Guideline sources The following summarized guidelines for the evaluation and management of folate deficiency are prepared by our editorial team based on guidelines from the British Society for Haematology (BSH 2014). 1 2 2 3 4 Definition Folate deficiency is dietary folate equivalents < 400 ug/day in adults and < 600 ug/day in pregnant women characterized by megaloblastic anemia, and risk of neural tube defects and congenital anomalies. 2 Epidemiology Folate deficiency is mostly caused by inadequate folate intake, pregnancy and lactation, alcoholism, gene polymorphism (C1561T), and certain medications (methotrexate, anticonvulsants, sufasalazine, pyrimethamine). 3 Pathophysiology The prevalence of folate deficiency anemia in the United States adults is estimated at < 0.1%. Disease course Clinical manifestations include megaloblastic anemia and increased incidence of various cancers (colorectal, prostate, and breast cancer). Pregnancy-related complications include neural tube defects )spina bifida, anencephaly), and other congenital anomalies (congenital heart defects, https://web.pathway.md/diseases/recxI4tG9TotECfWJ 1/4 6/29/23, 4:06 AM Folate deficiency Pathway oral cleft lip and palate) in neonates, maternal megaloblastic anemia, low infant birth weight, stillbirth, and premature delivery. 2 Prognosis and risk of recurrence Folate deficiency is associated with increased all-cause mortality with a hazard ratio of 1.33 (95% CI 1.01-1.76). 4 Pathway Folate deficiency Diagnosis and management Guidelines 1. Screening and diagnosis Indications for testing: test for folate deficiency in clinical situations similar to those in which testing for cobalamin deficiency is obtained. A Diagnostic criteria: recognize that a serum folate level < 7 nmol/L (< 3 g/L) is indicative of folate deficiency. B 2. Diagnostic investigations Serum folate and cobalamin: obtain cobalamin and folate assays concurrently, given the close relationship in their metabolism. A CBC and peripheral blood smear: consider suspecting cobalamin or folate deficiency in patients in whom blood film shows oval macrocytes and hypersegmented neutrophils in the presence of an elevated MCV. C Red blood cell folate: Avoid routine testing of RBC folate, since serum folate alone is sufficient in most cases. D Consider RBC folate assays in patients in whom serum folate is normal yet folate deficiency is strongly suspected, after having excluded cobalamin deficiency. C Serum homocysteine: consider plasma total homocysteine levels to confirm suspected folate deficiency only in special circumstances; consider a level above 15 mol/L as indicative of folate deficiency, but assess in relation to local reference ranges. C Evaluation for medication-associated folate deficiency: consult with pharmacy references to clarify any suspicion of low serum folate levels associated with prescribed medications. 3. Medical management Folate supplementation: https://web.pathway.md/diseases/recxI4tG9TotECfWJ 2/4 6/29/23, 4:06 AM Folate deficiency Pathway Treat folate deficiency according to the following schedules : due to dietary insufficiency, pregnancy, or antiepileptics: folic acid 5 mg PO daily for 4 months due to malabsorptive states: consider folic acid 15 mg PO daily for 4 months. A Continue folic acid supplementation until term in pregnant patients. 4. Specific circumstances Patients with pernicious anemia: avoid initial treatment with oral cobalamin in pernicious anemia, but consider in maintenance or correction of suboptimal levels in asymptomatic patients. D Clinical findings Symptoms Past medical history Confusion Lack of folic acid in diet Depression Medications Fatigue Visual disorder Memory impairment Social history Mouth ulcers Muscle weakness Alcohol consumption Paresthesia Hematological findings Past obstetric history Anemia Pregnancy Macrocytic anemia Pancytopenia Lab findings Hgb MCV reticulocyte count serum MMA serum homocysteine serum folate Histological findings Findings of celiac disease References 1. Devalia V, Hamilton MS, Molloy AM et al. Guidelines for the diagnosis and treatment of cobalamin and folate disorders. Br J Haematol. 2014 Aug;166 4 496 513. Open 2. Yen-Ming Chan, Regan Bailey, Deborah L O'Connor. Folate. Adv Nutr. 2013 Jan 1;4 1 123 5. Open 3. Lindsay H Allen. Causes of vitamin B12 and folate deficiency. 2008 Jun;29 2 Suppl):S20 34; discussion S35 7.2008 Jun;29 2 Suppl):S20 34; discussion S35 7. Open https://web.pathway.md/diseases/recxI4tG9TotECfWJ 3/4 6/29/23, 4:06 AM Folate deficiency Pathway 4. Yang Peng, Bin Dong, Zhiqiang Wang. Serum folate concentrations and all-cause, cardiovascular disease and cancer mortality: A cohort study based on 1999 2010 National Health and Nutrition Examination Survey NHANES . 2016 Sep 15;219 136 42.2016 Sep 15;219 136 42. Open 5. Snow CF. Laboratory diagnosis of vitamin B12 and folate deficiency: a guide for the primary care physician. Arch Intern Med. 1999 Jun 28;159 12 1289 98. Open 6. Oluwaseun A Odewole, Rebecca S Williamson, Neil A Zakai et al. Near-elimination of folate- deficiency anemia by mandatory folic acid fortification in older US adults: Reasons for Geographic and Racial Differences in Stroke study 2003 2007. Am J Clin Nutr. 2013 Oct;98 4 1042 7. Open 7. Lindsay H Allen. Causes of vitamin B12 and folate deficiency. Food Nutr Bull. 2008 Jun;29 2 Suppl):S20 34; discussion S35 7. Open 8. Yang Peng, Bin Dong, Zhiqiang Wang. Serum folate concentrations and all-cause, cardiovascular disease and cancer mortality: A cohort study based on 1999 2010 National Health and Nutrition Examination Survey NHANES . Int J Cardiol. 2016 Sep 15;219 136 42. Open 9. Julie Parrott, Laura Frank, Rebecca Rabena et al. American Society for Metabolic and Bariatric Surgery Integrated Health Nutritional Guidelines for the Surgical Weight Loss Patient 2016 Update: Micronutrients. Surg Obes Relat Dis. 2017 May;13 5 727 741. Open https://web.pathway.md/diseases/recxI4tG9TotECfWJ 4/4