Embargoed Until August 1, 1997
July 30, 1997
Contact:
Moira Saucer
(202) 872-1477
BENEFITS OF SUPPLEMENTS ARE RECOGNIZED; RELEVANCE OF DISSOLUTION TEST NEEDS STUDY
The scientific literature amply demonstrates the effectiveness of supplementation with multivitamins containing folic acid (a B vitamin). Numerous studies confirm that women who take multivitamins before they become pregnant, and very early in pregnancy, have a much lower chance of having a baby born with a birth defect such as spina bifida. The evidence of effectiveness is so strong that the U.S. Public Health Service in 1992 recommended that all women "who are capable of becoming pregnant should consume 0.4 milligrams of folic acid per day."
During pregnancy, almost all American women are advised by their doctors to take a prenatal multivitamin. A recent study confirmed that women taking prenatal multivitamins had higher blood levels of folic acid and a lower risk of having a preterm delivery or a low birth weight baby. In addition, taking a multivitamin with folic acid may help protect the general population against heart disease and stroke.
The July-August issue of the Journal of the American Pharmaceutical Association reports that six out of nine prenatal multivitamins failed a dissolution test developed by the U.S. Pharmacopeia (USP). However, the authors acknowledge that no correlation has been demonstrated between the USP dissolution test and actual human bioavailability of a multivitamin or other dietary supplement product containing folic acid. Studies have shown that multivitamin users have higher levels of folic acid in their blood and that they obtain health benefits from their supplements. (See attached summary of findings of some of these studies.)
"According to USP, none of the products tested in this study are required to meet a folic acid dissolution test," said Annette Dickinson, Ph.D., CRN's Director of Scientific and Regulatory Affairs. (See discussion of technical aspects of USP test requirements, attached.)
"Furthermore, there is controversy about this particular test. The methodology was extensively discussed at an April meeting of the USP Advisory Panel on Analytical Methods for Nonprescription Drugs and Nutritional Supplements, and additional data was requested from members of the advisory panel," added Dickinson. At that meeting, USP laboratory staff discussed the results of some modifications to the method, and company representatives indicated that test results were affected by the pH (acidity) of the medium and by interference by other components (excipients as well as other nutrients, especially minerals, in the formulation).
"Everyone wants the same thing æwe all want the products to work. The scientific evidence shows that multivitamins are working. People who take them have higher blood levels of nutrients, and have specific health benefits. Now we need to make a better connection between that recognized effectiveness and the USP test method. Our members will continue to work with USP to accomplish this," said John Cordaro, CRN's President and Chief Executive Officer.
Ralph Shangraw, Ph.D., of the University of Maryland, one of the co-authors of the dissolution study and Chairman of the USP Subcommittee that developed the test, said, "CRN's member companies have been very cooperative in working with USP to develop and improve products and test methods, and I look forward to working with all industry members to resolve this important issue."
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SUMMARY OF SOME STUDIES SHOWING HEALTH BENEFITS OF FOLIC ACID IN MULTIVITAMINS, AND SHOWING INCREASES IN BLOOD LEVELS OF NUTRIENTS IN PEOPLE WHO USE MULTIVITAMINS
WOMEN IN MINNESOTA:
Red cell folate levels in women in Minnesota were 50 percent higher in supplement users than in nonusers. The women were enrolled in a special project to study prenatal risk factors, and were attempting to become pregnant.
Red cell folate, women not taking supplements: 616 nmol/L
Red cell folate, women taking supplements: 983 nmol/L
Brown, et al. JAMA 1997; 277:548-552.
WOMEN IN NEW JERSEY:
Women who used prenatal multivitamins had increased blood levels of folic acid and ferritin. Women who did not use prenatal supplements were twice as likely to have low birth weight babies or preterm delivery.
Scholl, et al. Am J Epidemiol 1997; 146:134-141.
WOMEN IN CALIFORNIA:
(1) Twenty-five to 50 percent reduced risk of cleft palate and/or cleft lip in babies born in California to women who used multivitamins containing folic acid from one month before through two months after conception. Shaw, et al. Lancet 1995; 345:393-396.
(2) Thirty-five percent reduced risk of neural tube birth defects (NTDs) in babies born in California to women who used a vitamin containing folic acid in the three months before conception.
Shaw, et al. Epidemiology 1995; 6:219-226.
META-ANALYSIS OF 38 STUDIES:
Many studies show that folic acid supplements may reduce the risk of heart attack and stroke. People who take supplements of folic acid have substantially increased blood levels of folic acid. People who have higher blood folic acid levels have lower homocysteine levels and a lower risk of cardiovascular disease. Tens of thousands of deaths from cardiovascular disease every year could be avoided if people obtained adequate amounts of folic acid.
Boushey, et al. JAMA 1995; 274:1049-1057.
PEOPLE IN PORTLAND:
Serum folate levels were twice as high in multivitamin users as in nonusers, and homocysteine levels were lower. Additional supplementation with 1 or 2 milligrams of folic acid had more of an effect in nonusers than in users (since users were already getting an effect from their multivitamins).
Malinow, et al. Arterioscler Thromb Vasc Biol 1997; 17:1157-1162.
HEALTHY ELDERLY IN NEW MEXICO:
Blood folate levels in supplement users were about twice as high as in nonusers, in a group of healthy elderly in New Mexico. People with high levels of B vitamins had lower levels of homocysteine, indicating a lower risk of cardiovascular disease. Koehler, et al. J Am College Nutr 1996; 15:364-376.
ELDERLY SURVIVORS OF FRAMINGHAM COHORT:
Blood folate levels strongly related to folate intake in 1160 elderly survivors of the Framingham cohort. People with high folate levels had lower homocysteine levels, suggesting a lower risk of cardiovascular disease. Selhub, et al. JAMA 1993; 270:2693-2698.
WOMEN IN BOSTON, PHILADELPHIA, TORONTO:
Sixty percent reduced risk of NTDs in babies born to women in Boston, Philadelphia, and Toronto, if the women used a multivitamin with folic acid at least one month before and one month after conception. Werler, et al. JAMA 1993; 269:1257-1261.
WOMEN IN HUNGARY:
A prenatal multivitamin with minerals was given to over 7,500 young women planning a pregnancy. There were no babies with neural tube birth defects born to women given the multivitamin, compared to six in the control group.
Czeizel, et al. NEJM 1992; 327:1832-1835.
WOMEN IN GEORGIA:
Sixty percent reduced risk of NTDs in babies born in Georgia to women who used a multivitamin three months before and three months after conception. Mulinare, et al. JAMA 1988; 260:3141-3145.
WOMEN IN BOSTON:
Seventy-three percent reduced risk of NTDs in babies born to women in Boston who took multivitamins with folic acid during the first six weeks of pregnancy.
Milunsky, et al. JAMA 1989; 262:2847-2852.
TECHNICAL DETAILS OF THE USP DISSOLUTION REQUIREMENT
U.S. Pharmacopeia (USP) requirements for dissolution testing of vitamins and minerals vary according to the product and the label claims made on the product. It appears that none of the products tested by the authors of this article were required under USP to meet a folic acid dissolution test.
For prescription prenatal multivitamins, the USP requirement would be to test dissolution of the official "index vitamin," which is riboflavin (vitamin B-2), not folic acid. According to the article, the products tested in this study were all prescription prenatal multivitamins.
Multivitamins marketed as dietary supplements (as opposed to drug products) do not have to meet any USP requirements, unless their labels state that they comply with USP standards. If they are labeled as USP products, then they must meet the USP dissolution requirement, with riboflavin (not folic acid) as the index vitamin. According to the article, none of the products tested by the authors of this article were labeled "USP."
Folic acid dissolution testing is required under USP only if the product labeling for a multivitamin or a folic acid supplement includes a "health claim" regarding the relationship between folic acid and the risk of neural tube birth defects. None of the products tested had such a "health claim."
When USP began developing standards for vitamins and minerals in 1990, there was considerable controversy about the particular standards proposed by USP for disintegration and dissolution. Disintegration is a measure of whether a tablet "falls apart." Dissolution is a measure of whether a certain percentage of a nutrient in the tablet actually gets dissolved in a fluid, within a certain period of time. For multivitamins, USP requires that 75 percent of the assayed amount of the index vitamin (riboflavin) should be dissolved within 60 minutes. (If a health claim is made and folic acid is tested, this requirement would relate to the labeled amount, rather than the assayed amount.) The USP method requires that the product dissolve in an acid solution at physiological strength (or in water, in the case of folic acid).
Scientific studies were sponsored by the industry to determine whether there was any correlation between a product's performance on the USP disintegration or dissolution test and its actual bioavailability in humans. Nutrients analyzed included vitamin C and riboflavin. Formulations that performed well on disintegration and dissolution tests were not necessarily the ones best absorbed in the body. The implications of these findings are still being discussed.
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