuhouser ML; Beresford SA; Hickok DE; Monsen ER: Absorption of dietary and supplemental folate in women with prior pregnancies with neural tube defects and controls, J Am Coll Nutr, 1998 Dec; 17(6):625-30

Daily periconceptional intake of 0.4 mg of folic acid (generally a multivitamin) reduced the risk of neural tube defect by approximately 60%. The authors note that a high dietary intake of folic acid may also reduce the risk of neural tube defects.

Periconceptional Folic Acid Exposure and Risk of Occurrent Neural Tube Defects, Werler, M et al., JAMA, March 10, 1993;269(10):1257-1261.

Nursing Home

Nursing Home

Residents of a veterans home were evaluated for fasting serum folic acid levels. 29% were taking folic acid supplements. Six percent were taking phenytoin, a folate antagonist. None of the residents who consumed folic acid at 400 mcgs per day had a low serum folic acid level. Of the individuals who did not receive folic acid supplements, 3% had low folic acid levels less than 2.5 ng/mL.

Supplementing with a multivitamin that contains 400 mcgs of folic acid per day is warranted in nursing homes since this level can prevent low serum folate levels.

Low Serum Folic Acid Levels in a Nursing Home Population: A Clinical Experience. Drinka, Paul J., M.D., et al, Journal of the American College of Nutrition, 1993; 12(2):186-189.

Nutrition and Environment

Nutrition and Environment

Of 22,000+ pregnancies, 49 ended in neural tube defects. The prevalence of neural tube defect was 3.5 per 1,000 among women who had never used periconceptual multivitamins or used them only prior to conception. The prevalence of neural tube defects in those females who used multivitamins containing folic acid during the first 6 weeks of pregnancy was 0.9/ 1,000, which shows a 73% protective effect of the combined supplementation. In further analysis, zinc was evaluated in toenail clippings in the second trimester of pregnancy in over 1,700 women with normal offspring and 13 with neural tube defects. There was an odds ratio of 3.2 found for elevated toenail zinc in neural tube defects. These individuals were also evaluated for heat exposure and there was found a significant crude relative risk of 2.9 for hot tub use and neural tube defects. The relative risk for neural tube defects is 1.9 with only 1 heat exposure and 6.2 when exposed to 3 heat sources.

Nutrition and Other Environmental Factors in the Etiology of Neural Tube Defects, Milunsky, A: Beyond Deficiency: New Views on Functioning and Health Effects of Vitamins, New York Academy of Sciences, February 9-12, 1992/Abstract 12.

Preconception Health Care

Preconception Health Care

A general review for family physicians on appropriate components of preconception health care.

With regards to nutrition, obviously starvation increases the risk of congenital anomalies. Two factors associated with low birth weight infants are the mother's prepregnant weight and her weight gained during pregnancy. Maternal nutrition before conception also plays a very important role. It has been shown through the Supplemental Food Program for Women, Infants and Children (WIC) that

supplemental food definitely produces larger infants and mothers with higher hemoglobins and lower risks of obesity. Review the use of folic acid or multi-vitamins in the prevention of neural tube defects and conclude that the evidence is still debateable.

Preconception Health Care: A Critical Task For Family Physicians, Gjerdingen, DK & Fontaine, P, J of The American Board of Family Physician, 1991;4:237-50

Preconceptional Nutrition

Preconceptional Nutrition

This is a general review on the role of nutrition prior to pregnancy.

It is noted that, in addition to folic acid and zinc, the diets of American women are likely to be low in iron, magnesium, calcium and vitamin B6. Improved dietary patterns prior to pregnancy should be encouraged. Research in the area of preconceptual nutrition definitely suggests that, in the attempt to prevent infant mortality, we need to pay more attention to the time prior to conception. Results of preconceptional nutrition intervention provide additional encouragement to include nutrition assessment and counseling as part of postpartum and gynecologic care.

Preconceptional Nutrition, Dimperio, D: The J of Pediatric and Perinatal Nutrition, 1990;2(2):65-78.

Review Article

Review Article

Folic acid is needed for the production of red and white blood cells, central nervous system integrity, gastrointestinal function and growth of fetus. It is important in the synthesis of pyrimidine and purine bases for the production of DNA and RNA. Absorption mostly occurs in the proximal third of the small intestine. One percent of dietary folate is excreted in the urine. Serum folate levels are valuable markers for folate status. Red blood cell folate levels reflect tissue (hepatic stores) better than serum folate. Vitamin B 12 deficiency creates intracellular folate deficiency.

Sources of folic acid include the liver, kidney, wheat bran, yeast, spinach, asparagus, black-eyed peas, lentils, lima, navy beans, green leafy vegetables, whole grains, beef, almonds, peanuts, corn, beets, potatoes, turnips, turnip greens and broccoli. The RDA is 400 ug/d for adults, 800 ug/d for lactating women, 500 ug/d for pregnant women, 30-45 ug/d for infants and 100-300 ug/d for children. Alcoholics are frequently folate deficient. Nitrous oxide inhalation may reduce folate levels. Folic acid levels are reduced due to hemodilution and increased need during pregnancy. Diseases which may cause deficiency include sideroblastic and hemolytic anemias, chronic myelofibrosis, hyperthyroidism, exfoliative dermatitis and chronic hemodialysis.

Medications such as dilantin, sulfasalazine, triamterene, trimethoprim, pyrimethamine, methotrexate and neomycin affect folate metabolism. Folate deficiency signs include headaches, fatigue, megaloblastic anemia, thrombocytopenia, glossitis, hair loss, poor growth, weight loss, oral ulcers, nausea, anorexia, diarrhea, insomnia, irritability, forgetfulness, fever, jaundice, dyspnea, palpitations, pigmentation and vitiligo. Commercial products contain tablets from 0.25 to 1 mg of folic acid generally. Folic acid supplementation from I 00 to 1,000 ug/d in the first six months of pregnancy may reduce neural tube defects, though this is debated. One hundred times the RDA of folic acid may cause breakthrough epilepsy in patients on dilantin (phenytoin) therapy. In animal models mega doses may preciptate in kidneys. Folic acid supplements have been reported at 350 ug/d during pregnancy to reduce zinc absorption.

Folic Acid, 199 1: An Update, With New Recommended Daily Allowances, Kones, R, Southern Medical Journal, December 1990;83(12):1454-1458.

Spontaneous Abortion

Spontaneous Abortion

Folic acid status was evaluated in 79 patients with spontaneous abortion of unknown etiology and compared to healthy controls (#1 12). The serum and erythrocyte folate concentrations of the abortion group were significantly lower than controls.

Folate Status and Pregnancy Outcome, Pietrzik, K et al., Beyond Deficiency: New Views on the Function and Health Effects of Vitamins, N Y Academy of Sciences, February 9-12, 1992;P- 1 8.


Supplementation (USA)

Ideally, folic acid intake should be increased in the general U.S. population by increasing the intake of fresh vegetables, to the quantity that would make supplements unnecessary. It is a fact that marginal intakes appear to be widespread, with biochemical evidence of low folate status seen in 13 to 15% of women between 20 and 44 years of age, but deficiencies are much less common among users of supplements than nonusers. In some low income adolescent females, low folate status may be almost 50%. Folic acid fortification of flour is an option

Folic acid may be of benefit in the reduction of homocysteine levels, which is an emerging independent risk factor for cardiovascular disease, and also to help prevent cervical cancer. Even though the reason for the reduction of neural tube defects over the last half of the century in the United States is not certain, it is suspected that the widespread use of multivitamin/mineral supplements, general improvement in the diet, and fortification of breakfast cereals with folic acid have contributed. The author notes that this is a simple, safe, nutritional intervention.

Folic Acid and Neural Tube Defect: Can't We Come to Closure? Willett, WC: Am. J of Public Health, May 1992;82(5):666-668.

Purchasing vitamin supplements

Purchasing vitamin supplements

With the myriad of different products, it can be confusing. It is noted that almost all supplement makers buy most of their raw vitamins and minerals very cheaply from a small group of multinational firms.

Generally speaking, companies are ftee to put any amount of nutrient into their pills and capsules with few exceptions, such as in California, where vitamin A is limited, and folic acid is restricted to 400 mcgs in order not to mask a B 12 deficiency.

Vitamins 101: How to Buy Them, Schardt, D: Nutrition Action Health Letter, Jan/Feb 1993



Evaluated RBC and serum folate levels in schizophrenic patients. There were significantly lower concentrations of folate in both the RBC and serum in patients who were treated with neuroleptic medication compared with those not being treated with neuroleptics. There were lower levels of folate found in patients who were on more than 1 drug than those on a single medication.

Folic acid deficiency did not cause schizophrenia but folate deficiency is related to the severity of the disease, the chronicity of the disease and the medications use. Folate supplements should be given to schizophrenic patients along with their other medications.

RBC and Serum Folate Concentrations in Neuroleptic-Treated and Neuroleptic-Free Schizophrenic Patients, Ramchand, CN et al., J of Nutritional Medicine, 1992;3:303-309.


Therapy (1)

Twenty-two female patients with anorexia nervosa, restricted type, 14-35 years old, were treated with a 4-month course of combined cognitive-behavioral therapy, nutritional counselling and antidepressant drugs (nortriptyline for 7, fluoxetine for 15).

Patients were monitored for body mass index (BMI), for eating disorder symptoms by the Eating Disorder Inventory (EDI) and the Bulimic Investigation Test (BITE) and for depression and anxiety by the Hamilton Rating Scales for Depression and for Anxiety (HRS-D and -A). The scores were determined before and after 1, 2 and 4 months of therapy.

BMI, depression, anxiety and EDI scores improved significantly and equally in both groups during the 4 months of therapy, while BITE scores did not change.

Brambilla F et al., Combined cognitive-behavioral, psychopharmacological and nutritional therapy in eating disorders. 1. Anorexia nervosa--restricted type. Neuropsychobiology, 1995, 32:2, 59-63.

Therapy (2)

Research was conducted to obtain a profile of nutrition therapy currently in practice for patients with anorexia nervosa, bulimia nervosa, and anorexia/bulimia (mixed diagnosis) and to identify the areas of dietetics education and research regarding eating disorders that need more attention.

Nutrition therapy administered varied among dietitians treating inpatients, outpatients, and both. Three community groups were identified as most important to reach for prevention of eating disorders: junior high school students, coaches, and parents. Crucial areas of research were perceived by 94 dietitians to be comparative effectiveness of techniques of medical nutrition therapy (n = 55) and of techniques of prevention (n = 26) and increased understanding of etiology in relation to identification of high-risk groups and prevention (n = 21). Dietitians desired further information on multiple topics related to eating disorders.

Medical nutrition therapy for eating disorders is a specialization that requires education and training beyond the minimum required for dietetic registration. Some of the techniques required are unique to this specialization due, in part, to the psychological nature of the disorders. All dietitians, however, must be able to recognize and refer patients with eating disorders; these skills must be included in basic undergraduate programs and internships.

Whisenant SL & Smith BA: Eating disorders: current nutrition therapy and perceived needs in dietetics education and research. J Am Diet Assoc, 1995 Oct, 95:10, 1109-12.


Reviews the toxicologic manifestations of ethanol abuse. Hepatotoxicity of ethanol results from alcohol dehydrogenase-mediated excessive hepatic generation of nicotinamide adenine dinucleotide and acetaldehyde.

Alcohol also alters the degradation of key nutrients, thereby promoting deficiencies as well as toxic interactions with vitamin A and beta-carotene. Conversely, nutritional deficits may affect the toxicity of ethanol and acetaldehyde, as illustrated by the depletion in glutathione, ameliorated by S-adenosyl-L-methionine.

Lieber-CS: Mechanisms of ethanol-drug-nutrition interactions. J..Tox. Clin. Toxicol. 1994; 32(6): 631-81.

Vitamins A & B12

Vitamins A & B12

Reviews the potential clinical benefits of vitamins A, C, E, B 12, glutathione and folic acid. Folic acid's benefit in neural tube defects is discussed. Vitamin B 12 and zinc may also play a role in the prevention of neural tube defects.

Vitamin Undernutrition, Bates, C.J., Proceedings of the Nutrition Society, 1993;52:143-154.

Vitamin B12 (children)

Vitamin B12 (children)

Blood indices were studied in children with chronic diarrhea due to giardiasis. Folic acid malabsorption could occur in giardiasis since the trophocyte infects primarily the upper small intestine where folic acid absorption takes place. A correlation between the degree of mucosal damage and folic acid
malabsorption. Those patients with moderate to severe mucosal damage showed a reduction in several blood parameters including folic acid.

Giardiasis: Hematological Status and the Absorption of Vitamin B 12 and Folic Acid, Hjelt, K et al., ACTA Pediatrica, 1992;81:294-34.

Vitamin B12 Deficiency

Vitamin B12 Deficiency

In reviewing 30 cases of neurologic disease, in which patients who had normal serum B12 levels and low serum folate, ten patients had dementia, 19 had neurologic syndrome suggesting of cord degeneration and 10 had peripheral neuropathy. Folate supplementation helped many of these cases remarkably.

Postpartum depression with megaloblastic anemia often responds to folate supplementation.

Folate Deficient Neuropathy, Parry, T.E., et al, ACTA Hematologica, 1990;84:108.

Vitamin B12 and Multivitamin/Mineral Supplementation

For high risk populations the 4 mg/d dose should be considered and for the general population at less risk a 0.36 mg/d dosage could be utilized.

In the presence of a vitamin B 1 2 deficiency, larger doses of folic acid are needed for appropriate metabolism. He notes that vitamin B 12 was not included in the multivitamin mixture used in the original study. He further states there is evidence that vitamin B 12 values are low in mothers of anencephalics. From this data one cannot conclude whether the pharmacologic benefits of folic acid are making an impact due to a chronic folic acid deficiency, or to inadequate levels of vitamin B 12.

If neural tube defects are related to deficits specific to folic acid or to a lack of vitamin B 1 2, then these are probably not the only nutrients associated with these defects. It is important not to make simplistic conclusions especially with regards to developmental biology and the use of single supplements. A study concerned with intakes of 44 different nutrients in over 500 pregnant females revealed that mothers who produced low birth weight babies had significantly lower levels of 43 nutrients, including folic acid and vitamin B 12, than did mothers who were in the reference birth weight range. To lose sight of nutrient interdependence would be a mistake and that an integrated nutrient approach may be the best
for prevention of neurodevelopmental disorders.

Folic Acid Prevents Neural Tube Defects, Smithells, R.W., et al., The Lancet, August 10, 1991;338:379-380.

Vitamin B12

Vitamin B12

It has been shown that exocrine pancreatic insufficiency can result in vitamin B 12 malabsorption. Pancreatic replacement therapy has improved the absorption of vitamin B 12.

Vitamin B12 deficiency and folic acid deficiency are rarely found in chronic pancreatitis patients and do not play a relevant clinical role in chronic pancreatitis.

Vitamin B 12 and Folic Acid Deficiency in Chronic Pancreatitis: A Relevant Disorder?, Glasbrenner, B., et al, Klin Wochenschr, 199 1;69:168-172.

B12 and AIDS

B12 and AIDS

During a nine month period 74 HIV infected patients between 17-68 years of age were evaluated for folate and vitamin B 12. For those not supplemented with folic or folinic acid or taking antifolate drugs, serum and erythrocyte folic acid levels were significantly decreased. Over 50% of the HIV infected patients were deficient in serum and/or erythrocyte folate. For those not supplemented with vitamin B 12 the serum plasma vitamin B 1 2 level was significantly reduced. Vitamin B 12 deficiency, evidenced by decreased plasma vitamin levels, was present in only IO% of patients. The researchers only found elevated folate levels in vitamin supplemented patients. Folate deficiency in early HIV patients may be due to the fact that neopterin, which is raised in HIV infection from chronic macrophage stimulation, inhibits folate metabolism. Some drugs used in AIDS have antifolate effects. Demyelination can be the result of folate and/or B 12 deficiency which may be a cause of the neurologic damage of HIV infection.

Though vitamin B 12 deficiency was seen in AIDS patients it was less striking as compared to folate. The authors encourage serum vitamin B 12 analysis in HIV infected patients.

Folate, Vitamin B12, and HIV Infection, Boudes, P et al., The Lancet, June 9, 1990;335:1401-1402.

B12 in the Elderly (Spain)

B12 in the Elderly (Spain)

Evaluated B 12 and folic acid status in a group of noninstitutionalized Spanish elderly.

The results showed the average intake of vitamin B 12 was 3 times the recommended amount and blood levels were generally satisfactory. In 41.6% of the cases, folate intake was below the recommended daily amount. Serum and red blood cell folate levels also showed a deficiency in 80% of the adults studied.

Data suggests vitamin B 12 deficiency is not frequent among the elderly studied, but folate deficiency occurs frequently and has a negative effect on health.

Nutritional Assessment of Folate and Cyanocobalamin Status in a Spanish Elderly Group, Ortega, RM et al., International J of Vitamin and Nutrition Research, 1993;63:17-2 1.

Geriatric Patients

Geriatric Patients

Review of the roles of vitamin B 12 and folic acid in neuropsychiatric disorders in geriatric patients. Vitamin B 12 and folic acid are important in the synthesis of serotonin, norepinephrine and myelin. Normalizing serotonin synthesis helps regulate mood, sleep and appetite. They also are important in acetylcholine metabolism via S-adenosylmethione.

Poor vitamin B 12 and folic acid status in the geriatric population may be caused by poor absorption, decreased intrinsic factor, achlorhydria or dysfunction of coenzyme utilization. Specifically at risk for deficiency are depressed and demented elderly psychiatric patients.

Vitamin B 12 and Folate in Acute Geropsychiatric In Patients, Bell, IR: The Nutrition Report, January 1991;9(l):I,8.



Patients with vitiligo have been noted to have reduced levels of folic acid.

B 12 is known to facilitate the reduction of folic acid to tetrahydrofolic acid, a necessary prerequisite for the participation of folic acid enzyme reactions. Vitamin B 12 and folic acid require each other's presence for biological reactions, and will not proceed without one another. The action of vitamin B 12 in assisting in pigmentation may be due to its ability to enhance myelin synthesis, which would support the neural basis for vitiligo considered by many investigators. Ascorbic acid may be of value since it increases the stability of folic acid.

In the case of scurvy, folic acid reduction may occur as a secondary alteration. Ascorbic acid is important for the conversion of folic acid to folinic acid. Deficiencies of both folic acid and ascorbic acid induced an abnormality in tyrosine and phenylalanine metabolism.

Doses of folic acid up to 10 mgs/d. It was also noted that, with the addition of vitamins C and B 1 2, the repigmentation process was enhanced over folic acid alone.

Folic Acid and Vitamin B 12 in Vitiligo: A Nutritional Approach, Montes, L et al., Cutis, July 1992;50:39-42.

Zinc Supplementation

Zinc supplementation (1) INDIA

Determined whether daily zinc supplementation reduces the incidence and prevalence of acute diarrhea, especially in those with zinc deficiency.

Children 6-35 mo of age were randomly assigned to zinc (n = 286) and control (n = 293) groups and received a supplement daily for 6 mo. Zinc gluconate (10 mg elemental Zn) was given, with both zinc and control groups also receiving multivitamins.

The primary outcome measures determined by home visits every fifth day and physician examinations were the number of acute diarrheal episodes (incidence) and total diarrheal days (prevalence). Zinc supplementation had no effect in children 6-11 mo old.

In children aged > 11 mo there was significantly less diarrhea in the zinc group. In boys > 11 mo old, supplementation resulted in a 26% lower diarrheal incidence and a 35% lower prevalence. In zinc-supplemented girls > 11 mo of age, the incidence was 17% lower and the prevalence was 19% lower.

Overall, zinc supplementation resulted in a 17% lower diarrheal incidence in children with plasma zinc concentrations < 9.18 mumol/L at enrollment and a 33% lower incidence in children with concentrations < 50 mumol/L.

Zinc supplementation had a significant effect on acute diarrheal morbidity in children > 11 mo old and in children with low plasma zinc concentrations.

Sazawal S et al., Efficacy of zinc supplementation in reducing the incidence and prevalence of acute diarrhea--a community-based, double-blind, controlled trial. Am J Clin Nutr, 66:413-8, 1997 Aug.

Zinc supplementation (2) (Guatemala)

Measure the impact of zinc supplementation on young Guatemalan children's morbidity from diarrhea and respiratory infections.

High rates of diarrhea and respiratory infections were reported. Children from the placebo group had a 20% episodic prevalence of diarrhea, with 8 episodes/100 d, and a 7% episodic prevalence of respiratory infections, with 3 episodes/100 d.

The median incidence of diarrhea among children who received zinc supplementation was reduced by 22% (Wilcoxon rank test), with larger reductions among boys and among children with weight-for-length at baseline lower than the median of the sample (39% reductions in both subgroups).

Zinc supplementation also produced a 67% reduction in the percentage of children who had one or more episodes of persistent diarrhea.

No significant effects were found on the episodic prevalence of diarrhea, the number of days per episode, or the episodic prevalence or incidence of respiratory infections.

The large impact of zinc supplementation on diarrhea incidence suggests that young, rural Guatemalan children may be zinc deficient and that zinc supplementation may be an effective intervention to improve their health and growth.

Ruel MT et al., Impact of zinc supplementation on morbidity from diarrhea and respiratory infections among rural Guatemalan children. Pediatrics, 99:808-13, 1997 Jun.

Hyperhomocysteinemia in the Elderly

Hyperhomocysteinemia in the elderly

Elderly people who do not consume enough folic acid due to high alcohol use or lack of supplementation have high homocysteine levels, according to this cross-sectional study conducted on 278 men and women older than 65 years during 1993. Subjects with high folate intakes due to supplementation exhibited the lowest homocysteine levels. People who drank 60 alcoholic drinks/month or more had low folate levels and high homocysteine levels. Also, homocysteine levels increased as doses of coffee and tea increased.

Koehler KM, et al: Association of folate intake and serum homocysteine in elderly persons according to vitamin supplementation and alcohol use, Am J Clin Nutr 2001 Mar;73(3):628-37

Risk of Miscarriage

Risk of miscarriage

Folic acid supplements taken before and during early pregnancy do not seem to increase a mother's risk of miscarriage, according to this population-based study of Chinese women. The women asked to participate in this study had taken part in a folic acid campaign before their first pregnancy to reduce the incidence of neural tube defects in their unborn children. The miscarriage rate of women who had taken pills containing 400 mg folic acid before and during early pregnancy was compared to those who had not. The rate of miscarriage among women who had taken folic acid was 9.0% compared to 9.3% for women who had not taken the supplement. This finding suggests that daily consumption of 400 mg folic acid before pregnancy and during the first trimester does not heighten risk for miscarriage.
Gindler J: Folic acid supplements during pregnancy and risk of miscarriage, Lancet 2001 Sep 8;358(9284):796-800

Breast Cancer Risk

Breast cancer risk

High dietary intake of folate may be inversely associated with the risk of breast cancer, according to this study on women in urban Shanghai. The dietary habits of 1321 women and 1382 controls, all between the ages of 25 and 64, were assessed using food frequency questionnaires administered in person. None of the participants ever drank alcohol regularly or used vitamin supplements.
Dietary folate intake was highest among those women with the lowest risk of breast cancer according to unconditional logistic regression models used to analyze the questionnaire data. This correlation was most pronounced in women who consumed high levels of folate cofactors, including: methionine, vitamin B12, and vitamin B6.

Shrubsole MJ, Jin F, Dai Q, Shu XO, Potter JD, Hebert JR, Gao YT, Zheng W: Dietary folate intake and breast cancer risk: results from the Shanghai Breast Cancer Study, Cancer Res 2001 Oct 1;61(19):7136-41

Alzheimer's & Folic Acid


Folic acid deficiency may impede DNA repair in neurons and leave them vulnerable to oxidative damage that leads to Alzheimer's disease, according to this study. Human cells from the hippocampal region of the brain were incubated in folic acid-deficient medium, in the presence of methotrexate, or homocysteine. Each of these media induced cell death and rendered neurons vulnerable to mortality induced by amyloid beta-peptide, the major component of the amyloid plaques that characterize Alzheimer's.

Amyloid precursor protein mutant transgenic mice given a folic-acid deficient diet also had increased cellular DNA damage and hippocampal neurodegeneration, an effect not seen in wild-type mice. The levels of amyloid beta-peptide in the brains of the folate-deficient mice remained static.

Kruman II, et al: Folic Acid deficiency and homocysteine impair DNA repair in hippocampal neurons and senstitize them to amyloid toxicity in experimental models of Alzheimer's disease, J Neurosci 2002 Mar 1;22(5):1752-62

Coronary Artery Disease & Folic Acid

Coronary artery disease

According to this study, folic acid supplementation in the elderly diet may be a good way to reduce homocysteine levels, which are associated with coronary artery disease, peripheral vascular disease, and venous thrombosis. This randomized, double-blind, placebo-controlled trial tested the effects of 0, 50, 100, 200, 400 and 600 micrograms folic acid on plasma homocysteine in 368 participants aged 65 to 75. Plasma homocysteine levels were measured at three and six weeks during the six-week long trial. Homocysteine levels were only significantly lowered by the 400 and 600 microgram supplements. The results indicated that a total daily folic acid intake of 926 micrograms per day, as calculated by multiple linear regression, would be necessary to avoid cardiovascular risk from folate deficiency in 95% of the elderly population. Since this intake amount is relatively high to take in by diet alone, it is suggested that supplementation and fortification of food with folic acid would be beneficial to the elderly.

Rydlewicz A, Simpson JA, Taylor RJ, Bond CM, Golden MH: The effect of folic acid supplementation on plasma homocysteine in an elderly population, QJM 2002 Jan;95(1):27-35

Diarrhea & Folic acid


Folic acid may have a use as adjunctive therapy in diarrhea that affects children, according to this study conducted in Long-Evans rats. A total of ten rats were given a raw red kidney bean-based diet containing lectin to induce diarrhea for ten days - five were given folic acid supplements (160 microg/g feed) during and ten days before the experiment. The effects of folic acid were judged based on evaluations of fecal matter, small intestinal bacterial overgrowth, and translocation of enteric bacteria into mesenteric lymph nodes.

Folic acid supplementation did not prevent weight loss or fecal output associated with diarrhea, but it did reduce the amount of enteric bacteria translocated into the mesenteric lymph nodes. It also showed signs of reducing indigenous bacteria adhering to jejunal mucosa. This mechanism may be of use in the prevention of bacterial infections that result as a complication of diarrhea in malnourished children.

Shoda R, Mahalanabis D, Islam KN, Wahed MA, Albert MJ: Folic acid supplementation on red kidney bean-induced diarrhoea and enteric bacterial translocation into mesenteric lymph nodes in rats: a pilot study, Acta Paediatr 2002;91(1):51-4


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