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This article was originally published in The Tan Sheet

Executive Summary

FOLIC ACID ADVERSE EFFECTS SURVEILLANCE: CDC LOOKING AT TWO- TIER SYSTEM based on Medicare data and follow-up case control studies as one of several approaches that will be presented to FDA's Folic Acid Subcommittee at its next meeting this fall. A joint Food Advisory Committee and Folic Acid Subcommittee meeting is tentatively set for Oct. 25-26 ("The Tan Sheet" Aug. 16, p. 3). The Centers for Disease Control and Prevention convened a meeting of "qualified experts" on Aug. 12 to discuss options for instituting a folic acid surveillance program in response to FDA's interest in allowing folic acid fortification of certain foods as well as a health claim for preventing neural tube defects in newborns. FDA's Folic Acid Subcommittee unanimously recommended in April the establishment of a surveillance system that could measure the positive effect of wider availability of folic acid in the food supply as well as the potential adverse effects of folic acid consumption ("The Tan Sheet" April 19, p.4). However, the CDC panel was unable to reach a consensus on the best way to construct a surveillance mechanism for monitoring potential folic acid adverse effects. CDC's Division of Chronic Disease Control Associate Director for Science John Livengood, MD, indicated that the agency is considering a "crude surveillance system" using a population-based data source such as Medicare that would also make use of "some type of case control or longitudinal follow-up of patients either accrued through the surveillance mechanism or through some of the other alternatives" suggested at the meeting. The panel also discussed adverse effects that could pose severe health risks for certain segments of the population. The panelists were most concerned with the potential for folic acid to "mask" the hematologic manifestations of vitamin B[12] deficiency. The "masking of an anemic presentation," Livengood explained, would delay the diagnosis of pernicious anemia and thereby allow the neurologic conditions caused by pernicious anemia to progress undiagnosed. Other potential concerns expressed by the panel included the risk of folic acid "overdoses" (over 1 mg/day) from a combination of folic acid from dietary sources and supplements, and the risk of potential adverse effects of folic acid on epileptics. During the meeting, the CDC expert panel grappled with the difficulty of establishing a surveillance system that could monitor the masking effect of folic acid. The experts discussed screening for sensory neuropathy, a neurological condition caused by B[12] deficiency, as one monitoring option. However, the panel concluded that the diagnosis of sensory neuropathy would be too broad and, consequently, "would not serve well in terms of a surveillance system" for folic acid-related events, Livengood observed. Livengood also pointed out the difficulty of tracking the "relatively low level of incidence," which he estimated may be "as low as 1,000 people" in the U.S. who have both anemia and neurological effects and are at risk from folic acid in the food supply. "We're dealing with actually a rather small needle in the haystack," he emphasized. Other problems discussed by the panel include the lack of a baseline data source on which to analyze the results of the surveillance system. Without a baseline study, John Scott, PhD, University of Dublin, explained, it will be difficult to "distinguish between those [patients] who have developed a neuropathy [due to fortification] and those who would have developed a neuropathy anyway. So what will happen is folic acid will get blamed for all the cases of neuropathy." The expert panelists debated several surveillance options. Alan Leviton, MD, Harvard Medical School, supported the idea of a "passive surveillance system" based on Medicare cases that would provide baseline data for the surveillance system. However, Clark Heath, MD, American Cancer Society, questioned that approach, stressing that the "case definition" would then be limited to what is "available in the [Medicare] surveillance data source." Another possible "population-based study" suggested by CDC's Health Examination Statistics-Nutrition Branch Division Chief Cliff Johnson would make use of the current National Health and Nutritional Examination Survey as a baseline study. "NHANES III," Johnson continued, "has been designed not only as a baseline cross-sectional survey but as a longitudinal follow-up" that would offer ongoing monitoring. Leviton also proposed controlled, community studies based on HMO data or data from a defined population, such as Hawaii or the Mayo Clinic community, which might provide information for a larger percentage of persons with pernicious anemia than the Medicare data. A CDC backgrounder pointed out, however, that "this advantage would be offset by the relatively small size of the population, which would seriously reduce the statistical power available to track all but the largest changes in occurrence." Panelist Ralph Green, MD, Cleveland Clinic Foundation, reminded the panelists to weigh the "risk/benefit ratio" of folic acid fortification. Scott pointed out that folic acid has "potential benefits" beyond preventing neural tube defects that would benefit "the population as a whole." He suggested that folic acid also "reduces the plasma homocysteine level that . . . has become established as a risk factor for coronary artery disease."

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