CADTH Health Technology Review
Folate Testing in People With Suspected Folate Deficiency
Rapid Review
Authors: Khai Tran, Monika Mierzwinski-Urban, Quenby Mahood
Key Messages
No relevant literature was identified regarding the diagnostic test accuracy, clinical utility, and cost-effectiveness of serum folate testing in people with suspected folate deficiency.
Additionally, no evidence-based guidelines were identified regarding the use of serum folate testing in people with suspected folate deficiency.
Context and Policy Issues
Folate, also called vitamin B9, is a water-soluble vitamin and 1 of the essential vitamins required for synthesizing nucleic acids and methionine.1 It is present in foods as folate and in supplements as folic acid.1 The term folate encompasses different active forms of the vitamin.2 Circulating folate in the serum is mainly 5-methyltetrahydrofolate (82% to 93%).2 Other forms of folate exist, depending on dietary supplementation and food fortification, such as pteroylglutamic acid, 5-formyltetrahydrofolate, tetrahydrofolate, and unmetabolized folic acid.3,4
Folate deficiency due to low intake or poor absorption is associated with neural tube birth defects during pregnancy and macrocytic anemia.1 Folate deficiency has also been implicated in the development of various conditions, including cognitive impairment and dementia, cardiovascular disease, and colon cancer.1 The 1998 mandatory folic acid fortification of flour and grain products in Canada and the US at a rate of 150 mcg folic acid/100 g has significantly reduced the prevalence of folate deficiency in the general population from as high as 38% to less than 1% and has been linked to a more than 50% reduction in neural tube defects in newborns.5,6 A recent cross-sectional study7 that examined the association between macrocytosis and folate deficiency in a population of 46,827 individuals in Calgary, Alberta, found that only 0.2% of individuals were considered folate-deficient (cut off value of < 6 nmol/L), and macrocytosis was not a useful marker for folate deficiency.
Despite the low prevalence of folate deficiency in Canada and the US, serum folate tests continue to be routinely ordered in the assessment of macrocytic anemia or cognitive abnormalities.8,9 However, evidence has shown that serum folate tests in both outpatient and inpatient populations provide low yield in detecting folate deficiency and are associated with significantly high cost and charges per deficient result.8-10 This has led to the suggestion that serum folate tests should not be routinely ordered, even in patients with macrocytic anemia.11 A previous CADTH report12 found no evidence for the diagnostic accuracy of folate testing, no literature regarding the cost-effectiveness of folate testing, and insufficient evidence to support the clinical utility of folate testing in patients at risk of folate deficiency. Also in that report, evidence-based guidelines were identified that recommend folate status be tested in specific clinical populations with clear associations with folate deficiency.12
The objective of this report is to summarize the evidence regarding the diagnostic test accuracy, clinical utility, and cost-effectiveness of serum folate testing in people with suspected folate deficiency. This report also aims to summarize the recommendations from evidence-based guidelines regarding the use of serum folate testing in people with suspected folate deficiency.
Research Questions
What is the diagnostic accuracy of serum folate testing for the diagnosis of folate deficiency in people with suspected folate deficiency?
What is the clinical utility of serum folate testing in people with suspected folate deficiency?
What is the cost-effectiveness of serum folate testing in people with suspected folate deficiency?
What are the evidence-based guidelines regarding the use of serum folate testing in people with suspected folate deficiency?
Methods
Literature Search Methods
A limited literature search was conducted by an information specialist on key resources including MEDLINE, the Cochrane Database of Systematic Reviews, the International HTA Database, the websites of Canadian and major international health technology agencies, as well as a focused internet search. The search strategy comprised controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were folate deficiency AND testing. No filters were applied to limit the retrieval by study type. If possible, retrieval was limited to the human population. The search was also limited to English-language documents published between January 1, 2012, and February 15, 2022.
Selection Criteria and Methods
One reviewer screened citations and selected studies. Titles and abstracts were reviewed in the first screening level, and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1.
Criteria | Description |
|---|---|
Population | People of all ages with suspected folate deficiency (e.g., presence of unexplained anemia or macrocytosis, or due to variables such as age, diet, family and medical history, or lifestyle) |
Intervention | Serum folate testing |
Comparator | Q1: No comparator Q2 and Q3: No testing for folate deficiency Q4: Not applicable |
Outcomes | Q1: Diagnostic accuracy (e.g., sensitivity, specificity, positive predictive value, negative predictive value) Q2: Clinical utility (e.g., time to treatment, the severity of symptoms [e.g., fatigue, headaches, heart palpitations], quality of life, neurodevelopmental abnormalities, fetal and neonatal health, adverse events) Q3: Cost-effectiveness (e.g., cost per quality-adjusted life-year gained) Q4: Recommendations regarding best practices (e.g., appropriate patient populations, recommended testing strategies) |
Study designs | HTAs, SRs, RCTs, non-randomized studies, economic evaluations, and guidelines |
HTA = health technology assessment; Q = question; RCT = randomized controlled trial; SR = systematic review.
Exclusion Criteria
Articles were excluded if they did not meet the selection criteria outlined in Table 1, were duplicate publications, or were published before 2012. Studies included in the previous 2015 CADTH report12 were excluded. Guidelines with unclear methodology were also excluded.
Summary of Evidence
Quantity of Research Available
A total of 683 citations were identified in the literature search. Following the screening of titles and abstracts, 664 citations were excluded, and 19 potentially relevant reports from the electronic search were retrieved for full-text review. Twelve potentially relevant publications were retrieved from the grey literature search for full-text review. None of these 31 potentially relevant articles met the inclusion criteria and were excluded from this report for various reasons. Appendix 1 presents the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)13 flow chart of the study selection. Additional references of potential interest are provided in Appendix 2.
Summary of Findings
No relevant literature or evidence-based guidelines were identified regarding the diagnostic test accuracy, clinical utility, cost-effectiveness, or recommendations for serum folate testing in people with suspected folate deficiency; therefore, no summary can be provided.
Limitations
No potential limitations were identified as the literature search was extended up to 10 years.
Conclusions and Implications for Decision- or Policy-Making
Conclusions could not be drawn regarding the clinical effectiveness, cost-effectiveness, and recommendations for serum folate testing in people with suspected folate deficiency because no relevant literature was identified to answer the research questions.
Research examining the clinical utility and cost-effectiveness of serum folate testing in people with suspected folate deficiency is needed to investigate whether the test remains effective in the era of folic acid fortification diet. The absence of this evidence precludes the creation of new guidelines for folate testing to provide high-value patient care.
References
1.Lucock M. Folic acid: nutritional biochemistry, molecular biology, and role in disease processes. Mol Genet Metab. 2000;71(1-2):121-138. PubMed
2.Hannisdal R, Ueland PM, Svardal A. Liquid chromatography-tandem mass spectrometry analysis of folate and folate catabolites in human serum. Clin Chem. 2009;55(6):1147-1154. PubMed
3.Ferraro S, Panzeri A, Panteghini M. Tackling serum folate test in European countries within the health technology assessment paradigm: request appropriateness, assays and health outcomes. Clin Chem Lab Med. 2017;55(9):1262-1275. PubMed
4.Braga F, Frusciante E, Ferraro S, Panteghini M. Trueness evaluation and verification of inter-assay agreement of serum folate measuring systems. Clin Chem Lab Med. 2020;58(10):1697-1705. PubMed
5.Colapinto CK, O'Connor DL, Tremblay MS. Folate status of the population in the Canadian Health Measures Survey. CMAJ. 2011;183(2):E100-106. PubMed
6.Ami N, Bernstein M, Boucher F, Rieder M, Parker L. Folate and neural tube defects: the role of supplements and food fortification. Paediatr Child Health. 2016;21(3):145-154. PubMed
7.Budd M, Naugler C. Folate deficiency in an unselected population in Calgary, Alberta and its relationship with red blood cell macrocytosis. BMC Res Notes. 2015;8:314. PubMed
8.Ashraf MJ, Cook JR, Rothberg MB. Clinical utility of folic acid testing for patients with anemia or dementia. J Gen Intern Med. 2008;23(6):824-826. PubMed
9.Theisen-Toupal J, Horowitz G, Breu A. Low yield of outpatient serum folate testing: eleven years of experience. JAMA Intern Med. 2014;174(10):1696-1697. PubMed
10.Theisen-Toupal J, Horowitz GL, Breu AC. Utility, charge, and cost of inpatient and emergency department serum folate testing. J Hosp Med. 2013;8(2):91-95. PubMed
11.Breu AC, Theisen-Toupal J, Feldman LS. Serum and red blood cell folate testing on hospitalized patients. J Hosp Med. 2015;10(11):753-755. PubMed
12.Folate testing: a review of the diagnostic accuracy, clinical utility, cost-effectiveness and guidelines (Rapid response report: summary with critical appraisal). Ottawa (ON): CADTH; 2015: https://www.cadth.ca/sites/default/files/folate-testing-a-review-of-the-diagnostic-accuracy-clinical-utility-cost-effectiveness-and-guidelines.pdf. Accessed 2022 Mar 17.
13.Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol. 2009;62(10):e1-e34. PubMed
Appendix 1: Selection of Included Studies
Appendix 2: References of Potential Interest
Previous CADTH Reports
Folate testing: a review of the diagnostic accuracy, clinical utility, cost-effectiveness and guidelines (Rapid response report: summary with critical appraisal). Ottawa (ON): CADTH; 2015: https://www.cadth.ca/sites/default/files/folate-testing-a-review-of-the-diagnostic-accuracy-clinical-utility-cost-effectiveness-and-guidelines.pdf. Accessed 2022 Mar 17.
Additional References
American Society for Clinical Pathology. Do not order red blood cell folate levels at all. In adults, consider folate supplementation instead of serum folate testing in patients with macrocytic anemia. 2017; https://www.choosingwisely.org/clinician-lists/ascp-do-not-order-red-blood-cell-folate-levels/. Accessed 2022 Mar 17.
Canadian Association of Medical Biochemistry. Medical biochemists: five tests and treatments to question. 2020; https://choosingwiselycanada.org/medical-biochemistry/. Accessed 2022 Mar 17.
Folate deficiency - investigation & management. Victoria (BC): Government of British Columbia; 2012: https://www2.gov.bc.ca/gov/content/health/practitioner-professional-resources/bc-guidelines/folate-deficiency. Accessed 2022 Mar 17.
Guidelines for investigation and management of vitamin B12 and folate deficiency. Chatham (GB): Swale Clinical Commissioning Group; 2021: https://www.medwayswaleformulary.co.uk/media/1194/investiagtion-and-treatment-guidelines-for-b12-and-folate-deficiency-may-19-v7-final-copy.pdf. Accessed 2022 Mar 17.
ISSN: 2563-6596
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