An ever-increasing amount of data are available showing that the use of folic acid prior to conception significantly reduces the risk for neural tube defects (NTDs), both in the general population and in women with a history of NTDs on a prior pregnancy. Some recent research points to benefits of folic acid use for other segments of the population, beyond women of child- bearing age.
Maria L Moline is a certified genetic counselor. If you have any questions regarding this article your are welcomed to contact her at

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Some Findings About Folic Acid

• Periconceptual use of folic acid has been shown to reduce the risk for congenital heart defects (particularly conotruncal heart defects), obstructive urinary tract anomalies, limb deficiencies, orofacial clefts and congenital hypertrophic pyloric stenosis. Some studies suggest also a decreased risk for limb anomalies. (1) 
• Inadequate maternal folic acid supplementation is associated with preterm deliveries, intrauterine growth retardation, placental abruption and infarction, as well as habitual abortions. (2)
• A higher spontaneous abortion rate has been noted in the preceding pregnancies of women who had a pregnancy (fetus or newborn) with a NTD or congenital heart defects (CHD). (3)

Adequate folic acid intake in adults has been associated with a reduction in adult cardiovascular disease. (4, 5) 

A look at the biochemical effects of folic acid at the cellular level can explain some of these multiple benefits. The following summary is adapted from an excellent review article published in 1998. (6) Folates are a class of naturally occurring compounds (polyglutamates) with the vitamin properties of folic acid. The synthetic forms of folic acid contain only monoglutamates. Polyglutamates must be converted to absorbable monoglutamates in the upper small intestine. (7) Synthetic folic acid supplements, therefore, provide better bioavailability than folate from natural source, an important concept when determining the best way to deliver adequate amounts of folic acid to the target population (see below). 

Folate has two know important biologic effects. It acts as a cofactor for enzymes that are essential in DNA and RNA synthesis. Folate is also a required cofactor in the transfer of methyl groups in the amino acid methylation cycle, an essential step in the recycling of homocysteine back to methionine. With insufficient folate, nucleic acid synthesis is inhibited, and cells are unable to manufacture enough DNA for mitosis. Nucleic acid and protein synthesis is increased during embryogenesis. 

Moreover, insufficient folate causes hyperhomocysteinemia. Recent studies have suggested that elevated levels of homocysteine are teratogenic. Avian embryos treated with high levels of homocysteine showed an increased risk for anomalies, specifically neural tube defects and congenital heart disease. (8) Folate supplementation prevented this teratogenic effect. Hyperhomocysteinemia can also be caused by genetic mutations. These mutations are responsible for the production of enzymes involved in the methionine cycle that have decreased bioactivity. Folate supplementation can correct this problem by rendering the anomalous proteins more effective in their function.

Two recent studies have implicated high plasma homocysteine concentrations with an increased risk for occlusive cardiovascular disease. (4, 5) This widens the benefits of folate supplementation to include not just women of childbearing age, but other large segments of the population. The role of hyperhomocysteinemia in causing occlusive vascular disease is not as yet completely understood, but may explain the recent findings that low concentrations of plasma folate are associated with increased risk for preterm delivery, low birth weight, IUGR, as well as other pregnancy complications, such as placental abruption and preeclampsia. (2)

This mounting level of evidence on the benefits of folic acid has sparked a controversy on how to make adequate levels available to the target populations. Three avenues exist: dietary modification, supplementation, and food fortification. The principal dietary sources of folate are leafy green vegetable, legumes (beans, peas), citrus fruits and juices, liver, and whole wheat bread. The most recent study showed that only 8% of adult women consumed at least 0.4 mg of folic acid level from food sources. (9) Supplementation has been recommended by various agencies and national groups, including the United States Public Health Service, the US Preventive Services Task Force, ACOG, the March of Dimes, The Spina Bifida Association of America, the National Academy of Sciences, the American College of Medical Genetics, and the Center for Disease Control (see below for recommended doses).

The disadvantage of a supplementation program is two-fold: cost of a vitamin supplement, and compliance. It is estimated that half of all pregnancies in the United States are unplanned, and neural tube closure occurs before women realize that they are pregnant, and certainly before the first prenatal visit occurs. According to a 1997 U.S. survey, only between 23% and 30% of nonpregnant women consume multivitamin preparations containing folic acid. (10) Food fortification would resolve these concerns. Some foods in the United States are already fortified with folic acid, such as breakfast cereals, and instant breakfast drinks. The benefits of this fortification depend on consumer choice of products. Since January 1998, the Food and Drug Administration (FDA) has required fortification of flour supply at 0.14 mg/100 g of grain. This low level has sparked intense criticism and debate by various agencies, which consider this level too low. It is estimated that the fortification level now required by the FDA adds only 0.1 mg of folic acid to the average daily diet, well short of the recommended 0.4 mg dose. The FDA has justified this low dose with concerns over delaying the diagnosis of B12 deficiency, inhibition of anticonvulsant or other folate antagonistic drugs, interference with zinc absorption, and hypersensitivity reactions. To add an average of 0.4 mg of folic acid per day would require a fortification level of about 0.56 mg per 100 g of grain. 

Until fortification is increased, supplementation is recommended, as follows: 

1. Women of childbearing age: 0.4 mg per day, not to exceed 1 mg a day. It is important to advice against taking more than one multivitamin preparation a day, as high levels of certain vitamins (in particular vitamin A) are teratogenic. Even though the recommendation is for continuous ingestion of folic acid, starting one to two month prior to conception seems to be enough to ensure the preventive benefits of folic acid.

2. Women who have had a pregnancy affected with a neural tube defect: 0.4 mg of folic acid daily to be increased to 4.0 mg two months prior to conception and for the first three months of pregnancy. After the first trimester, back to 0.4 mg. Studies are available showing that folic acid decreases the occurrence and recurrence of NTD. For the other anomalies mentioned above (CHD, orofacial clefts, limb reduction defects) it is not known if increased levels of folic acid beyond 0.4 mg a day are helpful in preventing a second affected pregnancy.

3. Other women are known to be at an increased risk for NTDs: obese women, women on valproic acid or carbamazepine, women with a family (not a prior pregnancy) of NTDs, women with type I diabetes, or uncontrolled type II diabetes and early gestational diabetes causing severe hyperglycemia during the first trimester. In these cases, 4.0 mg of folic acid is not recommended as no studies have demonstrated any benefit of the 4-mg dose in these groups. It is speculated that different mechanisms may be responsible for the increased risk in these groups. Also, increased doses of folic acid may interfere with the efficacy of certain anticonvulsant medications.

References:

 
1. Hall J, Solehdin F. Folic Acid for the Prevention of Congenital Anomalies. Eur J Pediatr 1998 Jun;157(6):445-450.
2. Scholl TO, Johnson WG. Folic Acid: Influence on the Outcome of Pregnancy. Am J Clin Nutrition 2000 May;71(5 Suppl):1295S-1303S.
3. Carmi R, et al. Spontaneous Abortion-Higher Risk Factor for Neural Tube Defects in Subsequent Pregnancy. Am J Med Genet 1994 Jun 1;51(2):93-97.
4. Boushey CJ, et al. A Quantitative Assessment of Plasma Homocysteine as a Risk Factor for Vascular Disease: Probable Benefits of Increasing Folic Acid Intakes. JAMA 1995;274:1049-1057.
5. Nygard O, et al. Plasma Homocysteine Levels and Mortality in Patients with Coronary Artery Disease. N Eng J Med 1997;337:230-236.
6. Locksmith GL, Duff P. Preventing Neural Tube Defects:The Importance of Periconceptional Folic Acid Supplements. Obstet Gynecol 1998;91:1027-1034.
7. Erbe RW, Wang JC. Folate Metabolism in Humans. Am J Med Genet 1984;17:277-287.
8. Rosenquist TH, et al. Homocysteine Induces Congenital Defects of the Heart and Neural Tube: Effect of Folic Acid. Proc Natl Acad Sci USA. 1996 Dec 24;93(26):15227-15232.
9. Subar AF. Folate Intake and Food Sources in the US Population. Am J Clin Nutr 1989;50:508-516.
10. US Public Health Service. Knowledge and Use of Folic Acid by Women of Childbearing Age -United States, 1997. MMWR Morb Mortal Wkly Rep 1997;46:721-723.