Folic Acid and the Prevention of Neural-Tube Defects
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《新英格兰医药杂志》
To the Editor: In his Perspective article on folic acid and the prevention of neural-tube defects, Wald (Jan. 8 issue)1 overestimates the amount of folic acid needed to achieve blood folate levels that provide protection against neural-tube defects. The one study2 that actually measured folate levels in affected pregnancies showed a "dose response" curve, with most of the benefit occurring in women with low red-cell folate levels. The current fortification regimen has increased red-cell folate levels by approximately 50 percent and thus should be preventing many folate-related neural-tube defects.
Wald's statement that rates of neural-tube defects in the United States have dropped by approximately 20 percent since the implementation of food fortification is an underestimate.3 Most U.S. studies had only limited data on prenatally diagnosed cases of neural-tube defects, which account for the majority of cases. In Canada, where excellent data are available on prenatally and postnatally diagnosed cases (and where fortification is almost identical), several studies have shown a reduction of 50 percent in cases of neural-tube defects. Therefore, women's current intake of approximately 200 μg of folic acid per day may be close to the amount needed to reach the goal: preventing 50 to 70 percent of neural-tube defects.
Many randomized trials are under way to determine whether folic acid can prevent vascular disease. Its therapeutic benefit is not established. In fact, a large, randomized clinical trial recently showed that high-dose folic acid with pyridoxine and cobalamin lowered homocysteine levels but had no effect with regard to the prevention of recurrent cerebral infarction, coronary heart disease, or death.4
Anemia is an important clue to the diagnosis of vitamin B12 deficiency. Our study5 showed that current levels of exposure to folic acid have not increased the risk of masking of anemia; our study does not indicate that higher levels would be safe.
James L. Mills, M.D.
Caroline C. Signore, M.D.
National Institute of Child Health and Human Development
Bethesda, MD 20892
References
Wald NJ. Folic acid and the prevention of neural-tube defects. N Engl J Med 2004;350:101-103.
Daly LE, Kirke PN, Molloy A, Weir DG, Scott JM. Folate levels and neural tube defects: implications for prevention. JAMA 1995;274:1698-1702.
Mills JL, England L. Food fortification to prevent neural tube defects: is it working? JAMA 2001;285:3022-3023.
Toole JF, Malinow MR, Chambless LE, et al. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA 2004;291:565-575.
Mills JL, Von Kohorn I, Conley MR, et al. Low vitamin B-12 concentrations in patients without anemia: the effect of folic acid fortification of grain. Am J Clin Nutr 2003;77:1474-1477.
To the Editor: Wald's call for increased folate fortification concerns us for a number of reasons. By assuming that plasma folate levels plateaued after three weeks of folate supplementation, Wald's model underestimates the effect of fortification on plasma folate levels. Rather than leading to a 20 percent decrease in neural-tube defects, as Wald suggests, fortification should have decreased neural-tube defects by 45 percent. The disparity between Wald's model and the observed effects of folate supplementation may be explained in part by the fact that women who take supplements (approximately 30 percent of women), eat fortified breakfast cereals, or both would be expected to benefit less from fortification. Concurrently, Wald's model assumes that the population enrolled in the Medical Research Council (MRC) Vitamin Study and the U.S. population are comparable (e.g., genetically and nutritionally).
In addition, folate alone may not optimally prevent neural-tube defects. Cosupplementation with other vitamins (i.e., cobalamin and vitamin B6) may prove more beneficial than further increasing folate intake. For example, plasma homocysteine concentrations in women with 5,10-methylenetetrahydrofolate polymorphisms — those who are most vulnerable to pregnancies involving neural-tube defects — appear to be more dependent on cobalamin than homocysteine concentrations in women with the wild-type gene.1
Eoin P. Quinlivan, Ph.D.
Jesse F. Gregory III, Ph.D.
University of Florida
Gainesville, FL 32611-0370
eoin_quinlivan@ireland.com
References
Bailey LB, Duhaney RL, Maneval DR, et al. Vitamin B12 status is inversely associated with plasma homocysteine in young women with C677T and/or A1298C methylenetetrahydrofolate reductase polymorphisms. J Nutr 2002;132:1872-1878.
To the Editor: Dr. Wald reports on his important calculation regarding the dose–response relation between folic acid and neural-tube defects. I cannot agree with his recommendation that all women planning a pregnancy take 5 mg of folic acid daily.
My colleagues and I followed about 14,000 pregnant women, and 2 patients with epilepsy who took 1 mg and 6 mg of folic acid had status epilepticus during the second part of the pregnancy.1 In addition, both the population-based Hungarian Case–Control Surveillance of Congenital Abnormalities2 and Swedish Medical Birth Registry3 studies showed an increased rate of twins after the use of a pharmacologic dose (more than 1 mg) of folic acid, but a similar increase was not found after the use of 0.4 mg of folic acid.4
Andrew E. Czeizel, Ph.D., D.Med.Sci.
Foundation for the Community Control of Hereditary Diseases
1026 Budapest, Hungary
References
Er?s E, Géher P, G?m?r B, Czeizel AE. Epileptogenic activity of folic acid after drug induces SLE (folic acid and epilepsy). Eur J Obstet Gynecol Reprod Biol 1998;80:75-78.
Czeizel AE, Vargha P. Periconceptional folic acid/multivitamin supplementation and twins. Am J Obstet Gynecol (in press).
Ericson A, Kallen B, Aberg A. Use of multivitamins and folic acid in early pregnancy and multiple births in Sweden. Twin Res 2001;4:63-66.
Li Z, Gindler J, Wang H, et al. Folic acid supplements during early pregnancy and likelihood of multiple births: a population-based cohort study. Lancet 2003;361:380-384.
Dr. Wald replies: Mills and Signore and Quinlivan and Gregory question the recommendation of higher folate-supplementation levels. Data suggest that increasing the fortification level in North America (say, to 0.4 mg daily, as in Chile) would prevent more neural-tube defects. Current folic acid fortification (an extra 0.2 mg daily) has reduced rates of neural-tube defects in the United States by about 20 percent; the rates have been reduced by about 50 percent in case–control studies (with the use of 0.4 mg of folic acid), and by more than 80 percent in the MRC trial (with 4 mg) in women with a previous pregnancy involving a neural-tube defect who took supplements before pregnancy.1 These observations support the model cited.2 In this model, the reduction in neural-tube defects is greater with a lower background serum folate level. The higher underlying Canadian rates of neural-tube defects suggest lower background folate levels, and this might explain the greater effect observed in the Canadian provincial studies than in the U.S. study. The U.S. estimate is based on stable underlying rates and larger numbers, and it is corroborated by data on women presenting in the third trimester, who neither were screened nor had termination of pregnancy, making chance and confounding unlikely.
A 4-mg or 5-mg folic acid supplement daily is advised for women with a previous pregnancy involving a neural-tube defect. Recommending a lower level of supplementation (1/10) for other women is illogical. The higher dose was safe in the MRC trial, and the absence of health alerts, despite the use in practice of a 4-mg or 5-mg dose to prevent recurrent neural-tube defects, provides reassurance.
Anticonvulsant agents can increase the risk of neural-tube defects. Therefore, pregnant patients who have epilepsy need closer anticonvulsant controls; a 5-mg dose of folic acid is prudent. Although Czeizel notes possible concerns, the presence of two cases of status epilepticus among 14,000 pregnant women is not evidence of toxicity. The China–Centers for Disease Control and Prevention study provides strong evidence against a link between folic acid and twinning.3 Reported associations may be spurious, since assisted reproduction causes twinning and women who avail themselves of assisted reproduction are more likely than other women to take folic acid. Fortification in North America has not masked the anemia of vitamin B12 deficiency, but since anemia is absent in about 28 percent of patients with vitamin B12–associated neuropathy,4 serum vitamin B12 levels should be measured in all patients with relevant neurologic symptoms, whether or not they have anemia.
Although in the Vitamin Intervention for Stroke Prevention trial, cited by Mills and Signore, the estimated relative risks were 1.0 (95 percent confidence interval, 0.8 to 1.3) for stroke and 0.9 (95 percent confidence interval, 0.7 to 1.2) for ischemic heart disease in the group randomly assigned to receive 0.4 mg of folic acid, the confidence intervals include the expected 17 percent decrease in stroke and 11 percent decrease in ischemic heart disease events for the observed reduction of 2 μmol of serum homocysteine per liter derived from a meta-analysis of observational studies.5 The results of this trial are consistent with the expected preventive effects of folic acid, as well as with no effect.
Nicholas J. Wald, D.Sc., F.R.C.P.
Wolfson Institute of Preventive Medicine
London EC1M 6BQ, United Kingdom
n.j.wald@qmul.ac.uk
References
MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet 1991;338:132-137.
Wald NJ. Folic acid and the prevention of neural-tube defects. N Engl J Med 2004;350:101-103.
Li Z, Gindler J, Wang H, et al. Folic acid supplements during early pregnancy and likelihood of multiple births: a population-based cohort study. Lancet 2003;361:380-384.
Lindenbaum J, Healton EB, Savage DG, et al. Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N Engl J Med 1988;318:1720-1728.
Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ 2002;325:1202-1202.
Wald's statement that rates of neural-tube defects in the United States have dropped by approximately 20 percent since the implementation of food fortification is an underestimate.3 Most U.S. studies had only limited data on prenatally diagnosed cases of neural-tube defects, which account for the majority of cases. In Canada, where excellent data are available on prenatally and postnatally diagnosed cases (and where fortification is almost identical), several studies have shown a reduction of 50 percent in cases of neural-tube defects. Therefore, women's current intake of approximately 200 μg of folic acid per day may be close to the amount needed to reach the goal: preventing 50 to 70 percent of neural-tube defects.
Many randomized trials are under way to determine whether folic acid can prevent vascular disease. Its therapeutic benefit is not established. In fact, a large, randomized clinical trial recently showed that high-dose folic acid with pyridoxine and cobalamin lowered homocysteine levels but had no effect with regard to the prevention of recurrent cerebral infarction, coronary heart disease, or death.4
Anemia is an important clue to the diagnosis of vitamin B12 deficiency. Our study5 showed that current levels of exposure to folic acid have not increased the risk of masking of anemia; our study does not indicate that higher levels would be safe.
James L. Mills, M.D.
Caroline C. Signore, M.D.
National Institute of Child Health and Human Development
Bethesda, MD 20892
References
Wald NJ. Folic acid and the prevention of neural-tube defects. N Engl J Med 2004;350:101-103.
Daly LE, Kirke PN, Molloy A, Weir DG, Scott JM. Folate levels and neural tube defects: implications for prevention. JAMA 1995;274:1698-1702.
Mills JL, England L. Food fortification to prevent neural tube defects: is it working? JAMA 2001;285:3022-3023.
Toole JF, Malinow MR, Chambless LE, et al. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA 2004;291:565-575.
Mills JL, Von Kohorn I, Conley MR, et al. Low vitamin B-12 concentrations in patients without anemia: the effect of folic acid fortification of grain. Am J Clin Nutr 2003;77:1474-1477.
To the Editor: Wald's call for increased folate fortification concerns us for a number of reasons. By assuming that plasma folate levels plateaued after three weeks of folate supplementation, Wald's model underestimates the effect of fortification on plasma folate levels. Rather than leading to a 20 percent decrease in neural-tube defects, as Wald suggests, fortification should have decreased neural-tube defects by 45 percent. The disparity between Wald's model and the observed effects of folate supplementation may be explained in part by the fact that women who take supplements (approximately 30 percent of women), eat fortified breakfast cereals, or both would be expected to benefit less from fortification. Concurrently, Wald's model assumes that the population enrolled in the Medical Research Council (MRC) Vitamin Study and the U.S. population are comparable (e.g., genetically and nutritionally).
In addition, folate alone may not optimally prevent neural-tube defects. Cosupplementation with other vitamins (i.e., cobalamin and vitamin B6) may prove more beneficial than further increasing folate intake. For example, plasma homocysteine concentrations in women with 5,10-methylenetetrahydrofolate polymorphisms — those who are most vulnerable to pregnancies involving neural-tube defects — appear to be more dependent on cobalamin than homocysteine concentrations in women with the wild-type gene.1
Eoin P. Quinlivan, Ph.D.
Jesse F. Gregory III, Ph.D.
University of Florida
Gainesville, FL 32611-0370
eoin_quinlivan@ireland.com
References
Bailey LB, Duhaney RL, Maneval DR, et al. Vitamin B12 status is inversely associated with plasma homocysteine in young women with C677T and/or A1298C methylenetetrahydrofolate reductase polymorphisms. J Nutr 2002;132:1872-1878.
To the Editor: Dr. Wald reports on his important calculation regarding the dose–response relation between folic acid and neural-tube defects. I cannot agree with his recommendation that all women planning a pregnancy take 5 mg of folic acid daily.
My colleagues and I followed about 14,000 pregnant women, and 2 patients with epilepsy who took 1 mg and 6 mg of folic acid had status epilepticus during the second part of the pregnancy.1 In addition, both the population-based Hungarian Case–Control Surveillance of Congenital Abnormalities2 and Swedish Medical Birth Registry3 studies showed an increased rate of twins after the use of a pharmacologic dose (more than 1 mg) of folic acid, but a similar increase was not found after the use of 0.4 mg of folic acid.4
Andrew E. Czeizel, Ph.D., D.Med.Sci.
Foundation for the Community Control of Hereditary Diseases
1026 Budapest, Hungary
References
Er?s E, Géher P, G?m?r B, Czeizel AE. Epileptogenic activity of folic acid after drug induces SLE (folic acid and epilepsy). Eur J Obstet Gynecol Reprod Biol 1998;80:75-78.
Czeizel AE, Vargha P. Periconceptional folic acid/multivitamin supplementation and twins. Am J Obstet Gynecol (in press).
Ericson A, Kallen B, Aberg A. Use of multivitamins and folic acid in early pregnancy and multiple births in Sweden. Twin Res 2001;4:63-66.
Li Z, Gindler J, Wang H, et al. Folic acid supplements during early pregnancy and likelihood of multiple births: a population-based cohort study. Lancet 2003;361:380-384.
Dr. Wald replies: Mills and Signore and Quinlivan and Gregory question the recommendation of higher folate-supplementation levels. Data suggest that increasing the fortification level in North America (say, to 0.4 mg daily, as in Chile) would prevent more neural-tube defects. Current folic acid fortification (an extra 0.2 mg daily) has reduced rates of neural-tube defects in the United States by about 20 percent; the rates have been reduced by about 50 percent in case–control studies (with the use of 0.4 mg of folic acid), and by more than 80 percent in the MRC trial (with 4 mg) in women with a previous pregnancy involving a neural-tube defect who took supplements before pregnancy.1 These observations support the model cited.2 In this model, the reduction in neural-tube defects is greater with a lower background serum folate level. The higher underlying Canadian rates of neural-tube defects suggest lower background folate levels, and this might explain the greater effect observed in the Canadian provincial studies than in the U.S. study. The U.S. estimate is based on stable underlying rates and larger numbers, and it is corroborated by data on women presenting in the third trimester, who neither were screened nor had termination of pregnancy, making chance and confounding unlikely.
A 4-mg or 5-mg folic acid supplement daily is advised for women with a previous pregnancy involving a neural-tube defect. Recommending a lower level of supplementation (1/10) for other women is illogical. The higher dose was safe in the MRC trial, and the absence of health alerts, despite the use in practice of a 4-mg or 5-mg dose to prevent recurrent neural-tube defects, provides reassurance.
Anticonvulsant agents can increase the risk of neural-tube defects. Therefore, pregnant patients who have epilepsy need closer anticonvulsant controls; a 5-mg dose of folic acid is prudent. Although Czeizel notes possible concerns, the presence of two cases of status epilepticus among 14,000 pregnant women is not evidence of toxicity. The China–Centers for Disease Control and Prevention study provides strong evidence against a link between folic acid and twinning.3 Reported associations may be spurious, since assisted reproduction causes twinning and women who avail themselves of assisted reproduction are more likely than other women to take folic acid. Fortification in North America has not masked the anemia of vitamin B12 deficiency, but since anemia is absent in about 28 percent of patients with vitamin B12–associated neuropathy,4 serum vitamin B12 levels should be measured in all patients with relevant neurologic symptoms, whether or not they have anemia.
Although in the Vitamin Intervention for Stroke Prevention trial, cited by Mills and Signore, the estimated relative risks were 1.0 (95 percent confidence interval, 0.8 to 1.3) for stroke and 0.9 (95 percent confidence interval, 0.7 to 1.2) for ischemic heart disease in the group randomly assigned to receive 0.4 mg of folic acid, the confidence intervals include the expected 17 percent decrease in stroke and 11 percent decrease in ischemic heart disease events for the observed reduction of 2 μmol of serum homocysteine per liter derived from a meta-analysis of observational studies.5 The results of this trial are consistent with the expected preventive effects of folic acid, as well as with no effect.
Nicholas J. Wald, D.Sc., F.R.C.P.
Wolfson Institute of Preventive Medicine
London EC1M 6BQ, United Kingdom
n.j.wald@qmul.ac.uk
References
MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet 1991;338:132-137.
Wald NJ. Folic acid and the prevention of neural-tube defects. N Engl J Med 2004;350:101-103.
Li Z, Gindler J, Wang H, et al. Folic acid supplements during early pregnancy and likelihood of multiple births: a population-based cohort study. Lancet 2003;361:380-384.
Lindenbaum J, Healton EB, Savage DG, et al. Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N Engl J Med 1988;318:1720-1728.
Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ 2002;325:1202-1202.