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.
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Some Findings About Folic
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.
maternal folic acid supplementation is associated with preterm deliveries,
intrauterine growth retardation, placental abruption and infarction, as
well as habitual abortions. (2)
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)
folic acid intake in adults has been associated with a reduction in adult
cardiovascular disease. (4, 5)
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).
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.
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,
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.
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)
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).
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.
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.
fortification is increased, supplementation is recommended, as follows:
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
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.
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.
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.
Hall J, Solehdin F. Folic Acid for the Prevention of Congenital Anomalies.
Eur J Pediatr 1998 Jun;157(6):445-450.
Scholl TO, Johnson WG. Folic Acid: Influence on the Outcome of Pregnancy.
Am J Clin Nutrition 2000 May;71(5 Suppl):1295S-1303S.
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.
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.
Nygard O, et al. Plasma Homocysteine Levels and Mortality in Patients with
Coronary Artery Disease. N Eng J Med 1997;337:230-236.
Locksmith GL, Duff P. Preventing Neural Tube Defects:The Importance of
Periconceptional Folic Acid Supplements. Obstet Gynecol 1998;91:1027-1034.
Erbe RW, Wang JC. Folate Metabolism in Humans. Am J Med Genet 1984;17:277-287.
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
Subar AF. Folate Intake and Food Sources in the US Population. Am J Clin
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.