Cobalamin (vitamin B12) and Folate Deficiency

Revised Date: January 18, 2023

Recommendations and Topics

• Scope
• Key Recommendations
• Background
• Epidemiology
• Patient Risk Factors Associated with B₁₂ Deficiency
• Patient Risk Factors Associated with Folate Deficiency
• Prevention
• Diagnosis
• Management
• Ongoing Care
• References
• Resources
• Appendix A: Dietary sources of cobalamin

Scope

This guideline covers the primary care investigation and management of cobalamin (vitamin B₁₂ or simply B₁₂) and folate deficiency in adults. This guideline outlines the indications for B₁₂ testing and discusses an observed increase in B₁₂ testing in BC. Specifically:

• Outpatient and inpatient laboratory test volumes for B₁₂ investigations increased from 267,721 to 570,265 between 2013 and 2020. This resulted in an increase in annual B₁₂ testing expenditure from $3.0 million to $5.6 million during the same time period.
• On average, 420,303 tests cost $4.4 million per year.
• Patients ³ 65 years of age accounted for the majority (37%) of B₁₂ test volumes in 2019.
• Female patients account for 62% of annual test volumes while males account for 38%.

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Key Recommendations 

• Routine B₁₂ screening and testing in asymptomatic patients is not supported by evidence.
• Consider B₁₂ supplementation without testing in asymptomatic patients with risk factors for B₁₂ deficiency (see Table 1: Patient Risk Factors Associated with B₁₂ Deficiency). Patients can call 8-1-1 to speak with a HealthLink BC registered dietitian.
• B₁₂ deficiency can cause preventable permanent injury and should be considered with new onset neurological conditions and symptoms suggestive of B₁₂ deficiency (See Low B₁₂ symptoms section below).
• Folate testing is rarely indicated but may be available via consultation with the laboratory medicine physician or scientist.
• Folate deficiency in pregnancy is associated with preventable and serious fetal harm, i.e., neural tube defects (NTD). Folic acid supplementation is recommended during pregnancy.
• A daily multivitamin containing B₁₂ and folic acid is recommended for all people who could become pregnant, especially those with a vegan diet.

 

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Background

The terms cobalamin (cyanocobalamin) and vitamin B₁₂ can be used interchangeably. B₁₂ will be used throughout this guideline. A 2022 CADTH review¹ performed at the request of GPAC found:

• No studies evaluating the clinical utility of B₁₂ testing in people with suspected B₁₂ deficiency.
• No studies evaluating the cost-effectiveness of B₁₂ testing in people with suspected B₁₂ deficiency.
• No evidence-based guidelines regarding the use of B₁₂ testing in people with suspected B₁₂ deficiency.

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. 

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Vitamin B₁₂

B₁₂ is a water-soluble vitamin found in foods derived from animal products and from fortified foods.² (see HealthLink BC’s page on Quick Nutrition Check for Vitamin B₁₂ for dietary information).The prevalence of B₁₂ deficiency in the general population differs between older and younger people. For example, 6% of those < 60 years in the United Kingdom were found to be B₁₂ deficient, compared to 20% of those ≥ 60 years. B₁₂ deficiency also correlates to geographic location and ethnic background (e.g., 6% of those in the United States were found to be B₁₂ deficient, compared to 40% in Latin American countries and 70% in East Indian adults. Most cases of B₁₂ ³ deficiency in high-income countries are attributable to malabsorptive disorders. A specific form of malabsorption, pernicious anemia, is caused by autoimmunity to intrinsic factor resulting in failure to absorb dietary B₁₂. Other causes for malabsorption include Crohn’s disease, celiac disease, and medication interactions (e.g., proton pump inhibitor, metformin). A rare but serious form of B₁₂ deficiency can arise from the protracted use of nitrous oxide (N₂0) as a recreational inhalant. Vitamin B₁₂ deficiency may also be caused by diet (e.g., vegan diet, breastfed neonates born to B₁₂ deficient mothers).¹

As vitamin B₁₂ is stored in body tissue, mainly the liver, sub-clinical deficiency from dietary deficiency alone develops over the course of several years (e.g., 5-10 years).⁴ Manifestations of vitamin B₁₂ deficiency may be mild, such as fatigue and heart palpitations, but may progress to neurological manifestations, including peripheral neuropathy and dementia-like symptoms. ⁵

There is currently no agreed upon reference standard for measuring B₁₂, and all are susceptible to confounding factors. A lack of agreement around cut-off levels (i.e., thresholds) to diagnose deficiency adds another layer of difficulty in diagnosing deficiency, as these thresholds may differ.¹

Low B₁₂ Symptoms: Patients may present with any of the following (specific or red flag symptoms in Bold):

• Neurologic abnormalities associated with impaired nerve function and demyelination, including new onset and otherwise unexplained central nervous system symptoms (e.g., cognitive impairment), motor and/or sensory neuropathy, and subacute combined degeneration of the dorsal and lateral columns of the spinal cord⁴ (e.g., symmetric paresthesias, numbness, gait disorder, positive Babinski and exaggerated patellar reflex).
• Glossitis (including pain, swelling, tenderness, and loss of papillae of the tongue), and/or chronic (>3 months) unexplained gastrointestinal symptoms (e.g., pain or diarrhea), reflecting impaired regeneration of epithelial cells.
• Worsening macrocytic anemia: B₁₂ deficiency may also cause a macrocytic (megaloblastic) anemia BUT, in the presence of folate supplementation, this anemia may be masked so that B₁₂ deficiency may present with exclusively neurologic features. Therefore, in patients with neurologic symptoms do not rely on the complete blood cell count (CBC) to help rule in or out B₁₂ deficiency.
• If a patient has specific or red flag features B₁₂ deficiency testing should be initiated (see  Figure 1: B₁₂ Test Result Review and Process Algorithm for Patients with Risk Factor for B₁₂ Deficiency^* and/or Non-specific^** or Specific^† Symptom of B₁₂ Deficiency).

Folate

Folate is found in dark green vegetables, legumes (i.e. peas, beans and lentils), and citrus fruit (see HealthLink BC’s page on Getting Enough Folic Acid (Folate) for dietary information).^{2, 6} Mandatory folic acid fortification of foods (i.e. white flour, enriched pasta and cornmeal) was implemented in Canada in 1998.⁶ This was associated with a significant increase in average population folate levels, and folate deficiency is now rare in Canada. Two outpatient laboratories in BC reported > 99% of folate tests were normal in 2010.

In rare cases, folate deficiency is associated with megaloblastic anemia and birth defects, especially neural tube defects, in children born to mothers with folate deficiency.⁷

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Epidemiology

Between 2019 and 2021, 2.17 million B₁₂ tests were performed for 1.39 million patients in BC. Approximately 33% of patients had two or more tests during this time period. Nine percent of all B₁₂ tests had an abnormal result. The cost of a B₁₂ test in BC is $14.38.

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Patient Risk Factors Associated with B₁₂ Deficiency

There is no evidence to support regular B₁₂ screening for asymptomatic patients. In asymptomatic patients with risk factors (see Table 1: Patient Risk Factors Associated with B₁₂ Deficiency below) consider supplementation in lieu of testing.

Table 1: Patient Risk Factors Associated with B₁₂ Deficiency

Bold represents factors associated with more rapid onset of clinical symptoms i.e., within 5 years. Non-bold represents slower contributing factors (e.g., 5 to 10 years). Refer to Table 3: Treatment of B₁₂ deficiency for supplementation routes, dosage and duration. 

Factor	B12 Deficiency
Medications	•    Histamine 2 (H2) receptor antagonists4, 8, 9 * •    Proton pump inhibitors 8–10 * •    Metformin4, 9–13 •    Anticonvulsants9 (especially phenobarbital, pregabalin, primidone, or topiramate)14 •    Protracted use of N20 gas (when used as a recreational drug)4, 10
Factors contributing to inadequate intake	•    Low intake of B12 rich foods4, 10 •    Chronic excess alcohol use8, 10 •    Smoking8 •    Vegan or strict vegetarian diets9, 10 •    Vegetarian diet in pregnancy10 •    Age >60 years9 •    South Asian ethnicity (cultural promotion of vegetarian diet)15–17 •    Exclusively breast-fed infants of B12 deficient people18
Decreased Ileal Absorption	•    Gastric/bariatric surgery4, 8, 10 •    Small intestine resection10 •    Inflammation of small intestine: Crohn’s, celiac, tropical sprue3, 9, 10, 19 •    Tapeworm infection3, 4, 10 •    H. pylori infection10 •    Pancreatic insufficiency10 •    Infected with human immunodeficiency virus (HIV)9 infection
Decreased Intrinsic Factor	•     Atrophic gastritis10 •     Antibodies to anti-intrinsic factor (i.e., pernicious anemia)3, 4, 8, 10 alone, or in association with other autoimmune conditions (e.g., Type 1 Diabetes Mellitus) •     Post-gastrectomy syndrome

* Vitamin B₁₂ deficiency is associated with either long-term proton inhibitor (PPI) or Histamine-2 receptor blocker (H₂ blocker) use, but a causal relationship is not established.²⁰

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Patient Risk Factors Associated with Folate Deficiency

There is no evidence to support regular folate screening for asymptomatic patients. Consider supplementation in asymptomatic patients with risk factors (see Table 2: Patient Risk Factors Associated with Folate Deficiency below) consider supplementation. Refer to Table 6: Treatment of folate deficiency for supplementation routes, dosage and duration.

Table 2: Patient Risk Factors Associated with Folate Deficiency 

Folate Deficiency Patient Risk Factors

Neurologic abnormalities (more prominent in B12 deficiency) e.g., cognitive slowing and neuropathy Medically unexplained symptoms (e.g., fatigue, irritability, cognitive decline), where other causes have been excluded Oral ulcers4 Excessive consumption of alcohol4, 5 Dietary deficiency or malabsorption21 Methotrexate, phenytoin, sulfasalzin, trimethoprim21 Worsening macrocytic anemia. In such a patient, B12 should also be ordered Refer to the Society of Obstetricians and Gynaecologists of Canada (SOGC) Guideline No. 427: Folic Acid and Multivitamin Supplementation for Prevention of Folic Acid-Sensitive Congenital Anomalies for identified risk factors for fetal NTDs or low- folate status in pregnancy

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Prevention

Prevention of B₁₂ Deficiency

B₁₂ is present in many animal products e.g., dairy products, and eggs; therefore, a typical non-vegetarian diet contains adequate B₁₂. Practitioners should consider specific B₁₂ dietary counselling for patients currently on a vegetarian, or vegan diet, including patients who have recently initiated such a diet. To help prevent B₁₂ deficiency, encourage all individuals to consume a diet with sufficient B₁₂. Consider a dietitian referral for patients to call 8-1-1 to speak with a HealthLink BC dietitian. With respect to B₁₂ supplementation:

• Consider supplementation when patients adhere to a vegan or strict vegetarian diet.
• Consider supplementation when the patient has risk factors associated with B₁₂ Deficiency as described in see Table 1: Patient Risk Factors Associated with B₁₂ Deficiency above.  
• Doses usually used in supplementation¹⁶ are not associated with harm.⁷  (See Table 3: B₁₂ Medication Table below).
• Oral supplements are available over the counter in various doses and dosage forms. (Prices vary).
• Some PharmaCare plans provide coverage for select oral and parenteral formulations (1000 micrograms [mcg]/mL).

Prevention of Folate Deficiency

It is recommended that all people who could become pregnant take a daily supplement containing 400 mcg/0.4mg folic acid to reduce the risk of neural tube defects (NTDs).²² This is most easily obtained through a prenatal vitamin.²³

• Supplementation of 1 mg daily is recommended for patients with specific risk factors (e.g., bariatric/gastric surgery patients, those with severe malnutrition, chronic alcohol use, chronic hemolytic anemia and conditions with high cell turnover, and use of antimetabolite medications such as methotrexate).²¹
• The doses of folic acid used in supplementation (see Table 5: Folic Acid Medication Table below) are non-toxic and are not associated with harm.^{21, 23} Consider supplementation when the patient is prescribed medications causing folate deficiency, e.g., methotrexate.⁸
• Over the counter folate products include: 400 mcg/0.4 mg and 1 mg tablets.^†
• Prescription folate products covered by PharmaCare^‡ include: 5 mg tablets and 5 mg/mL injection.

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Diagnosis

B₁₂ Testing

Routine B₁₂ screening is not supported by the current body of evidence. The test has the following limitations:

• Levels of B₁₂ do not correlate well with clinical symptoms. Elderly patients may have normal B₁₂ levels with clinically significant B₁₂ deficiency.
• Women taking oral contraceptives may have decreased serum B₁₂ levels in the absence of clinical deficiency (due to decreases in the B₁₂ carrier protein, haptocorrin).
• There is a large ‘indeterminate zone’ between normal and abnormal levels (see Figure1: B₁₂ Test Result Review and Process Algorithm for Patients with Risk Factor for B₁₂ Deficiency* and/or Non- Specific** or Specific† Symptom of B₁₂ Deficiency below).
• The reference intervals may vary between laboratories. The conventional cut-off for serum B₁₂ deficiency varies from 150-220 pmol/L.²⁴

In a clinically symptomatic patient with specific features of B₁₂ deficiency, order a B₁₂ test, see Figure1: B₁₂ Test Result Review and Process Algorithm for Patients with Risk Factor for B₁₂ Deficiency* and/or Non- Specific** or Specific† Symptom of B₁₂ Deficiency for more detail. Refer to Perinatal Services BC's (PSBC) website for the Early Prenatal Care Summary and Checklist for Primary Care Providers.

Asymptomatic: In asymptomatic patients with risk factors (see Table 1: Patient Risk Factors Associated with B₁₂ Deficiency above) consider supplementation in lieu of testing.

High total B₁₂ pathway:
If the B₁₂ level is above the upper limit of normal, follow up should be organized as follows:

1. Was the patient already taking B₁₂? If yes, decrease the dose. If no, go to step ii.
2. Does the patient have end stage renal disease? If yes, no specific follow up for B₁₂ is required. If no, go to step iii.
3. Are there clinical features of liver disease, myeloproliferative disorder (e.g., blood film changes of unexplained cytopenia, thrombocytosis, or leukocytosis), or another cancer (e.g., cachexia, constitutional symptoms – fever, weight loss, night sweats)? If yes, refer to the appropriate specialist depending on symptoms. If no, go to step iv.
4. Verify that the elevated B₁₂ test result is not in error due to test interference (e.g., macroB₁₂ or heterophile antibody interference) by ordering another test (e.g., total homocysteine). If total homocysteine is normal, this corroborates the B₁₂ result. If the total homocysteine is elevated, contact the laboratory pathologist to facilitate further investigations.²⁵

Repeat Testing:
Repeat testing of B₁₂ may be warranted after a trial of therapy or as an assessment of adherence. Repeat testing should wait at least 2 months after therapy has been started.²⁶ If the B₁₂ is normal (rare probability of B₁₂ deficiency – see Table 3: B₁₂ Medication Table), a repeat investigation is not required in the absence of new signs of disease. In absence of a reversible factor therapy, supplementation in most cases is lifelong.

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Folate Testing

Serum folate and red blood cell (RBC) folate testing is no longer offered in BC.

In cases of unexplained macrocytic anemia associated with high homocysteine levels and normal B₁₂ testing results, folate testing may be arranged if supported by laboratory specialist consultation. Refer to Table 2: Patient Risk Factors Associated with Folate Deficiency for more information.

If folate deficiency is suspected, it is reasonable to give oral folic acid (0.4 – 1 mg/day) without doing laboratory investigation for deficiency at least until the hemoglobin and mean corpuscular volume normalizes (or longer if the underlying cause cannot be eliminated).

Figure 1: B₁₂ Test Result Review and Process Algorithm for Patients with Risk Factor for B₁₂ Deficiency* and/or Non-specific** or Specific^† Symptom of B₁₂ Deficiency

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Management

Treatment 

In suspected B₁₂ deficiency, supplement both B₁₂ and folate.^{23, 27}

Vitamin B₁₂

Early treatment of B₁₂ deficiency is particularly important because neurologic symptoms may be irreversible. Oral administration is extremely effective and less invasive compared to other routes. For selected symptomatic patients please review Figure 1: B₁₂ Test Result Review and Process Algorithm for Patients with Risk Factor for B₁₂ Deficiency* and/or Non-specific** or Specific^† Symptom of B₁₂Deficiency.

Table 3: Vitamin B₁₂ Medication Table

The table below is not an exhaustive list of all vitamin B₁₂ products and therapeutic considerations.

Product Dosage Forms and Strengths	Recommended Adult Dose	Approx. Cost per month†	PharmaCare Coverage‡	Therapeutic considerations
cyanocobalamin Vitamin B12 Oral/sublingual tablets: 250, 500, 1000, 2500 mcg Liquid: 200 mcg/mL	500 - 2000 mcg PO daily* pernicious anemia: 1000 mcg po dailyb  food-cobalamin malabsorption: 250 mcg po dailyb	$5 - 10	Regular benefit (Plan W): 250, 1000 mcg tablets	Oral is effective as parental therapy in improving hematologic and neurologic outcomesc No clinical meaningful differences between sublingual and oral routesd 1 - 5% of oral dose absorbed by passive diffusionb Dose and duration of initial therapy dependent on severity of B12 deficiencya
Injection (IM or subcut): 1000 mcg/mL	Initial:  1000mcg IM/subcut dailt for 7 daysa Maintenance: 1000 mcg IM/subcut monthly	$5	Regular benefit: 1000 mcg/mL	Injectable product contraindicated in infants due to presence of benzyl alcohol  Anaphylactic reactions are rare Usually nontoxic in large doses, however diarrhea, itch, urticaria have been reporteda
methylcobalamin Vitamin B12 Tablets: 1000, 2500, 5000 mcg	500 -  2000 mcg PO dailya	$5 - 10	Regular benefit (Plan W): 1000 mcg tablet	More active cobalamin coenzyme form, however not superior to cyanocobalamine

† Cost of generic without mark-up or professional fee rounded up to nearest $5; calculated from McKesson Canada https://www.mckesson.ca/ (Accessed February 17, 2022)
‡ Coverage is subject to drug price limits set by PharmaCare and to the patient’s PharmaCare plan rules and deductibles. See https://www2.gov.bc.ca/gov/content/health/ health-drug-coverage/pharmacare-for-bc-residents and https://pharmacareformularysearch.gov.bc.ca/.
Note: For complete details, please review product monographs at https://health-products.canada.ca/dpd-bdpp/index-eng.jsp and regularly review current Health Canada advisories, warnings and recalls at: http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/index_e.html for the most up to date information.)

Table 4: Treatment of B₁₂ deficiency (adapted from Means 2021)²⁷

Demographic	Route of administration	Dosage and frequency
Adults with normal absorption	Oral	1000 mcg orally once per day.
Adults with impaired absorption	Oral	Therapy with very high oral doses of oral vitamin B12 (e.g., 1000 to 2000 mcgg daily) will be effective if the dose is high enough to provide absorption via a mechanism that does not require intrinsic factor or a functioning terminal ileum (i.e., passive diffusion/mass action).
Adults with dietary deficiency	Oral	Individuals with diets that lack vitamin B12 (e.g., vegans, vegetarians, infants exclusively breastfed by vitamin B12- deficient mothers) are expected to have normal absorption via the oral route and can be treated with oral supplements that provide the recommended amount (500-2000 mcg).
Adults with pernicious anemia	Intramuscular** or deep subcutaneous injection High-dose oral vitamin B12	Parental vitamin B12 at an initial dose of 1000 mcg (1mg) once per week for four weeks, followed by 1000 mcg once per month. 1000 to 2000 mcg (1 to 2mg) daily (provided there are no acute symptoms of anemia or neurologic complications and adherence is assured).
Adults with altered gastrointestinal anatomy	Parenteral	If the alteration is permanent, then indefinite treatment with parenteral vitamin B12 is usually appropriate. If the alteration is reversed, then therapy may be discontinued, although it is reasonable to check the vitamin B12 level several months after stopping therapy. Check B12 level three or four times during the first year of therapy.
Adults with symptomatic anemia, neurologic or neuro-psychiatric findings, or pregnancy	Parenteral Oral	1000 mcg of vitamin B12 every other day initially for approximately two weeks, followed by administration once monthly (cyanocobalamin). Once the initial deficiency has been corrected, an oral trial is reasonable, based on patient preference and adequate B12 levels.

Note: Intranasal administration is generally not used. Transdermal forms of vitamin B₁₂ are available over the counter, but this route of administration has not been validated clinically in the setting of vitamin B₁₂ deficiency and should not be relied upon for treatment.

** “Individuals treated with parenteral vitamin B₁₂ can be taught to self-administer the injections, often with good results, minimal to no pain, and lower costs than office-based injection.”²⁷

 

Folate treatment

Refer to Table 6: Treatment of folate deficiency below for folate deficiency treatment options and the SOGC Guideline No. 427: Folic Acid and Multivitamin Supplementation for Prevention of Folic Acid-Sensitive Congenital Anomalies for more information.

Table 5: Folic Acid Medication Table

The table below is not an exhaustive list of all folic acid products and therapeutic considerations.

Product Dosage Forms and Strenghts	Recommended Adult Dose	Approx. Cost per month†	PharmaCare Coverage‡	Therapeutic Considerations
folic acid Tablets: 04.4, 1, 5 mg	1 - 5 mg PO dailyf	$5	Regular benefit: 1 mg (Plan W only), 5 mg tablets	Folic acidsupplementation alone may exacerbate neurological symptoms in patients with concurrent cobalamin deficiency May decrease serum concentration of phenytoin, fosphenytoing
Injection (IM, subcut): 5mg/mL	0.4 - 1 mg IM/subcut dailyf	$25	Non-benefit	Allergic reactions (erythrma, pruritus and/or urticaria) are rareg

† Cost of generic without mark-up or professional fee rounded up to nearest $5; calculated from McKesson Canada https://www.mckesson.ca/ (Accessed February 17, 2022)

‡ Coverage is subject to drug price limits set by PharmaCare and to the patient’s PharmaCare plan rules and deductibles. See https://www2.gov.bc.ca/gov/content/health/ health-drug-coverage/pharmacare-for-bc-residents and https://pharmacareformularysearch.gov.bc.ca/.

Note: For complete details, please review product monographs at https://health-products.canada.ca/dpd-bdpp/index-eng.jsp and regularly review current Health Canada advisories, warnings and recalls at: http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/index_e.html for the most up to date information.

References:

1. Vitamin B₁₂ CPhA Monograph. e-CPS. Ottawa, ON: Canadian Pharmacists Association. Accessed online February 17, 2022.
2. Andres E, Dali-Youcef N, Serraj K et al. Oral cobalamin (vitamin B₁₂) treatment. An update. Int Jnl Lab Hem 2009;31:1-8.
3. Vidal-Alaball J, Butler C, Cannings-John R et al. Oral vitamin B₁₂ versus intramuscular vitamin B₁₂ for vitamin B₁₂ deficiency. Cochrane Database Syst Rev. ; (3): CD004655. doi:10.1002/14651858.CD004655.pub2.
4. Sharabi A, Cohen E, Sulkes J, et al. Replacement therapy for vitamin B₁₂ deficiency: comparison between the submingual and oral route. Br J Clin Pharmacol 2003;56(6):635-638.
5. Obeid R, Fedosov SN, Nexo E. Cobalamin coenzyme forms are not likely to be superior to cyano- and hydroxyl-cobalamin in prevention or treatment of cobalamin deficiency. Mol Nutr Food Res 2015;59:1364-1372.
6. Folic Acid: Drug information. UpToDate. Waltham WA: UpToDate Inc. Accessed online February 17, 2022.
7. Folic Acid CPhA Monograph. e-CPS. Ottawa, ON: Canadian Pharmacists Association. Accessed online February 17, 2022.

 

Table 6: Treatment of folate deficiency (adapted from Means 2021)²⁷

Demographic	Route of administration	Dosage and frequency
Individuals with reversible cause of deficiency	Oral	1 to 5 mg daily given for one to four months or until there is laboratory evidence of hematologic and/or neurologic worsening occur).
Individuals with chronic cause of deficiency	Oral	1 to 5 mg daily, may be indefinitely (some advocate repeat testing for vitamin B12 deficiency in patients receiving long-term folic acide, especially if hematologic and/or neurologic worsening occur).
Individuals who are unable to take an oral medication (e.g., due to vomiting) or those who have severe or symptomatic anemia due to folate deficiency and hence have a more urgent need for rapid correction	Intravenous	1 to 5 mg daily

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Ongoing Care 

Ongoing Management

Vitamin B₁₂
Duration of therapy 
Once a diagnosis of B₁₂ deficiency due to poor absorption of B₁₂ has been made, therapy should be maintained lifelong.²⁵ 

Folate
Duration of therapy
Patients with pernicious anemia require lifelong therapy, while patients with malabsorption require treatment until underlying condition or diet is corrected.²⁷

Monitoring
Increased clinical surveillance is suggested for patients with non-nutritional folate folate deficiency.²⁷

Quality Check Point
To help practitioners review their own practice, some relevant measures have been included below. These measures may be obtained using your Electronic Medical Records (EMR) or with assistance from the Health Data Coalition: 

• % patients on B₁₂
• % patients on folate
• % active patients with B₁₂ test in last year
• % active patients with folate test in last year 
• % pregnant patients on folate/B₁₂

This process would count towards Mainpro+ credits or College of Physicians and Surgeons of British Columbia (CPSBC) accreditation processes. 

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References

1. Hamel C, Spry C. Vitamin B₁₂ Testing in People With Suspected Vitamin B₁₂ Deficiency. Can J Health Technol [Internet]. 2022 Mar 24 [cited 2022 Apr 7];2(3). Available from: http://canjhealthtechnol.ca/index.php/cjht/article/view/rc1413
2. Health Canada. Foods to which vitamins, mineral nutrients and amino acids may or must be added [D.03.002, FDR] [Internet]. Health Canada; 2022 [cited 2022 Oct 4]. Available from: https://inspection.canada.ca/food-labels/labelling/industry/nutrient-content/reference-information/ eng/1389908857542/1389908896254?chap=1
3. Langan RC, Goodbred AJ. Vitamin B₁₂ Deficiency: Recognition and Management. Am Fam Physician. 2017 Sep 15;96(6):384–9.
4. Means R, Fairfield K. Clinical manifestations and diagnosis of vitamin B₁₂ andfolate deficiency. Date [Internet]. 2021 Mar 26; Available from: https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-vitamin-b12-and-folate-deficiency?search=Clinical%20manifestations%20and%20 diagnosis%20of%20vitamin%20B12%20andfolate%20deficiency&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1
5. Vitamin B₁₂ & Health. Vitamin B₁₂ and health: vitamin B₁₂ deficiency test [Internet]. Vitamin B₁₂ & Health; [cited 2022 Apr 7]. Available from: https://www.b12-vitamin.com/deficiency-test/
6. Health Canada. Folate [Internet]. Health Canada; 2012 [cited 2022 Sep 10]. Available from: https://www.canada.ca/en/health-canada/services/food-nutrition/food- nutrition-surveillance/health-nutrition-surveys/canadian-health-measures-survey/folate-nutrition-biomarkers-cycle-1-canadian-health-measures-survey-food-  nutrition-surveillance-health-canada.html
7. Wilson RD, Audibert F, Brock JA, Carroll J, Cartier L, Gagnon A, et al. Pre-conception Folic Acid and Multivitamin Supplementation for the Primary and Secondary Prevention of Neural Tube Defects and Other Folic Acid-Sensitive Congenital Anomalies. J Obstet Gynaecol Can. 2015 Jun;37(6):534–49.
8. Green R, Allen LH, Bjørke-Monsen AL, Brito A, Guéant JL, Miller JW, et al. Vitamin B₁₂ deficiency. Nat Rev Dis Primer. 2017 Dec 21;3(1):17040.
9. Oh R. Vitamin B₁₂ deficiency [Internet]. BMJ Best Practice; 2021 [cited 2021 Dec 20]. Available from: https://bestpractice.bmj.com/topics/en-gb/822
10. Means R, Fairfield K. Causes and pathophysiology of vitamin B₁₂ and folate deficiencies. Date [Internet]. 2019 Nov 22 [cited 2021 Dec 1]; Available from: https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-vitamin-b12-and-folate-deficiency?search=vitamin+b12+deficiency&source=sear ch_result&selectedTitle=1%7E150&usage_type=default&display_rank=1
11. Anastasi L, Jacobsen J, Nicolopoulos K, Rochet E, Foerster V, Vreugdenburg T. Effectiveness and safety of vitamin B₁₂ tests [Internet]. Switzerland Federal Office of Public Health; 2021 [cited 2021 Dec 1]. Available from: https://www.bag.admin.ch/bag/en/home/versicherungen/krankenversicherung/krankenversicherung- leistungen-tarife/hta/hta-projekte/vitaminb12tests.html
12. Infante M, Leoni M, Caprio M, Fabbri A. Long-term metformin therapy and vitamin B₁₂ deficiency: an association to bear in mind. World J Diabetes. 2021 Jul 15;12(7):916–31.
13. Chapman LE, Darling AL, Brown JE. Association between metformin and vitamin B₁₂ deficiency in patients with type 2 diabetes: A systematic review and meta- analysis. Diabetes Metab. 2016 Nov;42(5):316–27.
14. Linnebank M, Moskau S, Semmler A, Widman G, Stoffel-Wagner B, Weller M, et al. Antiepileptic drugs interact with folate and vitamin B₁₂ serum levels. Ann Neurol. 2011 Feb;69(2):352–9.
15. Quay TAW, Schroder TH, Jeruszka-Bielak M, Li W, Devlin AM, Barr SI, et al. High prevalence of suboptimal vitamin B₁₂ status in young adult women of South Asian and European ethnicity. Appl Physiol Nutr Metab. 2015 Dec;40(12):1279–86.
16. Schroder TH, Sinclair G, Mattman A, Jung B, Barr SI, Vallance HD, et al. Pregnant women of South Asian ethnicity in Canada have substantially lower vitamin B₁₂ status compared with pregnant women of European ethnicity. Br J Nutr. 2017 Sep 28;118(6):454–62.
17. Jeruszka-Bielak M, Isman C, Schroder T, Li W, Green T, Lamers Y. South Asian Ethnicity Is Related to the Highest Risk of Vitamin B₁₂ Deficiency in Pregnant Canadian Women. Nutrients. 2017 Mar 23;9(4):317.
18. Hasbaoui BE, Mebrouk N, Saghir S, Yajouri AE, Abilkassem R, Agadr A. Vitamin B₁₂ deficiency: case report and review of literature. Pan Afr Med J. 2021;38:237.
19. Ward MG, Kariyawasam VC, Mogan SB, Patel KV, Pantelidou M, Sobczyńska-Malefora A, et al. Prevalence and Risk Factors for Functional Vitamin B₁₂ Deficiency in Patients with Crohnʼs Disease: Inflamm Bowel Dis. 2015 Dec;21(12):2839–47.
20. Dela Cruz MT, Patel S, Ngo L, Sullivan K. Does long-term use of proton pump inhibitors cause vitamin B₁₂ deficiency? Evid-Based Pract. 2017 Oct;20(10):8–9.
21. Office of Dietary Supplements. Folate Fact Sheet for Health Professionals [Internet]. National Institutes of Healht; 2021 [cited 2021 Nov 8]. Available from: https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/
22. Health Canada. Folic acid and neural tube defects [Internet]. Health Canada; 2018 [cited 2022 Sep 10]. Available from: https://www.canada.ca/en/public-health/ services/pregnancy/folic-acid.html
23. Douglas Wilson R, Van Mieghem T, Langlois S, Church P. Guideline No. 410: Prevention, Screening, Diagnosis, and Pregnancy Management for Fetal Neural Tube Defects. J Obstet Gynaecol Can. 2021 Jan;43(1):124-139.e8.
24. Allen LH. How common is vitamin B-12 deficiency? Am J Clin Nutr. 2009 Feb 1;89(2):693S-696S.
25. Wolffenbuttel BHR, Muller Kobold AC, Sobczyńska‐Malefora A, Harrington DJ. Macro-B₁₂ masking B₁₂ deficiency. BMJ Case Rep. 2022 Jan;15(1):e247660.
26. Lang T, Croal B. National minimum retesting intervals in pathology [Internet]. The Royal College of Pathologists; 2021 [cited 2022 Jan 31]. Available from: https://www.rcpath.org/uploads/assets/253e8950-3721-4aa2-8ddd4bd94f73040e/g147_national-minimum_retesting_intervals_in_pathology.pdf
27. Means R, Fairfield K. Treatment of vitamin B₁₂ and folate deficiencies. Uptodate [Internet]. 2021 [cited 2022 Jan 10]; Available from: https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies?sectionName=Treatment%20of%20vitamin%20B12%20 deficiency&search=vitamin%20b12%20deficiency%20gatric%20resection&topicRef=7155&anchor=H1540931056&source=see_link#H1540931056

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Abbreviation

H2	Histamine
HIV	Human Immunodeficiency virus
IM	Intramuscular
NTDs	Neural tube defects N20 Nitrous oxide
PPI	Proton pump inhibitor
RBC	Red Blood cell

Diagnostic code

Vitamin B₁₂: 92450
Folate: 281.2

Associated Document

• List of contributors (PDF, 59KB)

Practitioner Resources

 

This guideline is based on scientific evidence current as of the effective date.

This guideline was developed by the Guidelines and Protocols Advisory Committee in collaboration with the Provincial Laboratory Medicine Services, and adopted under the Medical Services Act and the Laboratory Services Act.

For more information about how BC Guidelines are developed, refer to the GPAC Handbook available at 
BCGuidelines.ca: GPAC Handbook.

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THE GUIDELINES AND PROTOCOLS ADVISORY COMMITTEE

The principles of the Guidelines and Protocols Advisory Committee are to: encourage appropriate responses to common medical situations recommend actions that are sufficient and efficient, neither excessive nor deficient permit exceptions when justified by clinical circumstances Contact Information: Guidelines and Protocols Advisory Committee PO Box 9642 STN PROV GOVT Victoria BC V8W 9P1 Email: hlth.guidelines@gov.bc.ca Website: www.BCGuidelines.ca Disclaimer The Clinical Practice Guidelines (the “Guidelines”) have been developed by the Guidelines and Protocols Advisory Committee on behalf of the Medical Services Commission. The Guidelines are intended to give an understanding of a clinical problem, and outline one or more preferred approaches to the investigation and management of the problem. The Guidelines are not intended as a substitute for the advice or professional judgment of a health care professional, nor are they intended to be the only approach to the management of clinical problem. We cannot respond to patients or patient advocates requesting advice on issues related to medical conditions. If you need medical advice, please contact a health care professional.

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