Effectiveness in Disease and Injury Prevention Use of Folic Acid for Prevention of Spina Bifida and Other Neural Tube Defects -- 1983-1991

Neural tube defects--including spina bifida, anencephaly, and encephalocele--are common, serious birth defects that are important causes of infant mortality and disability (1). Women in the United States who have had a pregnancy resulting in an infant or fetus with a neural tube defect have a 2%-3% risk for having another pregnancy resulting in an infant or fetus with a neural tube defect (i.e., a recurrence) (2). The British Medical Research Council (MRC) Vitamin Study Group recently reported the results of a randomized prevention trial that indicated that daily oral supplementation with folic acid before conception and during early pregnancy substantially reduces the recurrence of neural tube defects (3). This report summarizes the findings of that study and provides recommendations for supplementation with folic acid to prevent the recurrence of neural tube defects.

The study, which began in July 1983 and was halted in April 1991, involved 33 centers (17 in the United Kingdom and 16 in six other countries). Study participants were women who had had a previous pregnancy that resulted in an infant or fetus with a neural tube defect and who were planning a subsequent pregnancy. Each participant was randomly assigned to one of four supplementation groups (groups A, B, C, and D). Group A received 4 mg of folic acid (the only dose of folic acid studied); group B, a multivitamin preparation* plus 4 mg of folic acid; group C, neither the multivitamin preparation nor folic acid; and group D, the multivitamin preparation without folic acid. All capsules (including those for group C) contained two mineral supplements--ferrous sulfate (120 mg) and di-calcium phosphate (240 mg). Compliance was assessed by counting capsules and by measuring folic acid levels before and after starting supplementation. To test the effect of folic acid supplementation, the MRC study group compared the outcomes of groups A and B with those in groups C and D. To test the effect of the multivitamin preparation, the MRC study group compared the outcomes in groups B and D with those in groups A and C.

During the study period, complete information was available on 1195 pregnancy outcomes. Neural tube defects recurred in six (1.0%) of 593 infants or fetuses of women who received folic acid (groups A (two of 298) and B (four of 295)), compared with 21 (3.5%) of 602 women who did not receive folic acid (groups C (13 of 300) and D (eight of 302)) (relative risk=0.29; 95% confidence interval=0.12-0.71). Thus, folic acid supplementation was associated with a 71% reduction in the recurrence of neural tube defects.

Use of multivitamins without folic acid was not associated with a protective effect. Neural tube defects recurred in 12 (2.0%) of 597 infants or fetuses of women who received multivitamins (groups B and D) compared with 15 (2.5%) of 598 women who did not receive multivitamins (groups A and C) (difference not statistically significant).

The six women whose pregnancies resulted in infants or fetuses with neural tube defects had serum folic acid levels similar to those of all women who received folic acid supplements.

Although adverse effects of folic acid were not detected, limitations in the size of the study groups could have precluded detection of a low frequency effect. However, because of the substantial protective effect, the study data monitoring group recommended halting the study early, so that all women at risk could receive the potential benefits of supplementation. Adapted from: Lancet 1991;338:131-7, 153-4. Reported by: Birth Defects and Genetic Diseases Br, Div of Birth Defects and Developmental Disabilities, National Center for Environmental Health and Injury Control, CDC.

Editorial Note

Editorial Note: Neural tube defects are common serious birth defects in the United States, and worldwide they contribute substantially to infant mortality and disability. Spina bifida is an inclusive name for various conditions associated with lack of closure of the spine, which, in turn, often causes permanent damage to the spinal cord and spinal nerves (4). Such damage results in varying degrees of paralysis and may result in loss of bowel and bladder control. Complications such as severe hydrocephalus may lead to cognitive impairment. Anencephaly is a lethal malformation characterized by the absence of the cranial vault and cerebral hemispheres often resulting in only a small mass of brain tissue attached to the base of the skull (4). Encephalocele is a defect in the skull that results in herniation of the meninges and brain tissue (4).

Each year, approximately 4000 infants with neural tube defects are born in the United States; worldwide, nearly 400,000 are born with these conditions. The estimated annual medical and surgical costs in the United States (based on 1985 dollars) for all persons with spina bifida exceed $200 million (5).

In the study population reported here, daily supplementation with 4 mg of folic acid starting before conception and continuing through the first 3 months of pregnancy prevented 71% of the recurrences of neural tube defects--a 3.5-fold protective effect. This study provides a scientific basis for prevention of a substantial proportion of the recurrences of neural tube defects. However, supplementation with folic acid did not prevent all the recurrences of neural tube defects--possibly because these disorders may be heterogenous in etiology (6-8).

Based on these and other findings (9-12), CDC recommends the use of folic acid supplementation (4 mg per day) for women who previously have had an infant or fetus with spina bifida, anencephaly, or encephalocele (see box). The only dose of folic acid evaluated by the MRC study was 4 mg per day. However, in an earlier and less definitive nonrandomized study, 0.36 mg per day was associated with a substantial reduction in the recurrence of neural tube defects (9). Therefore, use of 4 mg per day should be considered as an interim recommendation, pending further research. Four milligrams of folic acid daily is a high dose--10 times the recommended dietary allowance (RDA) (i.e., 400 ug) for pregnant women in the United States, and more than 20 times the RDA for nonpregnant women (i.e., 180 ug) (13). The Food and Drug Administration (FDA) regards the marketing of folic acid at this dosage to require an approved new drug application (NDA). No NDA has been approved by FDA for folic acid for prevention of neural tube defects. Finally, physicians should be aware that folic acid at this dosage (i.e., 4 mg daily) may complicate the diagnosis of vitamin B12 deficiency because the dosage may mask the megaloblastic anemia while neurologic manifestations progress.

References

1. Lynberg MC, Khoury MJ. Contribution of birth defects to infant mortality among racial/ethnic minority groups, United States, 1983. In: CDC surveillance summaries, July 1990. MMWR 1990;39(SS-3):1-12.

2. Little J, Elwood JM. Epidemiology of neural tube defects. In: Kiley M, ed. Reproductive and perinatal epidemiology. Boca Raton, Florida: CRC Press, 1991:251-336.

3. MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet 1991;338:131-7.

4. International Clearinghouse for Birth Defects Monitoring Systems. Congenital malformations worldwide: a report from the International Clearinghouse for Birth Defects Monitoring Systems. Amsterdam: Elsevier, 1991:41-51.

5. CDC. Economic burden of spina bifida--United States, 1980-1990. MMWR 1989;38:264-7.

6. Anonymous. Folic acid and neural tube defects (Editorial). Lancet 1991;338:153-4.

7. Khoury MJ, Erickson JD, James LM. Etiologic heterogeneity of neural tube defects: clues from epidemiology. Am J Epidemiol 1982;115:538-48.

8. Khoury MJ, Erickson JD, James LM. Etiologic heterogeneity of neural tube defects. II. Clues from family studies. Am J Hum Genet 1982;34:980-7.

9. Smithells RW, Sheppard S, Schorah CJ, et al. Apparent prevention of neural tube defects by periconceptional vitamin supplementation. Arch Dis Child 1981;56:911-8. 10. Bower C, Stanley FJ. Dietary folate as a risk factor for neural tube defects: evidence from a case-control study in Western Australia. Med J Aust 1989;150:613-9. 11. Milunsky A, Jick H, Jick SS, et al. Multivitamin/folic acid supplementation in early pregnancy reduces the prevalence of neural tube defects. JAMA 1989;262:2847-52. 12. Mulinare J, Cordero JF, Erickson JD, Berry RJ. Periconceptional use of multivitamins and the occurrence of neural tube defects. JAMA 1988;260:3141-5.

13. National Research Council. Recommended dietary allowances: report of the Committee on Dietary Allowances, Food and Nutrition Board, Division of Biological Sciences, Assembly of Life Sciences. 10th ed. Washington, DC: National Academy Press, 1989. *The multivitamin preparation contained vitamin A, 4000 U; vitamin D, 400 U; vitamin B1, 1.5 mg; vitamin B2, 1.5 mg; vitamin B6, 1.0 mg; vitamin C, 40 mg; and nicotinamide, 15 mg.

Interim CDC Recommendations for Folic Acid Supplementation for Women who have had an Infant or Fetus with Spina Bifida, Anencephaly, or Encephalocele -- August 1991

1. Women who have had a pregnancy resulting in an infant or fetus with a neural tube defect should be counseled about the increased risk in subsequent pregnancies and should be advised that folic acid supplementation may substantially reduce the risk for neural tube defects in subsequent pregnancies.

2. Women who have had a pregnancy resulting in an infant or fetus with a neural tube defect should be advised to consult their physician as soon as they plan a pregnancy. Unless contraindicated, they should be advised to take 4 mg per day of folic acid starting at the time they plan to become pregnant. Women should take the supplement from at least 4 weeks before conception through the first 3 months of pregnancy.

3. The 4 mg daily dose should be taken only under a physician's supervision. Tablets containing 1 mg folic acid are available as a prescription item. The folic acid dose should be obtained from pills containing only folic acid. Multivitamin (over-the-counter and prescription) preparations containing folic acid should not be used to attain the 4 mg dose because harmful levels of vitamins A and D could also be taken. Prescribing physicians should be aware of the potential for high doses of folic acid to complicate the diagnosis of vitamin B12 deficiency. Anemia resulting from vitamin B12 deficiency may be prevented with high doses of folic acid; however, the neurologic damage that can result from vitamin B12 deficiency could continue.

4. These recommendations are provided only for women who previously have given birth to an infant or had a fetus with a neural tube defect; they are not intended for 1) women who have never given birth to an infant or had a fetus with a neural tube defect, 2) relatives of women who have had an infant or fetus with a neural tube defect, 3) women who themselves have spina bifida, or 4) women who take the anticonvulsant valproic acid--a known cause of spina bifida.

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