ABSTRACT
The American Academy of Pediatrics endorses the US Public Health
Service (USPHS) recommendation that all women capable of becoming
pregnant consume 400 µg of folic acid daily to prevent neural
tube defects (NTDs). Studies have demonstrated that periconceptional
folic acid supplementation can prevent 50% or more of NTDs such as
spina bifida and anencephaly. For women who have previously had an
NTD-affected pregnancy, the Centers for Disease Control and Prevention
(CDC) recommends increasing the intake of folic acid to 4000 µg
per day beginning at least 1 month before conception and continuing
through the first trimester. Implementation of these recommendations
is essential for the primary prevention of these serious and disabling
birth defects. Because fewer than 1 in 3 women consume the amount
of folic acid recommended by the USPHS, the Academy notes that the
prevention of NTDs depends on an urgent and effective campaign to
close this prevention gap.
ABBREVIATIONS
NTDs, neural tube defects; USPHS, US Public Health Service; CDC,
Centers for Disease Control and Prevention; MRC, Medical Research
Council; IOM, Institute of Medicine; AAP, American Academy of Pediatrics.
BACKGROUND
Neural tube defects (NTDs) are among the most common birth defects
contributing to infant mortality and serious disability. NTDs, which
include anencephaly, spina bifida, and encephalocele, occur in approximately
1 of 1000 births in the United States.1 An estimated 4000 pregnancies
are affected with NTDs each year. More than one third of these pregnancies
are spontaneously lost or electively terminated; thus, about 2500
infants per year are born with an NTD. The results of 2 randomized
controlled trials and several observational studies showed that 50%
or more of NTDs can be prevented if women consume a folic acid-containing
supplement before and during the early weeks of pregnancy2,3 in addition
to the folate in their diet. Based on a synthesis of these data, the
US Public Health Service (USPHS) and Centers for Disease Control and
Prevention (CDC) recommendations were developed.4,5 Because the evidence
for folic acid prevention evolved over time, there are two separate
recommendations: one for women who have no history of a previous NTD-affected
pregnancy and one for women who have had a previous NTD-affected pregnancy.
WOMEN WITH NO HISTORY OF A PREVIOUS NTD-AFFECTED PREGNANCY
Of children with an NTD, 95% are born to couples with no family history
of these defects. Evidence to date suggests that supplementation with
a multivitamin containing 400 (0.4 mg) µg of folic acid prevents
the occurrence of >50% of NTDs when it is taken before conception
and continued throughout the first trimester of pregnancy.5 The USPHS
recommends that all women of childbearing age who are capable of becoming
pregnant take 400 µg of folic acid daily.5 Implementing this
recommendation may provide the opportunity for primary prevention
of 50% or more of these serious disabling birth defects. Regular and
ongoing ingestion of folic acid by women of childbearing age is necessary
because approximately half of the pregnancies in the United States
are unplanned,6 and neural tube closure occurs during the first 4
weeks of gestation.7 Despite the publication of the USPHS recommendation
in September 1992, a 1998 poll showed that 70% of women aged 18 to
45 years still are not following the USPHS recommendation.8
WOMEN WHO HAVE HAD A PREVIOUS NTD-AFFECTED PREGNANCY
Among US couples who have had a child with an NTD, the recurrence
risk is 2% to 3% in subsequent pregnancies.9 In 1991, the Medical
Research Council (MRC) Vitamin Study Group reported the results of
a well-designed, prospective, randomized trial of folic acid supplementation
for the prevention of NTDs in pregnancies of women who had a previous
child with an NTD, and the CDC published its recommendations for consumption
of 4000 (4 mg) µg of folic acid.4 The results of the MRC study
conclusively demonstrated that a daily dosage of 4000 µg of
folic acid, in addition to folate in the diet, before and during early
pregnancy resulted in a 71% reduction of recurrence of NTDs. The addition
of other vitamins to the dosage of folic acid did not reduce the risk
further. Use of multivitamins without folic acid did not result in
a reduced risk for NTDs. The MRC study did not explore the possible
benefit of a dosage lower than 4000 µg of folic acid. However,
an earlier nonrandomized study conducted in the United Kingdom suggested
that a lower dosage, 360 µg daily, resulted in a comparable
reduction of recurrence of NTDs.10 Although adverse maternal or fetal
effects of a daily 4000 µg dosage of folic acid were not detected
by the MRC study, the small size of the study groups precluded detection
of uncommon adverse effects.
FOLATE AND FOLIC ACID
Folic acid, also known as pteroylmonoglutamic acid, is a synthetic
compound used in dietary supplements and fortified foods. The term
folate includes all compounds that have the vitamin properties of
folic acid--including folic acid and naturally occurring compounds
in food.11 The average diet in the United States contains 200 µg
of naturally occurring food folate, which is less bioavailable than
folic acid.12 Additional intake of foods rich in folate could raise
the average intake, but it has not been demonstrated that increased
consumption of food folate would prevent NTDs as effectively as a
daily vitamin supplement containing 400 µg of folic acid. A
small comparison study suggests that blood folate concentrations are
increased much more by folic acid supplementation than by naturally
occurring food folate in the diet.13 Economic and social circumstances
may make an adequate increase in dietary folate difficult or unlikely,
and the behavioral change required among a large fraction of women
may take years to achieve.
Folic acid is a water-soluble vitamin that has no known toxicity.
However, higher doses of folic acid can correct the anemia of vitamin
B12 deficiency (pernicious anemia), which might be an important clue
to the presence of vitamin B12 deficiency in some instances. Folic
acid does not prevent the neurologic consequences of vitamin B12 deficiency,
and, for this reason, the USPHS recommendation cautioned that intake
of folate should be not >1000 µg per day. However, the Institute
of Medicine (IOM) Food and Nutrition Board recently set the tolerable
upper intake limit of synthetic folic acid at 1000 µg, thus
eliminating food folate from the calculation.14 Because pernicious
anemia rarely occurs before the age of 50 years, it is likely to be
rare among women consuming folic acid during the reproductive years.
Folic acid has been consumed by about a quarter of all women for many
years and extensively during later pregnancy without apparent adverse
effects; however, studies that definitively address the question of
maternal and fetal safety of folic acid are not available.
The IOM Food and Nutrition Board's recommended dietary allowance
(RDA) for folate is 400 µg for adults and 600 µg for pregnant
women.14 To reduce the risk for NTDs, the IOM recommended that women
capable of becoming pregnant consume 400 µg of folic acid daily
from fortified foods, vitamin supplements, or a combination of the
two. This is in addition to the naturally occurring folate obtained
from a varied diet.14 The majority of multivitamin preparations contain
400 µg of folic acid. These preparations are available over
the counter and are already being taken by about 30% of nonpregnant
women aged 18 to 45 years in the United States.8 Tablets containing
folic acid alone are available over the counter in dosages up to 800
µg but the availability is very limited when compared with multivitamin
preparations. Folic acid tablets in a 1000 µg dose are available
by prescription only. This preparation is most frequently utilized
by women who are taking 4000 µg because of a previous NTD-affected
pregnancy.
In March 1996, the Food and Drug Administration mandated that enriched
cereal-grain products be fortified with 140 µg of folic acid
per 100 g of flour.15 This measure increases the proportion of women
who consume the USPHS-recommended daily dosage of 400 µg of
folic acid only an additional 3%, because this fortification level
will provide the average woman only an additional 100 µg of
folic acid per day (unpublished data, 1992).
RECOMMENDATIONS
1. Prevention for Women With No History of a Previous NTD-Affected
Pregnancy. The American Academy of Pediatrics (AAP) endorses the USPHS
recommendation that all women of childbearing age who are capable
of becoming pregnant should consume 400 (0.4 mg) µg of folic
acid daily. Because of the high rate of unplanned pregnancies in the
United States, the AAP encourages efforts at devising a program of
food fortification to provide all women a daily intake of 400 µg
of folic acid. In the absence of optimal fortification, the AAP encourages
women to consume 400 µg of folic acid daily in addition to eating
a healthy diet. At present, the most convenient, inexpensive, and
direct way to meet the recommended dosage is by taking a multivitamin
containing 400 µg of folic acid, but efforts to increase the
availability of folic acid-only supplements should be encouraged for
women who prefer not to take multivitamins. Because the risk for NTDs
is not totally eliminated by folic acid use, routine prenatal screening
for NTDs is still advisable.
2. Prevention for Women Who Have Had a Previous NTD-Affected Pregnancy.
Women with a history of a previous pregnancy resulting in a fetus
with an NTD should be advised of the results of the MRC study. During
times in which a pregnancy is not planned, these high-risk women should
consume 4000 (4 mg) µg of folic acid per day. However, they
should be offered treatment with 4000 µg of folic acid per day
starting 1 month before the time they plan to become pregnant and
throughout the first 3 months of pregnancy, unless contraindicated.
Women should be advised not to attempt to achieve the 4000 µg
daily dosage of folic acid by taking over-the-counter or prescription
multivitamins containing folic acid because of the possibility of
ingesting harmful levels of other vitamins, for example, Vitamin A.17
It should be noted that 4000 µg of folic acid did not prevent
all NTDs in the MRC study. Therefore, high-risk patients should be
cautioned that folic acid supplementation does not preclude the need
for counseling or consideration of prenatal testing for NTDs.
3. Prevention for Other High-Risk Persons. No intervention or observational
studies address prevention for other high-risk persons. Women with
a close relative (eg, sibling, niece, or nephew) who has an NTD (risk
is approximately 0.3% to 1.0%), women with type 1 diabetes mellitus
(risk is approximately 1%), women with seizure disorders being treated
with valproic acid or carbamazepine (risk is approximately 1%), and
women or their partners who have an NTD (risk may be 2% to 3%)18 and
are planning a pregnancy should discuss with their physician the risk
for an affected child and the advantages and disadvantages of increasing
their daily periconceptional folic acid intake to 4000 µg.
4. Public Health Programs: Supplementation, Surveillance, and Food
Fortification. The AAP recommends that the Department of Health and
Human Services expeditiously devise and implement an educational program
to prevent folic acid-preventable NTDs throughout the use of supplements,
fortified foods, or a combination of both. The program should support
surveillance of effectiveness and adverse outcomes to further refine
the effective folate dose and mechanisms of actions. In light of the
recent IOM recommendation, the AAP also encourages additional efforts
at devising a program of food fortification with folic acid to provide
all women capable of becoming pregnant a daily intake of 400 µg
of folic acid.
REFERENCES
1. Centers for Disease Control and Prevention. Surveillance for
anencephaly and spina bifida and the impact of prenatal diagnosis.
United States, 1985-1994. MMWR. 1996;44(SS-4):1-13
2. MRC Vitamin Study Research Group. Prevention of neural tube defects:
results of the Medical Research Council Vitamin Study. Lancet. 1991;338:131-137
3. Czeizel AE, Dudás I. Prevention of the first occurrence
of neural-tube defects by periconceptional vitamin supplementation.
N Engl J Med. 1992;327:1832-1835
4. Centers for Disease Control and Prevention. Use of folic acid for
prevention of spina bifida and other neural tube defects: 1983-1991.
MMWR. 1991;40:513-516
5. Centers for Disease Control and Prevention. Recommendations for
the use of folic acid to reduce the number of cases of spina bifida
and other neural tube defects. MMWR. 1992;41:1-8
6. Forrest JD. Epidemiology of unintended pregnancy and contraceptive
use. Am J Obstet Gynecol. 1994;170:1485-1489
7. Moore KL. Formulation of the trilaminar embryo. In: The Developing
Human. Philadelphia, PA: WB Saunders Co; 1988:55-64
8. Centers for Disease Control and Prevention. Knowledge and use of
folic acid by women of childbearing age--United States, 1995 and 1998.
MMWR. 1999;48:325-327
9. Hall JG, Solehdin F. Genetics of neural tube defects. Ment Retard
Dev Disabil. 1999;4:269-281
10. Smithells RW, Nevin NC, Seller MJ, et al. Further experience of
vitamin supplementation for prevention of neural tube defect recurrences.
Lancet. 1983;1:1027-1031
11. Cornel MC, Erickson JD. Comparison of national policies on periconceptional
use of folic acid to prevent spina bifida and anencephaly. Teratology.
1997;55:134-137
12. Bailey LB. Folate requirements and dietary recommendations. In:
Bailey LB, ed. Folate in Health and Disease. New York, NY: Marcel
Dekker, Inc; 1995:123-151
13. Daly LE, Kirke PN, Molloy A, Weir DG, Scott JM. Folate levels
and neural tube defects: implications for prevention. JAMA. 1995;274:1698-1702
14. Institute of Medicine. Dietary reference intakes: folate, other
B vitamins, and choline. In: Dietary Reference Intakes for Thiamin,
Riboflavin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin,
and Choline. Washington, DC: National Academy Press; 1998:(8)32
15. US Department of Health and Human Services, Food and Drug Administration.
Food standards: amendment of the standards of identity for enriched
grain products to require addition of folic acid. Federal Register.
1996;61:8781-8807
16. Oakley GP. Let's increase folic acid fortification and include
vitamin B12. Am J Clin Nutr. 1997;65:1889-1890
17. Oakley GP Jr, Erickson JD. Vitamin A and birth defects: continuing
caution is needed. N Engl J Med. 1995;333:1414-1415
18. Tolmie J. Neural tube defects and other congenital malformations
of the central nervous system. In: Rimoin DL, Connor JM, Pyeritz RE,
eds. Emery and Rimoin's Principles and Practice of Medical Genetics.
New York, NY: Churchill Livingstone Inc; 1997:2145-2176