Folate tests for suspected folate deficiency

Forel D, Vandepeer M, Vreugdenburg T, Duncan J
Record ID 32018005507
Original Title: Folate testing
Authors' objectives: Objective The aim of this health technology assessment (HTA) is to evaluate the safety, effectiveness and economic impact of folate testing in an asymptomatic general population and in patients with suspected folate deficiency due to the presence of symptoms, underlying medical disorders or external factors. In addition, ethical, legal, social and organisational issues related to folate testing are investigated.
Authors' results and conclusions: Clinical evaluation No direct from-test-to-health-outcomes evidence was identified, thus a linked evidence approach was used to evaluate the safety and effectiveness of folate testing. Diagnostic accuracy A single study published in 1984, which measured red blood cell (RBC) folate in 110 patients compared to haematological and clinical findings as the reference standard reported the sensitivity of folate testing to be 96% and the specificity to be 71% depending on the group of patients measured. The diagnostic accuracy findings are based on very low certainty evidence, the single study informing these results was considered at high risk of bias, and there is a high risk the findings are not applicable to Swiss practice given the test used is not reflective of currently methods; thus the results should be interpreted with great caution. Change in management No studies reported change in management (i.e. comparing treatment decisions made with and without folate test results); however, 8 single-arm studies reported clinician management decisions following a low folate test result. These studies had inherently high risk of bias due to their study design (either case series or case control). It was consistently reported that, among patients suspected of folate deficiency and warranting a test, rates of folate deficiency were low (0.4%– 4.9%). Clinician response to folate test results was universally low across all studies; among patients with a low folate diagnosis, only 24–62% received supplementation. There are concerns about the applicability of this data to the Swiss context, as most were collected from countries with mandatory folic acid fortification; however, a single study from Denmark (without mandatory fortification) reported results that were consistent with the rest of the evidence. Overall, the certainty of the management outcome data was considered very low due to risk of bias and applicability concerns. Impact of change in management Due to the limited evidence for accuracy, and the absence of evidence for change in management, the impact of change in management could not be assessed. Safety of folic acid supplementation without testing An umbrella review of meta-analyses indicates that folic acid supplementation is generally considered safe. Supplementation was associated with a decreased risk of a range of chronic condition and adverse health outcomes; however, higher rates of prostate cancer (RR 1.24, 95% CI 1.04, 1.49) and colorectal adenoma (RR 1.34, 95% CI 1.06, 1.70) were reported. With the exception of colorectal adenoma, these results were informed by high- or moderate-quality meta-analyses of randomised controlled trials (RCTs) as assessed by GRADE. Data from observational studies also showed an association between maternal folic acid supplementation and subsequent child asthma and/or wheeze for some measurements of these outcomes; however, data was mixed and this association is considered uncertain. Budget impact assessment Based on the limited evidence for the effectiveness of folate testing, cost-effectiveness analysis was not conducted. A budget impact assessment was conducted, which projects the current trends in the utilisation of folate testing and folic acid supplementation from 2022–2026. Assuming no change to the current reimbursement policies, the total budget expenditure on folate testing is projected to increase from CHF 14.3 million in 2022 to CHF 21.5 million in 2026; folic acid supplementation is projected to increase from CHF 7.9 million in 2022 to CHF 9.3 million in 2026. Due to the limited evidence for the effectiveness of folate testing, scenarios investigating the impact of possible policy changes were not modelled. Ethical, legal, social and organisational (ELSO) issues A total of 8 studies were identified that addressed various ethical, social and organisational aspects of folate testing. No studies reporting legal issues were identified. Most studies identified addressed organisational issues relating to test restriction. Unsurprisingly, the 4 studies that described interventions to restrict folate testing noted significant cost savings. Ethical issues identified included potential adverse events from taking a supplement, a potential scenario owing to false positive test results or incorrect diagnosis in the absence of a test. Studies on social issues were in relation to physicians’ opinions and concerns regarding an initiative to reduce folate test orders, which were mostly supportive, and citizens’ opinions on test disinvestment. Guidelines and existing HTAs Five clinical practice guidelines (CPGs) were identified that focused on 2 specific populations; patients undergoing bariatric surgery and patients with suspected neurological deficiency as indicated by worsening gait ataxia. None of the CPGs were on folate testing, specifically. Evidence informing recommendations was either not reported or was of low quality (i.e. expert opinion). Only one CPG reported a threshold for identifying a folate deficient patient, and none made recommendations regarding timing or frequency of testing or follow-up testing in the case of deficiency. The searches identified 4 health technology assessments (HTAs) on folate testing (3 Canadian, 1 Australian). The findings were generally congruent with this current HTA, that there is a lack of evidence available to determine the effectiveness of folate testing. Conclusions Due to an absence of evidence the safety and effectiveness of folate testing is uncertain. There is no direct evidence examining the impact of folate testing on patient outcomes; similarly, evidence of the diagnostic accuracy of folate tests is limited to a single study published in 1984 with a high risk of bias and questionable applicability to current practice. There are no studies examining change in management based on the results of folate testing compared to no folate testing. These results broadly reflect the same results of prior HTA reports published on the topic.
Authors' methods: Methods A systematic literature search was conducted on 3 databases (PubMed, Embase, Cochrane Library) up to 1 August 2022. In addition, grey literature sources were searched for clinical practice guidelines and ongoing clinical trials. Direct from-test-to-health-outcomes evidence was preferentially sought. This evidence refers to studies that compare groups of people receiving either the current diagnostic test or the proposed diagnostic test, and measures the differential impact of the tests on patient health outcomes. In the absence of this evidence a linked evidence approach was undertaken, including an evaluation of diagnostic accuracy, change in clinical management, and the impact of management decisions on clinical outcomes. Risk of bias was assessed using appraisal tools appropriate to the included study designs: systematic reviews and meta-analyses were evaluated using the ASMTAR-2 tool, diagnostic accuracy studies were evaluated using the QUADAS-2 tool, single-arm studies were evaluated using the Institute of Health Economics (IHE) quality appraisal tool for case series. Due to the limited evidence available, meta-analysis was not possible. Therefore, the results are summarised narratively.
Project Status: Completed
Year Published: 2023
English language abstract: An English language summary is available
Publication Type: Full HTA
Country: Switzerland
MeSH Terms
  • Folic Acid
  • Folic Acid Deficiency
  • Diagnostic Tests, Routine
  • PROMs
  • efficacy
  • effectiveness
  • safety
  • costs
  • economics
  • cost-effectiveness
  • budget impact
  • legal
  • social
  • ethical
  • organisational
  • folate testing
  • folate test
  • folate deficiency
  • diagnostic test
  • Diagnostic folate testing
  • serum folate
  • red blood cell folate
  • Laboratory analyses
Organisation Name: Swiss Federal Office of Public Health (FOPH)
Contact Address: Federal Office of Public Health, Schwarzenburgstrasse 157, CH-3003 Berne, Switzerland
Contact Name: Stephanie Vollenweider
Contact Email:
Copyright: Swiss Federal Office of Public Health
This is a bibliographic record of a published health technology assessment from a member of INAHTA or other HTA producer. No evaluation of the quality of this assessment has been made for the HTA database.