Managing folate deficiency implies filling the gap between laboratory and clinical assessment

Clin Nutr. 2022 Feb;41(2):374-383. doi: 10.1016/j.clnu.2021.12.012. Epub 2021 Dec 10.


The characterization of folate status in subjects at risk of deficiency and with altered vitamin homeostasis is crucial to endorse preventive intervention health policies, especially in developed countries. Several physiological changes (i.e. pregnancy), clinical situations and diseases have been associated to increased requirement, impaired intake and absorption of folate. However clinical practice guidelines (CPG) endorse folic acid supplementation generally discarding the use of its determination in serum to assess the risk of deficiency and/or its concentration at baseline. Poor confidence on the diagnostic accuracy of serum folate assays still persists in the current CPGs although recent standardization efforts have greatly improved inter-method variability and precision. In this review we critically appraise the methodological issues concerning laboratory folate determination and the evidence on the potential adverse effects of folic acid exposure. The final aim is to build a sound background to promote serum folate-based cost-effective health care policies by optimizing folic acid supplementation in subjects at risk of deficiency and with altered folate homeostasis. Our first result was to adjust in relation to current serum folate assays the thresholds reported by CPGs as index of folate status, defined on the association with metabolic and hematologic indicators. We identify a statistically significant difference between the estimated thresholds and accordingly show that the assessment of folate status actually changes in relation to the assay employed. The use of the method-dependent thresholds here reported may pragmatically endorse the stewardship of folic acid supplementation in clinical practice and increase the cost-effectiveness of health care policies.

Keywords: Deficiency; Immunoassay; Pharmacovigilance; Regression analysis; Stewardship; Supplementation.

Publication types

  • Review

MeSH terms

  • Adult
  • Dietary Supplements / standards*
  • Female
  • Folic Acid / administration & dosage*
  • Folic Acid / blood
  • Folic Acid Deficiency / prevention & control
  • Folic Acid Deficiency / therapy*
  • Humans
  • Nutrition Therapy / methods
  • Nutrition Therapy / standards*
  • Nutritional Status
  • Practice Guidelines as Topic
  • Pregnancy
  • Reference Values
  • Risk Assessment / methods*


  • Folic Acid