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Problems with Folic Acid Dissolution: Public Health Perspective
COMMENTARY
Problems vvith Folic Acid Dissolution: Public Health Perspective by Rosalie Sagraves, PharmD
Folate deficiency during pregnancy can result in serious fetal abnormalities, induding neural tube defects (NTDs) , spontaneous abortions, and intrauterine growth retardation. Case-control studies have shown clearly that folic acid supplementation during pregnancy reduces the incidence of NTDs (spina bifida, anencephaly, encephalocele) and may decrease other potential problems. 1-6 Thus, the study by Hoag et al? in this issue ofJAPhA raises a serious and disturbing question: whether prescriptiononly prenatal multivitamin products meet United States Pharmacopeia (USP) standards that became effective in 1993. These were published in USP 23. 8 ,9 Folic acid deficiency occurs commonly during pregnancy, especially in malnourished women and those not receiving supplementation. In women who require anticonvulsant therapy during pregnancy, the risk of NTDs is increased because these medications produce folate deficiency by interfering with metabolism. 10 Folic acid supplementation during pregnancy decreases NlDs by 50% in infants of women who have no prior history of N1Ds in their other children and by 72% in infants born to women with such a history. 2 The Food and Drug Administration (FDA) believes that adequate folic acid dietaty intake is of such importance-especially in women of child-bearing age-that it has recently approved the addition of folic acid to enriched flour (140 mcg per 100 grams of flour). 11 The Centers for Disease Control and Prevention (CDC) recommends that all women of child-bearing age consume 0.4 mg of folic acid daily from dietary sources and/or vitamin supplementation to ensure maternal and fetal well-being. 12 In the study by Hoag et al., conducted at the University of Maryland at Baltimore, six of nine products failed dissolution tests; this is quite disturbing. Although the study did not address in vivo results, dissolution is accepted as a necessary ftrst step before absorption can occur. Without dissolution, absorption cannot occur, and pregnant women who believe they are receiving adequate amounts of folic acid are in fact at risk of having babies born with serious abnormalities. Furthermore, one must wonder whether other components in these multivitamin preparations are also not dis-
JOumal of the American Pharmaceutical Association
solving. Even if the folic acid problem is solved through food supplementation, which becomes mandatory on January 1, 1998, other important vitamins and minerals may also remain bound in the undissolved tablet matrix. This problem requires study and possibly action by the industry, FDA, CDC, and USP. Until Americans can be sure that prenatal vitamins deliver the amount of nutrients claimed on product labels, our children will be at risk of birth defects that are easily preventable. Rosalie Sagraves, PharmD, FCCP, is dean of the College of Pharmacy, University of Illinois at Chicago, and associate pharmacy editor of Pharmacy Today.
References 1. Centers for Disease Control and Prevention. Surveillance for anencephaly and spina bifida and the impact of prenatal diagnosisUnited States, 1985-1994. MMWR. 1995;44(55-4). 2. MRC Vitamin Study Research Group. Prevention of neural tube defects: result of the Medical Research Council Vitamin Study. Lancet. 1991;338:131-7.
3. Laurence KM, James N, Miller MH, Tennant GB, et al. Increased risk of recurrence of pregnancies complicated by fetal neural tube defects in mothers receiving poor diets, and possible benefit of dietary counseling. Br Med J. 1980;281:1592-4. 4. Mulinare J, Cordero JF, Erickson D, et al. Periconceptional use of multivitamins and the occurrence of neural tube defects. JAMA 1988;260;3131-5. 5. Bower C, Stanley FJ. Dietary folate as a risk factor for neural tube defects: evidence for a case-control study in western Australia. Med
J Austral. 1989;150:613-8. 6. 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. 7. Hoag SW, Ramachandruni H, Shangraw RF. Failure of prescription prenatal vitamin products to meet USP standards for folic acid dissolution. JAm Pharm Assoc. 1997;NS37:397-400. 8. Srinivasan V, Valentino JG, Corken A, Halperin JA Standards setting for nutritional supplements-a new approach. Nutr Today.
1993(Nov/Dec);26-33. 9. U.S. Pharmacopeial Convention, Inc. The United States Pharmacopeia. 23rd rev. 1995:2129-92, and Second Supplement, 1995;283~. 10. Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lacta· tion. 4th ed. Baltimore: Williams & Wilkins, 1994:378-92. 11. U.S. Food and Drug Administration. Food standards: amendment of standard of identity for enriched grain products to require addition of folic acid. Fed Regist. 1996;61:8761-97. 12. Centers for Disease Control and Prevention. Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neu ral tube defects. MMWR. 1992;41 (RR-14): 1-7.
July/August 1997
Vol. NS37,No. 4
Problems vvith Folic Acid Dissolution: Public Health Perspective by Rosalie Sagraves, PharmD
Folate deficiency during pregnancy can result in serious fetal abnormalities, induding neural tube defects (NTDs) , spontaneous abortions, and intrauterine growth retardation. Case-control studies have shown clearly that folic acid supplementation during pregnancy reduces the incidence of NTDs (spina bifida, anencephaly, encephalocele) and may decrease other potential problems. 1-6 Thus, the study by Hoag et al? in this issue ofJAPhA raises a serious and disturbing question: whether prescriptiononly prenatal multivitamin products meet United States Pharmacopeia (USP) standards that became effective in 1993. These were published in USP 23. 8 ,9 Folic acid deficiency occurs commonly during pregnancy, especially in malnourished women and those not receiving supplementation. In women who require anticonvulsant therapy during pregnancy, the risk of NTDs is increased because these medications produce folate deficiency by interfering with metabolism. 10 Folic acid supplementation during pregnancy decreases NlDs by 50% in infants of women who have no prior history of N1Ds in their other children and by 72% in infants born to women with such a history. 2 The Food and Drug Administration (FDA) believes that adequate folic acid dietaty intake is of such importance-especially in women of child-bearing age-that it has recently approved the addition of folic acid to enriched flour (140 mcg per 100 grams of flour). 11 The Centers for Disease Control and Prevention (CDC) recommends that all women of child-bearing age consume 0.4 mg of folic acid daily from dietary sources and/or vitamin supplementation to ensure maternal and fetal well-being. 12 In the study by Hoag et al., conducted at the University of Maryland at Baltimore, six of nine products failed dissolution tests; this is quite disturbing. Although the study did not address in vivo results, dissolution is accepted as a necessary ftrst step before absorption can occur. Without dissolution, absorption cannot occur, and pregnant women who believe they are receiving adequate amounts of folic acid are in fact at risk of having babies born with serious abnormalities. Furthermore, one must wonder whether other components in these multivitamin preparations are also not dis-
JOumal of the American Pharmaceutical Association
solving. Even if the folic acid problem is solved through food supplementation, which becomes mandatory on January 1, 1998, other important vitamins and minerals may also remain bound in the undissolved tablet matrix. This problem requires study and possibly action by the industry, FDA, CDC, and USP. Until Americans can be sure that prenatal vitamins deliver the amount of nutrients claimed on product labels, our children will be at risk of birth defects that are easily preventable. Rosalie Sagraves, PharmD, FCCP, is dean of the College of Pharmacy, University of Illinois at Chicago, and associate pharmacy editor of Pharmacy Today.
References 1. Centers for Disease Control and Prevention. Surveillance for anencephaly and spina bifida and the impact of prenatal diagnosisUnited States, 1985-1994. MMWR. 1995;44(55-4). 2. MRC Vitamin Study Research Group. Prevention of neural tube defects: result of the Medical Research Council Vitamin Study. Lancet. 1991;338:131-7.
3. Laurence KM, James N, Miller MH, Tennant GB, et al. Increased risk of recurrence of pregnancies complicated by fetal neural tube defects in mothers receiving poor diets, and possible benefit of dietary counseling. Br Med J. 1980;281:1592-4. 4. Mulinare J, Cordero JF, Erickson D, et al. Periconceptional use of multivitamins and the occurrence of neural tube defects. JAMA 1988;260;3131-5. 5. Bower C, Stanley FJ. Dietary folate as a risk factor for neural tube defects: evidence for a case-control study in western Australia. Med
J Austral. 1989;150:613-8. 6. 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. 7. Hoag SW, Ramachandruni H, Shangraw RF. Failure of prescription prenatal vitamin products to meet USP standards for folic acid dissolution. JAm Pharm Assoc. 1997;NS37:397-400. 8. Srinivasan V, Valentino JG, Corken A, Halperin JA Standards setting for nutritional supplements-a new approach. Nutr Today.
1993(Nov/Dec);26-33. 9. U.S. Pharmacopeial Convention, Inc. The United States Pharmacopeia. 23rd rev. 1995:2129-92, and Second Supplement, 1995;283~. 10. Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lacta· tion. 4th ed. Baltimore: Williams & Wilkins, 1994:378-92. 11. U.S. Food and Drug Administration. Food standards: amendment of standard of identity for enriched grain products to require addition of folic acid. Fed Regist. 1996;61:8761-97. 12. Centers for Disease Control and Prevention. Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neu ral tube defects. MMWR. 1992;41 (RR-14): 1-7.
July/August 1997
Vol. NS37,No. 4