Low Clinical Utility of Folate Determinations in Primary Care Setting
March 6, 2013
Shlomo Vinker, MD; Eli Krantman, MD; Michal Shani, MD; and Sasson Nakar, MD
Folic acid is a B group vitamin, essential for DNA synthesis and the metabolism of homocysteine. Folate deficiency has been associated with macrocytic anemia, unfavorable pregnancy outcomes such as low birth weight and neural tube defects, cardiovascular disease, and possibly neoplasms of the colon. Folate deficiency is common during pregnancy; however, it can occur at any age due to a poor diet, malabsorption, alcoholism, or use of certain drugs. The Recommended Dietary Allowance for folic acid is daily, similar to the Reference Nutrient Intake in the United Kingdom. In 1998, the US Food & Drug Administration mandated the fortification of all enriched cereal products with folic acid at a concentration of 140 μg per 100 g of product.1 Follow-up research, using data from the Framingham Offspring Cohort Study, has estimated that the prevalence of folate deficiency has declined dramatically from an estimated 50% to 7%.2,3 Other studies report smaller declines from 4.8% to 0.6%,4 18.4% to 0.2%, or 22% to 1.7%.5 Although fortification of cereal products with folic acid is not mandatory in Israel, many products are fortified, whether imported or locally manufactured. A retrospective review of all folate determinations between January 2004 and February 2007 in the central district of Clalit Health Services (CHS) revealed that only 4.3% of the 43,176 tests ordered were below the norm (5.6 nmol/L). In light of the decreasing prevalence of this vitamin deficiency in the United States and the apparent scarcity of low folic acid levels in Israel, we evaluated the utility of folate determinations in the primary care setting in Israel in individuals with no known predisposition for folate deficiency.
Because determination of serum folate status is regarded as the most appropriate screening test for folate deficiency,6 our objective was to determine whether clinical or laboratory parameters can serve to identify and assist in adequately managing folate-deficient individuals without known predisposing factors for folate deficiency in a community setting.
We conducted a retrospective review of all folate level determinations performed over a 3-year period between January 1, 2004, and January 1, 2007, in 13 large urban clinics in CHS in Israel. Clalit Health Services is the largest health maintenance organization in Israel. It serves more than 50% of the population and more than 70% of the elderly patients. Patient records in CHS have been computerized for more than a decade. These records include demographic data, working diagnoses, medications, laboratory results, hospitalizations, referrals, and administrative data. All laboratory tests are sent to a central laboratory, and the results are electronically entered in the patient’s medical record. We reviewed the charts of all patients between 17 and 75 years of age who had low serum folate levels (<5.6 nmol/L).
We excluded patients who required folic acid monitoring or were at risk of folate deficiency, such as those with a known malabsorption disorder, mental retardation, or schizophrenia; those residing in an old age home or other institution; pregnant women; hemodialysis patients; and those treated with anti-epileptics or methotrexate.
We further divided this group into 2 subgroups: patients with anemia and patients without anemia. Anemia was defined as a hemoglobin level below /dL in men and below /dL in women. A control group with normal serum folate levels was matched by sex, age group, clinic location, and anemia status.
We reviewed the electronic medical records in search of possible indications for folic acid measurement and whether folate-deficient patients were prescribed a folate supplement. Indications were classified into the following 5 groups: routine evaluation, anemia workup, macrocytosis or macrocytic anemia workup, gastrointestinal symptoms, and neurologic symptoms. In cases where folate determinations were sent by consultants, this was recorded, and when possible, the indication was noted. If obtained, results of hemoglobin, hematocrit, red blood cell indices, ferritin, iron, transferrin, transferrin saturation, and vitamin B12 tests were reviewed as well.
We used the statistical software Epi Info 2002 (Centers for Disease Control and Prevention, Atlanta, Georgia). Because we expected the majority of folic acid tests to be in the normal range, we matched each case of folate deficiency with 4 subjects who had normal folate values. We chose a sample that allowed us to find the incidence of this phenomenon (change in diagnosis) with statistical significance of P <.05 and an incidence power of 80%. Relying on these assumptions, the minimal sample size was 54 patients in the research group and 216 in the control group.
Single variable comparisons of the patients’ characteristics were performed using the x2 test to compare noncontinuous variables (eg, sex, clinical indication for folate determination, physician actions) and analysis of variance and the t test for comparison of the continuous variables (eg, age, serum folate level). We used a multinomial logistic regression model controlling for anemia status, age, and sex to compare laboratory parameters between folate-deficient cases and controls.
A total of 152 folate-deficient subjects (37 with anemia) fulfilled the inclusion criteria, and we matched them with 556 controls (141 with anemia). Demographic characteristics were similar in both groups (Table 1).
Table 2 shows the laboratory values for folate-deficient cases and controls. Hematologic indices, including mean cell volume, were similar in both groups. We performed a separate analysis comparing the laboratory results for all folate- deficient individuals with those of a randomly selected matched group of individuals with normal folate status who were not matched on anemia status (n = 4910). The results of this analysis (Table 3) also show no differences in laboratory parameters between folate-deficient cases and controls.
Indications for Folate Determinations
Overall, the indications for folate status determinations did not differ between the 2 groups (Table 4). When all folate-deficient cases were compared with all controls, no specific indication was found more often in the folate-deficient group than in the control group. When the groups with anemia were compared, the test was sent as part of an anemia workup at the same rate in both the folate-deficient and control groups (51% vs 48%, respectively; P >.05). Similar results were seen when the test was performed for other indications or as a request for periodic blood tests by the patient (22% for folate-deficient cases vs 28% for controls; P >.05). In the groups without anemia, the test was sent as part of a routine workup in 53% of folate-deficient cases compared with 46% of those with normal folate status (P = .154).
Physician Response to Folate Deficiency
The files of all individuals with folic acid deficiency were examined to see whether the deficiency was properly addressed by either documenting the deficiency or administratingfolic acid supplements. Patients with a folic acid level below the norm were prescribed a folate supplement in 68 of 152 (44.7%) cases; in only 1 case the file was updated with a diagnosis of folic acid deficiency without prescription of a folate supplement.
Laboratory determinations of serum folate status are commonly obtained in adult primary care as part of the evaluation of anemia, whether macrocytic or not; nutritional status; and other clinical scenarios.7 Although regarded as the most appropriate screening test for folate deficiency, true folic acid deficiency is rarely detected in clinical practice.8 There are no clear guidelines in Israel regarding folate status determinations. Among our goals was to inquire into why the test is ordered so often and whether such guidelines could possibly be formulated based on the results.
In the era of folate fortification, the utility of this test is questionable.9 In this sample only 4.3% of tests were positive for folate deficiency over a 3-year period. Hematologic indices were not helpful in distinguishing folate-deficient patients from their controls. This finding was consistent in both subgroup analyses based on anemia status. As noted in previous studies, evaluations of elevated mean cell volume could not identify patients with folate deficiency,4,8,10 thus suggesting that macrocytosis alone should no longer be considered an indication for folate status evaluation. Our results suggest low serum iron levels may serve as an indicator of folate deficiency, possibly as a marker of nutrition deficiencies, although other parameters of iron metabolism such as transferrin saturation and ferritin levels do not support such a correlation.
Concerns that this analysis was confounded by matching groups based on anemia status prompted us to perform an additional analysis comparing the folate-deficient group with a separately matched control group, regardless of anemia status. The results of this analysis reinforce those of the primary analysis, showing that laboratory indices are incapable of identifying folate-deficient patients.
Clinical presentation did not differ between the 2 groups. Tests that were part of a clinical workup were ordered at similar rates among both groups. Among the symptoms which prompted doctors to send folate determinations were abdominal pain; those suggestive of malabsorption, inflammatory bowel disease, or peptic ulcer disease; and those suggestive of possible vitamin deficiencies such as aphthous stomatitis or alopecia. Based on previous studies, there is little evidence that alopecia is caused by folic acid deficiency11,12 and the role of folic acid in aphthous stomatitis is debatable.13
Fewer than half of the folate-deficient patients received a prescription for folate supplementation. We presume that when tests are ordered without a clear clinical indication or without laboratory parameters suggesting folate deficiency, there may be a tendency to mistakenly overlook the results. Assuming our study represents the general population without known risk factors for folate deficiency, only 1.9% of all folate tests in our district resulted in a change in management. In their studies, Robinson and Mladenovic9 and Latif and colleagues8 suggest empiric folate supplementation as an alternative to ordering determinations of folic acid status. It may be unethical to prescribe vitamins that a patient may not require. In light of recent studies that question the safety of folate supplementation,14,15 this approach may not be appropriate. Furthermore, doing so would require pretreatment evaluation of cobalamin status and supplementation as required in order to avoid a masked cobalamin deficiency.
Neither laboratory parameters nor clinical findings in patients’ charts were capable of distinguishing folate deficiency in patients without known risk factors in comparison with controls. The low response rate of physicians to the test results further cast doubt on the utility of this test. The diagnostic value of a broad screening strategy is limited for conditions such as folate deficiency that are not prevalent in the general population. For the 152 cases that were found deficient, there may be clinical significance to the findings. The fact that only half of them were prescribed a folate supplement speaks to a separate issue of how physicians respond to abnormal laboratory values. The findings in our study reinforce our belief that either limiting folate tests to cases suggestive of nutritional deficiencies or providing empiric folic acid treatment in such cases will reduce unnecessary laboratory tests. We recommend to the Israeli Task Force for Preventive Medicine incorporation of such a policy when formulating guidelines for folate status determinations.
1. Food standards: amendment of standards of identity for enriched grain products to require addition of folic acid. Final rule. Fed Regist. 1996;61(44):8781-8797.
2. Choumenkovitch SF, Selhub J, Wilson PW, Rader JI, Rosenberg IH, Jacques PF. Folic acid intake from fortification in United States exceeds predictions. J Nutr. 2002;132(9):2792-2798.
3. Jacques PF, Selhub J, Bostom AG, Wilson PW, Rosenberg IH. The effect of folic acid fortification on plasma folate and total homocysteine concentrations. New Engl J Med. 1999;340(19):1449-1454.
4. Joelson DW, Fiebig EW, Wu AH. Diminished need for folate measurements among indigent populations in the post folic acid supplementation era. Arch Pathol Lab Med. 2007;131(3):477-480.
5. Selhub J, Jacques PF, Bostom AG, Wilson PW, Rosenberg IH. Relationship between plasma homocysteine and vitamin status in the Framingham study population: impact of folic acid fortification. Public Health Rev. 2000;28(1-4):117-145.
6. Galloway M, Rushworth L. Red cell or serum folate? results from the National Pathology Alliance benchmarking review. J Clin Pathol. 2003;56(12):924-926.
7. Bailey RL, Dodd KW, Gahche JJ, et al. Total folate and folic acid intake from foods and dietary supplements in the United States: 2003- 2006. Am J Clin Nutr. 2010;91(1):231-237.
8. Latif T, His ED, Rybicki LA, Adelstein DJ. Is there a role for folate determinations in current clinical practice in the USA? Clin Lab Haematol. 2004;26(6):379-383.
9. Robinson AR, Mladenovic J. Lack of clinical utility of folate levels in the evaluation of macrocytosis or anemia. Am J Med. 2001;110(2): 88-90.
10. Savage DG, Ogundipe A, Allen RH, Stabler SP, Lindenbaum J. Etiology and diagnostic evaluation of macrocytosis. Am J Med Sci. 2000; 319(6):343-352.
11. Springer K, Brown M, Stulberg DL. Common hair loss disorders. Am Fam Physician. 2003;68(1):93-102.
12. Shapiro J, Wiseman M, Lui H. Practical management of hair loss. Can Fam Physician. 2000;46:1469-1477.
13. Koybasi S, Parlak AH, Serin E, Yilmaz F, Serin D. Recurrent aphthous stomatitis: investigation of possible etiologic factors. Am J Otolaryngol. 2006;27(4):229-232.
14. Hirsch S, Sanchez H, Albala C, et al. Colon cancer in Chile before and after the start of the flour fortification program with folic acid. Eur J Gastroenterol Hepatol. 2009;21(4):436-439.
15. Figueiredo JC, Grau MV, Haile RW, et al. Folic acid and risk of prostate cancer: results from a randomized clinical trial. J Natl Cancer Inst. 2009;101(6):432-435.Author Affiliations: Family Medicine (SV), Tel Aviv University, Ashdod, Israel; Family Medicine Central District (EK, MS, SN), Clalit Health Service, Rehovot, Israel.
Funding Source: None.
Author Disclosures: The authors (SV, EK, MS) report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.
Authorship Information: Concept and design (SV, SN); acquisition of data (SV, EK); analysis and interpretation of data (SV, EK, MS, SN); drafting of the manuscript (SV, EK, MS, SN); critical revision of the manuscript for important intellectual content (SV, EK, MS, SN); statistical analysis (SV, MS); and supervision (SN).
Address correspondence to: Shlomo Vinker, MD; Family Medicine, Tel Aviv University, PO 14238, Ashdod, 77042, Israel. E-mail: email@example.com.