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Haematology

Anaemia - B12 and folate deficiency

Last revised in March 2024

Deficiency of vitamin B12 or folate is the most common cause of megaloblastic anaemia.

Anaemia - B12 and folate deficiency: Summary

  • Deficiency of vitamin B12 or folate are the most common causes of megaloblastic anaemia.
  • Megaloblastic anaemia is characterized by the development of larger than normal red blood cells (macrocytosis), with immature nuclei due to defective DNA synthesis.
    • This results in red cells with a mean cell volume (MCV) above the normal range (greater than 100 femtolitres).
  • Pernicious anaemia is the most common cause of severe vitamin B12 deficiency in the UK. Other causes of vitamin B12 deficiency are rare, but include:
    • Drugs — colchicine, metformin, nitrous oxide, protein pump inhibitors, H2-receptor antagonists.
    • Gastric causes — total or partial gastrectomy, congenital intrinsic factor deficiency or abnormality, Zollinger-Ellison syndrome.
    • Inherited — intrinsic factor receptor deficiency (Imerslund Gräsback syndrome).
    • Intestinal causes — malabsorption, ileal resection, Crohn's disease.
    • Nutritional — malnutrition, vegan diet. 
  • Folate deficiency is often caused by problems with dietary intake alone, or in a combination with increased folate usage, or malabsorption. For example: 
    • Drugs — alcohol, anticonvulsants, nitrofurantoin, sulfasalazine, methotrexate, trimethoprim.
    • Excessive requirements in pregnancy, malignancy, blood disorders, or malabsorption.
    • Excessive urinary excretion.
    • Liver disease.
  • Diagnosis of anaemia caused by vitamin B12 or folate deficiency should be made through history, examination, and investigations, including taking a full blood count, blood film, and measuring serum concentrations of folate, and either total B12 (serum cobalamin) or active B12 (serum holotranscobalamin). 
    • An anti-intrinsic factor antibody test should be considered if autoimmune gastritis is suspected, or there are strong clinical features of B12 deficiency.
    • If folate levels are low, and the history suggests malabsorption, tests for anti-endomysial or anti-transglutaminase antibodies should be done (depending on the local laboratory) to exclude coeliac disease.
  • Treatment of B12 deficiency in people with neurologic involvement should include:
    • Seeking urgent specialist advice from a haematologist.
    • If specialist advice is not immediately available, initially treating with hydroxocobalamin 1 mg intramuscularly on alternate days until there is no further improvement, then hydroxocobalamin 1 mg intramuscularly every 2 months should be considered.
  • Treatment of B12 deficiency in other people should depend on the suspect cause.
    • Medicine-induced — intramuscular or oral vitamin B12 should be offered and if appropriate, the medicine reviewed to see if it is still needed or can be changed.
    • Recreational nitrous oxide use — intramuscular or oral vitamin B12 should be offered, and the person advised to stop using nitrous oxide recreationally.
    • Dietary cause — oral vitamin B12 should be considered or intramuscular B12 injections if necessary. 
  • If hydroxocobalamin injection is necessary 1 mg should initially be injected intramuscularly three times a week for 2 weeks — the maintenance dose should depend on whether the deficiency is diet-related or not. 
    • Not diet related — maintenance treatment should usually be with hydroxocobalamin 1 mg intramuscularly every 2-3 months for life. Alternatively, daily large oral doses (500 to 1000 micrograms) should be considered.  
    • Diet related — people should be advised to take cyanocobalamin tablets 50-150 micrograms daily, or have a twice-yearly hydroxocobalamin 1 mg injection. 
  • Treatment of folate deficiency should include:
    • Prescribing oral folic acid 5 mg daily. In most people, treatment will be required for 4 months.
    • Providing dietary advice — good sources of folate are broccoli, Brussels sprouts, asparagus, peas, chickpeas, and brown rice.

Have I got the right topic?

From age 16 years onwards.

This CKS topic is based on expert opinion in medical textbooks, including a chapter on Macrocytic anaemias in the ABC of Clinical Haematology [Hoffbrand, 2023], Hoffbrand's essential haematology [Hoffbrand, 2019], and a chapter on Megaloblastic anaemia and miscellaneous deficiency anaemias in the Oxford textbook of medicine [Hoffbrand, 2020], as well as the British Journal of Haematology Guidelines for the diagnosis and treatment of cobalamin and folate disorders [Devalia, 2014],  a narrative review article Vitamin B12 deficiency [Hunt, 2014] and the BMJ Best Practice guidelines Folate deficiency [BMJ Best Practice, 2021] and Vitamin B12 deficiency [BMJ Best Practice, 2022].

This CKS topic covers the management of the most common macrocytic anaemias: vitamin B12 deficiency anaemia (including pernicious anaemia) and folate deficiency anaemia.

This CKS topic does not cover the management of other causes of macrocytic anaemia, other types of anaemia, macrocytosis in the absence of anaemia, or vitamin B12 deficiency or folate deficiency without anaemia.

There is a separate CKS topic on Anaemia - iron deficiency.

The target audience for this CKS topic is healthcare professionals working within the NHS in the UK, and providing first contact or primary healthcare.

How up-to-date is this topic?

Changes

March 2024 — minor update. Recommendations from the NICE guideline Vitamin B12 deficiency in over 16s: diagnosis and management have been incorporated into this topic.  

Previous changes

April 2023 — reviewed. A literature search was conducted in March 2023 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials published since the last revision of the topic. No major changes to recommendations have been made. Update to the prevalence data for B12 deficiency added. 

March 2022 — minor update. Update to the management of neurological complications added the recommendation to seek advice from a neurologist. 

June 2020 — minor update. Recommendations on how to manage people during the COVID-19 pandemic who normally receive intramuscular injections of vitamin B12 have been added in line with the British Society for Haematology (BSH) guidance on Vitamin B12 replacement during the COVID-19 pandemic.

February 2019 — minor update. Maintenance dose schedule for hydroxocobalamin changed to every 2-3 months in line with the British National Formulary (BNF) .

April 2018 — reviewed. A literature search was conducted in March 2018 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials published since the last revision of the topic. 

July 2015 — minor update. The section on prescribing issues has been amended to reflect the fact that cyanocobalamin tablets are no longer listed in Part XVIIIB of the Drug Tariff, hence prescriptions no longer need to be endorsed with 'SLS' (Selected List Scheme).

November 2014 — minor update. Text about how and when to check for an underlying cause of vitamin B12 deficiency such as pernicious anaemia has been amended to be in line with the British Journal of Haematology Guidelines for the diagnosis and treatment of cobalamin and folate disorders.

February 2013 — reviewed. A literature search was conducted in January 2013 to identify evidence-based guidelines, UK policy, systematic reviews, and key RCTs published since the last revision of the topic. No major changes to clinical recommendations have been made.

January 2011 — topic structure revised to ensure consistency across CKS topics — no changes to clinical recommendations have been made.

February 2009 — minor update. Summary of Product Characteristics for Neo-cytamen®(hydroxocobalamin) updated to include information regarding monitoring platelets. Prescribing information has been updated.

December 2007 to April 2008 — converted from CKS guidance to CKS topic structure. The evidence-base has been reviewed in detail, and recommendations are more clearly justified and transparently linked to the supporting evidence. There are no major changes to the recommendations. The topic has been retitled as it covers in detail the management of vitamin B12and folate deficiency anaemia, but not other causes of macrocytic anaemia. New sections have been included on how to investigate and when to refer a person with vitamin B12 or folate deficiency anaemia.

November 2005 — minor technical update. 

July 2005 — updated to incorporate the Referral guidelines for suspected cancer published by the National Institute for Health and Clinical Excellence. 

August 2004 — reviewed. Validated in November 2004 and issued in February 2005.

July 2001 — reviewed. Validated in November 2001 and issued in April 2002.

October 2000 — updated to incorporate the Department of Health Referral Guideline for Suspected Upper Gastrointestinal Cancer.

January 1999 — written. Validated in March 1999 and issued in May 1999.

Update

New evidence

Evidence-based guidelines

HTAs (Health Technology Assessments)

No new HTAs since 1 March 2023.

Economic appraisals

No new economic appraisals relevant to England since 1 March 2023.

Systematic reviews and meta-analyses

No new systematic reviews published since 1 March 2023.

Primary evidence

No new primary evidence which reaches the CKS threshold for inclusion published since 1 March 2023.

New policies

No new national policies or guidelines since 1 March 2023.

New safety alerts

No new safety alerts since 1 March 2023.

Changes in product availability

No changes in product availability since 1 March 2023.

Goals and outcome measures

Goals

To support primary healthcare professionals to:

  • Make a diagnosis of vitamin B12 and folate deficiency anaemia.
  • Investigate the underlying cause.
  • Treat B12 and folate deficiency anaemia effectively.
  • Refer to specialists where appropriate.

Outcome measures

No outcome measures were found during review of this topic. 

Audit criteria

No audit criteria were found during the review of this topic.

QOF indicators

No QOF indicators were found during the review of this topic.

QIPP - Options for local implementation

No QIPP indicators were found during the review of this topic.

NICE quality standards

No NICE quality standards were found during the review of this topic.

Background information

What is it?

  • Deficiencies of vitamin B12 or folate are the most frequent causes of megaloblastic anaemia.
    • Megaloblastic anaemia is characterized by larger than normal red blood cells developing in the bone marrow (macrocytosis), with immature nuclei due to defective DNA (deoxyribonucleic acid) synthesis. Macrocytosis is an increase in the mean red cell volume to above the normal range (greater than 100 femtolitres).
    • For causes of non-megaloblastic macrocytic anaemia, see the section on Differential diagnosis.
  • Anaemia is defined by haemoglobin (Hb) levels:
    • In children aged 12–14 years — Hb concentration less than 120 g/L.
    • In men (aged over 15 years) — Hb concentration less than 130 g/L.
    • In women (aged over 15 years) — Hb concentration less than 120 g/L.
    • In women who are pregnant — Hb concentration less than 110 g/L.
      • An Hb level of 110 g/L or more appears adequate in the first trimester, a level of 105 g/L appears adequate in the second and third trimesters.
    • Postpartum — Hb concentration less than 100 g/L.
    • Note: the normal range for Hb differs between different populations in the UK, and so it is reasonable to use the lower limit of the normal range for the laboratory performing the test to define anaemia.
  • There is no gold standard test for measuring vitamin B12 deficiency, but the likelihood of deficiency can be determined by measuring serum cobalamin. 
    • A serum cobalamin of less than 200 nanograms/L is sensitive enough to diagnose 97% of people with vitamin B12 deficiency.
  • There is no clear consensus on the level of serum folate that indicates deficiency. Conventionally, a serum folate lower than 3 micrograms/L is used as a guideline as the risk of megaloblastic anaemia greatly increases below this level.

[Goddard, 2011; Hoffbrand, 2019; Hoffbrand, 2020; Pavord, 2020; BMJ Best Practice, 2021; BMJ Best Practice, 2022; Hoffbrand, 2023]

What causes it?

Vitamin B12 deficiency

  • Body stores of vitamin B12 are in the region of 2–5 mg, which is sufficient to last for 2–5 years.
  • Vitamin B12 combines with intrinsic factor (IF), which is produced by parietal cells in the stomach, to form an IF–B12 complex. The complex binds to surface receptors for IF in the distal ileum, which then allows absorption of vitamin B12 to take place.
  • Pernicious anaemia (an autoimmune disorder which results in reduced production of IF) is the most common cause of severe vitamin B12 deficiency.
  • Other causes of vitamin B12 deficiency are rare, but include:
    • Drugs — colchicine, metformin, nitrous oxide, protein pump inhibitors, H2-receptor antagonists. 
    • Gastric — total or partial gastrectomy, congenital intrinsic factor deficiency or abnormality, Zollinger-Ellison syndrome.
    • Inherited — intrinsic factor receptor deficiency (Imerslund Gräsback syndrome), congenital intrinsic factor deficiency (juvenile pernicious anaemia), cobalamin mutation, transcobalamin deficiency.
    • Intestinal — malabsorption (for example gluten-induced enteropathy), ileal resection, Crohn's disease, blind loop syndrome, parasites (for example, giardiasis, fish tapeworm).
    • Nutritional — malnutrition, vegan diet.

[Devalia, 2014; Hoffbrand, 2019; Hoffbrand, 2020; BMJ Best Practice, 2022; Hoffbrand, 2023]

Pernicious anaemia

  • Pernicious anaemia is caused by an autoimmune process which affects the gastric mucosa, leading to atrophy. This atrophy reduces the number of parietal cells which secrete intrinsic factor (IF). IF is essential for the absorption of vitamin B12. 
    • Antibodies to IF are very specific for pernicious anaemia, however, they are present in only 50% to 70% of people with the condition.
    • Anti-parietal cell antibodies occur in 90% of people with pernicious anaemia, however, they are less specific and common in older people (for example, 16% of women aged over 60 years) who do not have pernicious anaemia.
  • Pernicious anaemia affects more women than men, with a ratio of 1.6:1, and a peak occurrence in those aged 60 years. 
  • People with pernicious anaemia are at increased risk of developing gastric cancer (2–3% of all cases of pernicious anaemia), and there is an association with other autoimmune diseases (including myxoedema, thyrotoxicosis, Hashimoto's disease, Addison's disease, and vitiligo).

[Hoffbrand, 2019; BMJ Best Practice, 2022]

Folate deficiency

  • Folate is usually absorbed through the upper part of the small intestine and body stores are around 10–12 mg, which is sufficient for around 4 months.
  • Folate deficiency is often caused by problems with dietary intake alone, or in a combination with increased folate usage, or malabsorption. Causes can be categorised as due to:
    • Drugs — alcohol, anticonvulsants, nitrofurantoin, sulfasalazine, methotrexate, trimethoprim.
    • Increased requirements, for example, due to:
      • Pregnancy and lactation, prematurity.
      • Malignancy (for example leukaemia, carcinoma, or lymphoma).
      • Blood disorders (for example haemolytic anaemias, sickle cell anaemia, myelofibrosis).
      • Inflammatory diseases (for example tuberculosis, Crohn's disease, or malaria).
      • Exfoliative skin diseases.
    • Excessive urinary excretion (for example due to congestive heart failure, acute liver damage, or chronic dialysis).
    • Liver disease.
    • Malabsorption — due to coeliac disease, tropical sprue, congenital specific malabsorption, jejunal resection, or inflammatory bowel disease.
    • Nutrition — alcoholism or poor diet.

[Hoffbrand, 2019; Hoffbrand, 2020; BMJ Best Practice, 2021; Hoffbrand, 2023]

How common is it?

  • The prevalence of B12 deficiency anaemia in the UK is not well-defined. However, from international data (USA and Netherlands) it would appear to affect at least 3% of those aged 20–39 years old, 4% of those aged 40–59 years, and 6% of those 60 years or over rising to over 20 % in the age group 85 and older.
    • Marginal depletion, where serum cobalamin ranges from 148–221 picomol/L, affects 15% of those aged 20–59 years old and more than 20% of those aged 60 years or over.
    • For people with vegan diets, around 11% are deficient in vitamin B12.
  • Adult pernicious anaemia (the most common cause of B12 deficiency and megaloblastic anaemia) occurs most commonly in people aged 40–70 years, with a mean age of onset of 60 years among white people.
    • In black people the mean age is 50 years, with a bimodal distribution due to an increased occurrence in young black females.
    • The prevalence of pernicious anaemia varies geographically but overall has been estimated at 0.1% in the general population and 1.9% in those aged 60 years and over.
  • The prevalence of folate deficiency (serum folate below the World Health Organization [WHO] clinical threshold for folate deficiency [7 nanomol/L]) amongst adults and children is no more than 5%.

[Shipton, 2015; Stouten, 2016; PHE, 2017; Hoffbrand, 2019; Hoffbrand, 2020; BMJ Best Practice, 2021; Htut, 2021; BMJ Best Practice, 2022; Hoffbrand, 2023]

What are the complications?

  •  Complications of anaemia
    • Adults (especially the elderly) with severe anaemia are at risk of cardiopulmonary complications, such as heart failure.
  • Complications of vitamin B12 deficiency
    • Neurological symptoms — for example, paraesthesia, ataxia, progressive symmetrical neuropathy which affects the legs more than the arms, numbness, poor motor coordination, memory lapses, and age-related cognitive impairment.
      • Optic atrophy and severe psychiatric symptoms occur rarely. 
    • Note: neurological disorders can occur independently of the haematological manifestations of pernicious anaemia.
  • Complications of folate deficiency
    • Maternal folate deficiency in pregnancy is associated with prematurity.
      • However, a systematic review of 31 trials (involving 17,771 women) showed that folic acid supplementation during pregnancy did not reduce the risk of preterm birth.
    • Folate deficiency may be associated with cardiovascular disease, and studies have produced conflicting results regarding cancer risk.
      • However, meta-analysis has shown no difference in cancer risk between people randomised in clinical trials to take folic acid for two years or more, and those taking placebo.
  • Complications that can occur with either vitamin B12 or folate deficiency
    • Vitamin B12 or folate deficiency in pregnancy increases the risk of neural tube defects (such as spina bifida, anencephaly, and encephalocele) in the foetus. Incidence of neural tube defects increases with decreasing serum folate or vitamin B12 levels.
    • Nutritional deficiency of vitamin B12 or folate may cause ineffective production of any types of blood cells derived from bone marrow.
    • Vitamin B12 or folate deficiency may cause sterility. This is reversible with appropriate vitamin supplementation.

[Lassi, 2013; Sinning, 2013; Hoffbrand, 2019; Hoffbrand, 2020; BMJ Best Practice, 2021; BMJ Best Practice, 2022; Hoffbrand, 2023]

Diagnosis of anaemia - B12 and folate deficiency

How should I assess a person with suspected vitamin B12 or folate deficiency?

  • Diagnosis of anaemia caused by vitamin B12 or folate deficiency is made through history, examination and investigations.
  • Take a detailed medical history, and ask about:
    • Symptoms of anaemia, vitamin B12 and folate deficiency.
    • Possible causes of deficiency, such as:
      • Personal or family history of autoimmune diseases. 
      • Diet — vegan or vegetarian.
      • Drug history.
  • Examine the person to look for signs of anaemia, B12 and folate deficiency.
  • Arrange necessary investigations.
  • Consider non-megaloblastic causes of macrocytosis. 

Basis for recommendation

The recommendations on assessment of a person with suspected vitamin B12 or folate deficiency are based on expert opinion in the British Journal of Haematology Guidelines for the diagnosis and treatment of cobalamin and folate disorders [Devalia, 2014], the National Institute for Health and Care Excellence (NICE) guideline Vitamin B12 deficiency in over 16s: diagnosis and management [NICE, 2024], and BMJ Best Practice guidelines Folate deficiency [BMJ Best Practice, 2021] and Vitamin B12 deficiency [BMJ Best Practice, 2022].

Arranging diagnostic tests for B12 deficiency

  • NICE recommends offering an initial diagnostic test for vitamin B12 deficiency to people who have at least one common symptom or sign and at least one common risk factor for the condition, and using clinical judgement when deciding whether to test people who have at least one common symptom or sign but no common risk factors [NICE, 2024].

What are the signs and symptoms of vitamin B12 or folate deficiency anaemia?

  • The main clinical features of megaloblastic anaemia are similar regardless of the underlying cause. This includes whether it is caused by folate deficiency, or vitamin B12 deficiency, except that severe neuropathy does not occur with folate deficiency.
    • The onset of megaloblastic anaemia is usually insidious, with gradually progressive signs and symptoms. 
    • Anaemia due to pernicious anaemia may develop gradually over several years, and symptoms may not appear until it is severe.
    • Note: clinical features of vitamin B12 deficiency can occur without anaemia and without low serum levels of vitamin B12.
  • Symptoms of vitamin B12 and folate deficiency include:
    • Cognitive changes. 
    • Dyspnoea. 
    • Headache.
    • Indigestion.
    • Loss of appetite.
    • Palpitations.
    • Tachypnoea.
    • Visual disturbance. 
    • Weakness, lethargy. 
  • People with pernicious anaemia may present with symptoms of associated disorders, for example, myxoedema, other thyroid disorders, vitiligo, stomach cancer, or Addison's disease.
  • Signs of vitamin B12 and folate deficiency include:
    • Anorexia.
    • Angina (in older people). 
    • Angular cheilosis.
    • Brown pigmentation affecting nail beds and skin creases (but not mucous membranes).
    • Congestive heart failure (in older people).
    • Episodic diarrhoea.
    • Glossitis — red smooth and shiny tongue, perhaps with ulcers.
    • Heart murmurs. 
    • Liver enlargement. 
    • Mild jaundice — a lemon-yellow tint. 
    • Mild pyrexia.
    • Oropharyngeal ulceration. 
    • Pallor of mucous membranes or nail beds. 
    • Tachycardia. 
    • Weight loss.
  • Neurological complications associated with vitamin B12 deficiency include:
    • Loss of cutaneous sensation.
    • Loss of mental and physical drive. 
    • Muscle weakness.
    • Optic neuropathy.
    • Psychiatric disturbances – these range from mild neurosis to severe dementia. 
    • Symmetrical neuropathy affecting the legs more than the arms — this usually presents with ataxia or paraesthesia.
    • Urinary or faecal incontinence.

Basis for recommendation

The information on signs and symptoms of B12 and folate deficiency is based on expert opinion in the medical textbook Hoffbrand's essential haematology [Hoffbrand, 2019], a chapter on Megaloblastic anaemia and miscellaneous deficiency anaemias in the Oxford textbook of medicine [Hoffbrand, 2020], the BMJ Best Practice guidelines Folate deficiency [BMJ Best Practice, 2021] and Vitamin B12 deficiency [BMJ Best Practice, 2022] and a narrative review article Vitamin B12 deficiency [Hunt, 2014].

What investigations should I do to confirm vitamin B12 or folate deficiency?

  • For people with suspected vitamin B12 or folate deficiency, initially arrange: 
    • A full blood count to determine mean cell volume (MCV), haematocrit and haemoglobin levels, and a blood film, which help to identify megaloblastic anaemia. 
    • Measurement of either total B12 (serum cobalamin) or active B12 (serum holotranscobalamin) as the initial test for suspected vitamin B12 deficiency unless: 
      • The test needs to be done during pregnancy — use active B12 as the initial test.
      • Recreational nitrous oxide use is the suspected cause of deficiency — use serum methylmalonic acid (MMA) as the initial test, or plasma homocysteine (this requires referral to secondary care).
    • Measurement of folate levels. 
    • Additional investigations, such as liver function tests, gamma-glutamyl transpeptidase, and/or thyroid function tests  — may be required depending on clinical judgement to rule out other causes of macrocytic anaemia. For more information, see the section on Differential diagnosis.
  • When offering an initial diagnostic test, ask the person if they are already using an over-the-counter preparation that contains vitamin B12 (including vitamin B12 tablets, injections or transdermal patches), and what type and dosage they are using. 
  • Do not delay vitamin B12 replacement while waiting for the test results of people with suspected megaloblastic anaemia and neurological symptoms, especially symptoms related to sub-acute combined degeneration of the spinal cord.
  • Consider starting vitamin B12 replacement while waiting for test results for people with suspected vitamin B12 deficiency that is suspected to be an adverse effect of a medicine. 
  • For information on how to interpret results, see the section on interpreting investigation results.

Basis for recommendation

The recommendations on investigations for people with suspected B12 or folate deficiency are based on expert opinion in the British Journal of Haematology Guidelines for the diagnosis and treatment of cobalamin and folate disorders [Devalia, 2014], the National Institute for Health and Care Excellence (NICE) guideline Vitamin B12 deficiency in over 16s: diagnosis and management [NICE, 2024], a narrative review article Vitamin B12 deficiency [Hunt, 2014], and the chapter on Megaloblastic anaemia and miscellaneous deficiency anaemias in the medical textbook Oxford textbook of medicine [Hoffbrand, 2020].

How should I interpret investigation results?

  • Full blood count
    • A high mean cell volume ([MCV] greater than 100 femtolitres) is indicative of macrocytosis, however, MCV may be normal if there is associated iron deficiency, or if anaemia develops more rapidly over the course of a few weeks. For more information, see the CKS topic on Anaemia - iron deficiency.
    • A normal MCV does not exclude the need for cobalamin testing, as neurological impairment occurs with a normal MCV in 25% of cases.
    • The white cell count and platelet count may be reduced if the anaemia is severe.
    • There may be a low reticulocyte count in relation to the degree of anaemia (usually 1–3%).
  • Blood film 
    • Hypersegmented neutrophils (more than 5% of neutrophils with five or more lobes, or one or more neutrophils with 6 or more lobes) and the presence of oval macrocytes, may suggest either vitamin B12 or folate deficiency, but their presence is not sensitive or specific in early cobalamin deficiency.
      • Oval macrocytes, hypersegmented neutrophils and circulating megaloblasts in the blood film, as well as megaloblastic change in the bone marrow, are typical features of clinical cobalamin deficiency.
  • Vitamin B12 level
    • Interpret the results of the serum cobalamin test taking into account clinical symptoms, other laboratory findings and the following limitations:
      • The clinically normal level for cobalamin is unclear, although it is thought that serum cobalamin of less than 200 nanograms/L (148 picomol/L) is sensitive enough to diagnose 97% of people with vitamin B12 deficiency.
      • Cobalamin levels are not easily correlated with clinical symptoms, although people with cobalamin levels of less than 100 nanograms/L (75 picomol/L) usually have clinical or metabolic evidence of vitamin B12 deficiency. In the elderly, low serum cobalamin concentrations usually in the range 100–160 nanograms/L may occur in the absence of anaemia or macrocytosis, and clinically significant vitamin B12 deficiency may be present even with cobalamin levels in the normal range.
      • Women taking oral contraceptives may show decreased cobalamin levels because of a decrease in cobalamin carrier protein, however, this may not result in deficiency.
      • People already taking vitamin B12 may have increased total or active B12 concentrations without fully treating deficiency.  
      • Serum cobalamin levels fall in pregnancy and are less reliable in determining deficiency. 
      • Note: reference values (and units) may vary between laboratories.
    • NICE recommends using the following thresholds to interpret test results: 
      • Confirmed deficiency — total B12 (serum cobalamin) concentration less than 180 nanograms/L (133 picomol/L) or active B12 concentration (serum holotranscobalamin) less than 25 picomol/L. 
      • Possible deficiency — total B12 concentration 180-350 nanograms/L (133-258 picomol/L) or active B12 concentration 25-70 picomol/L. 
      • Unlikely to be deficiency — total B12 concentration more than 350 nanograms/L (258 picomol/L) or active B12 concentration more than 70 picomol/L. 
    • Consider a further test to measure serum methylmalonic acid (MMA) concentrations in people who have symptoms or signs of vitamin B12 deficiency and an indeterminate total or active B12 test result. 
    • Be aware that people of Black ethnicity may have a higher reference range for serum vitamin B12 concentrations than people of White or Asian ethnicity. 
  • Folate level
    • Serum folate of less than 7 nanomol/L (3 micrograms/L) is used as a guide to indicate folate deficiency.
    • However, there is an indeterminate zone with folate levels of 7–10 nanomol/L (3–4.5 micrograms/L), so low folate should be interpreted as suggestive of deficiency and not diagnostic.
    • If there is a strong clinical suspicion of folate deficiency but normal serum levels, red cell folate can be measured once cobalamin deficiency has been ruled out.
      • A red cell folate level below 340 nanomol/L (150 micrograms/L) is consistent with clinical folate deficiency in the absence of vitamin B12 deficiency.
  • For information on how to manage people with confirmed B12 or folate deficiency, see the section on confirmed deficiency.

Basis for recommendation

The recommendations on interpreting investigation results are based on expert opinion in the British Journal of Haematology Guidelines for the diagnosis and treatment of cobalamin and folate disorders [Devalia, 2014], the National Institute for Health and Care Excellence (NICE) guideline Vitamin B12 deficiency in over 16s: diagnosis and management [NICE, 2024], the chapter on Megaloblastic anaemia and miscellaneous deficiency anaemias in the Oxford textbook of medicine [Hoffbrand, 2020] and the BMJ Best Practice guideline Folate deficiency [BMJ Best Practice, 2021].

Oral contraception or hormone replacement therapy (HRT)

  • Asymptomatic women taking oral contraception or HRT with mildly reduced serum cobalamin (150–200 nanograms/L or 110–148 picomol/L) do not require further investigation, but should be advised to review their dietary intake of cobalamin-rich foods. Cobalamin supplements may also be considered [Devalia, 2014].

B12 thresholds

  • NICE advises that where there is substantial local variation in total B12 validated thresholds, thresholds set by the laboratory doing the testing should be used [NICE, 2024].

How should I manage people with confirmed vitamin B12 or folate deficiency?

  • Determine whether there is an underlying cause for the vitamin B12 or folate deficiency — this may require specialist referral.
  • If folate levels are low, assess dietary folic acid intake, and if history suggests malabsorption, check for coeliac disease by testing for antiendomysial or antitransglutaminase antibodies (depending on the local laboratory).
    • The main cause of folate malabsorption is gluten-induced enteropathy. 
  • For people with confirmed vitamin B12 deficiency, consider an anti-intrinsic factor antibody test if autoimmune gastritis is suspected and they have not previously had: 
    • A positive anti-intrinsic factor antibody test at any time, or
    • An operation that could affect vitamin B12 absorption (such as total gastrectomy or complete terminal ileal resection).
  • Also consider checking for serum anti-intrinsic factor antibodies in people with strong clinical features of B12 deficiency, such as megaloblastic anaemia or subacute combined degeneration of the cord, despite a normal cobalamin level. 
  • If vitamin B12 deficiency is diagnosed in pregnancy or during breastfeeding and autoimmune gastritis is the suspected cause start treatment with intramuscular vitamin B12 replacement without waiting for the test result. 
  • When interpreting anti-intrinsic factor antibody test results follow the guidance provided by the laboratory doing the test and be aware that a negative test result does not rule out the presence of autoimmune gastritis. 
  • Offer serological testing for coeliac disease where the cause of vitamin B12 deficiency is still unknown after further investigations. 
  • Determine whether the person has experienced complications of anaemia, vitamin B12 or folate deficiency.
  • Refer or treat the person where appropriate depending on the suspected cause.

Basis for recommendation

The recommendations on further tests required for people with confirmed B12 or folate deficiency are based on expert opinion in the British Journal of Haematology Guidelines for the diagnosis and treatment of cobalamin and folate disorders [Devalia, 2014], the National Institute for Health and Care Excellence (NICE) guideline Vitamin B12 deficiency in over 16s: diagnosis and management [NICE, 2024], the chapter on Macrocytic anaemias in the ABC of Clinical Haematology, the chapter on Megaloblastic anaemia and miscellaneous deficiency anaemias in the Oxford textbook of medicine [Hoffbrand, 2020] and the BMJ Best Practice guidelines Folate deficiency [BMJ Best Practice, 2021] and Vitamin B12 deficiency [BMJ Best Practice, 2022].

Anti-intrinsic factor antibodies

  • Anti-intrinsic factor antibody is extremely specific for pernicious anaemia, with a high positive predictive value of 95%, but a low sensitivity of 40–60%. If anti-intrinsic factor antibody is present, pernicious anaemia is very likely, but its absence does not rule out a diagnosis of pernicious anaemia [Devalia, 2014].

What else might it be?

  • Vitamin B12 and folate deficiencies are not the only causes of macrocytosis.
  • Other (non-megaloblastic) causes of macrocytosis include:
    • Alcohol — may cause macrocytosis with neither anaemia nor a change in liver function.
      • Alcohol is the most frequent cause of a raised mean cell volume (MCV) in the absence of anaemia.
    • Drugs — antimetabolites, such as hydroxycarbamide, methotrexate and azathioprine.
    • Haematological abnormalities such as:
      • Myelodysplasia.
      • Aplastic anaemia.
      • Pure red cell aplasia.
      • Plasma protein changes (for example myeloma).
      • Reticulocytosis.
    • Liver disease — chronic liver disease is associated with anaemia that is mildly macrocytic.
    • Pregnancy and the neonatal period.
    • Severe thyroid deficiency — anaemia caused by hypothyroidism is often macrocytic. However, MCV falls once thyroxine treatment is started. 
    • Smoking.

Basis for recommendation

The information on the differential diagnoses of B12 and folate deficiency is based on expert opinion in the medical textbook Hoffbrand's essential haematology [Hoffbrand, 2019], a chapter on Macrocytic anaemias in the ABC of Clinical Haematology [Hoffbrand, 2023], a chapter on Megaloblastic anaemia and miscellaneous deficiency anaemias in the Oxford textbook of medicine [Hoffbrand, 2020], and the BMJ Best Practice guidelines Folate deficiency [BMJ Best Practice, 2021] and Vitamin B12 deficiency [BMJ Best Practice, 2022].

Management

Scenario: Management of anaemia - vitamin B12 and folate deficiency

From age 16 years onwards.

How should I treat a person with vitamin B12 deficiency anaemia?

For people with neurological involvement

  • Seek urgent specialist advice from a neurologist and/or haematologist.
  • Ideally, management should be guided by a specialist, but if specialist advice is not immediately available, consider the following:
    • Initially administer hydroxocobalamin 1 mg intramuscularly on alternate days until there is no further improvement, then administer hydroxocobalamin 1 mg intramuscularly every 2 months.

For people with no neurological involvement

  • If B12 deficiency is medicine-induced: 
    • Offer either intramuscular or oral vitamin B12 replacement (based on clinical judgement and the person's preference) while they are taking the medicine causing the adverse effect, and if appropriate, review the use of the medicine that is causing the adverse effect to see if it is still needed or can be changed.
    • Review the need for vitamin B12 replacement if the medicine causing the adverse effect is stopped or changed and the person no longer has symptoms of vitamin B12 deficiency.
  • If B12 deficiency is caused by recreational nitrous oxide use: 
    • Offer either intramuscular or oral vitamin B12 replacement (based on clinical judgement and the person's preference).
    • Advise the person to stop using nitrous oxide recreationally.
    • Review the need for vitamin B12 replacement if the person stops using nitrous oxide recreationally and no longer has symptoms of vitamin B12 deficiency.
  • If B12 deficiency has a suspected dietary cause: 
    • Ask what they eat or drink, including any foods or drinks that contain vitamin B12. 
    • Ask if they are taking, or planning to take, any over-the-counter preparations containing vitamin B12 — if the person is taking, or plans to take, over-the-counter oral supplements that contain vitamin B12: 
      • Explain that some supplements do not contain enough, or the right type, of vitamin B12 to be effective.
      • Advise them to pick an oral supplement that contains at least one of the following: cyanocobalamin, methylcobalamin, or adenosylcobalamin.
    • Check whether they have any symptoms, signs or risk factors that could suggest another cause of vitamin B12 deficiency.
    • Be aware that diet (for example, a vegetarian or vegan diet) may not be the cause, or the only cause, of a person's vitamin B12 deficiency.
      • Consider further investigations to explore other causes of vitamin B12 deficiency if, during discussions, the person suggests or gives information that raises suspicion that the deficiency is not linked to their diet.
    • If the person has suspected or confirmed vitamin B12 deficiency because their diet is lacking in vitamin B12: 
      • Tell them where to find information on how to improve their intake of vitamin B12, including information about food sources — for example, the NHS webpage on B vitamins.  
      • Consider oral vitamin B12 replacement. 
    • Consider intramuscular vitamin B12 injections instead of oral replacement for suspected or confirmed vitamin B12 deficiency caused by diet if: 
      • The person has another condition that may deteriorate rapidly and have a major effect on their quality of life (for example, a neurological or haematological condition such as ataxia or anaemia). 
      • There are concerns about adherence to oral treatment, for example, if the person is older, is or has recently been in hospital and has either multimorbidity or frailty, has delirium or cognitive impairment, or is affected by social issues that may prevent them accessing care, such as homelessness. 
  • If the cause of B12 deficiency is unknown:
    • Offer vitamin B12 replacement and consider oral instead of intramuscular vitamin B12 replacement and review response to treatment at the person's first follow-up appointment.
  • If hydroxocobalamin injection is considered necessary, initially administer 1 mg intramuscularly three times a week for 2 weeks. 
  • The maintenance dose depends on whether the deficiency is diet-related or not. For people with B12 deficiency that is: 
    • Not thought to be diet related — administer hydroxocobalamin 1 mg intramuscularly every 2–3 months for life. Alternatively, daily large oral doses (500 to 1000 micrograms) can be considered for maintenance therapy. 
      • When offering oral vitamin B12 replacement in pregnancy or during breastfeeding, consider a dosage of at least 1 mg a day. 
    • Thought to be diet related — advise people either to take oral cyanocobalamin tablets 50–150 micrograms daily between meals, or have a twice-yearly hydroxocobalamin 1 mg injection. 
      • In vegans, treatment may need to be life-long, whereas in other people with dietary deficiency replacement treatment can be stopped once the vitamin B12 levels have been corrected and the diet has improved.

Basis for recommendation

The recommendations on treating vitamin B12 deficiency anaemia are based on expert opinion in medical textbooks, including Hoffbrand's essential haematology [Hoffbrand, 2019], a chapter on Megaloblastic anaemia and miscellaneous deficiency anaemias in the Oxford textbook of medicine [Hoffbrand, 2020], the National Institute for Health and Care Excellence (NICE) guideline Vitamin B12 deficiency in over 16s: diagnosis and management [NICE, 2024], and a chapter on Macrocytic anaemias in the ABC of Clinical Haematology [Hoffbrand, 2023], as well as a BMJ Best Practice guideline Vitamin B12 deficiency [BMJ Best Practice, 2022], a narrative review article Vitamin B12 deficiency [Hunt, 2014], and the British National Formulary (BNF) [BNF, 2023]​​​​.

Acute parenteral therapy
  • Expert opinion is that people with megaloblastic anaemia and/or neuropathy caused by B12 deficiency should initially be offered B12 injections to rapidly correct the deficiency [Hoffbrand, 2019; Hunt, 2014]. 
High-dose oral maintenance therapy
  • After initial correction of a vitamin B12 deficiency, daily large oral doses of B12 can be considered for maintenance therapy as an alternative to three-monthly injections, in people whose B12 deficiency is not diet-related [Hoffbrand, 2019; BMJ Best Practice, 2022].
  • Large doses are required to achieve sufficient absorption in people with pernicious anaemia (PA) [Hoffbrand, 2019].
  • CKS pragmatically recommends that clinical judgement is exercised when determining the most appropriate exposure route for maintenance therapy, as the underlying condition is likely to affect absorption, and compliance with high-dose long-term oral therapy may be an issue for some people.
  • This is supported by expert opinion that oral cobalamin may be less suitable in severely deficient patients and those with malabsorption, and that high-dose oral cobalamin should only be considered in specific cases, where intramuscular injections are not tolerated, and compliance is likely [Hunt, 2014].

How should I treat a person with folate deficiency anaemia?

  • Prescribe oral folic acid 5 mg daily — in most people, treatment will be required for 4 months.
    • However, folic acid may need to be taken for longer (sometimes for life) if the underlying cause of deficiency is persistent.
  • Check vitamin B12 levels in all people before starting folic acid — treatment can improve wellbeing, mask underlying B12 deficiency, and allow neurological disease to develop.
  • Give dietary advice about foods that are a good source of folic acid — good sources of folate include:
    • Asparagus.
    • Broccoli.
    • Brown rice.
    • Brussels sprouts.
    • Chickpeas.
    • Peas.
  • For information on folic acid supplementation in pregnancy, see the CKS topic on Pre-conception - advice and management.

Basis for recommendation

The recommendations on treating folate deficiency are based on expert opinion in the chapter on Megaloblastic anaemia and miscellaneous deficiency anaemias in the Oxford textbook of medicine [Hoffbrand, 2020] and a BMJ Best Practice guideline Folate deficiency [BMJ Best Practice, 2021].

When should I refer a person with vitamin B12 or folate deficiency anaemia?

  • Seek urgent advice from a haematologist if the person has neurological symptoms, or is a pregnant woman.
  • Refer to a haematologist if:
    • The cause of vitamin B12 or folate deficiency is uncertain, or unclear following investigations.
    • Haematological malignancy or other blood disorder is suspected — refer urgently using a suspected cancer pathway referral (for an appointment within 2 weeks). 
    • The person does not respond to treatment.
    • The mean cell volume is persistently greater than 105 femtolitres.
  • Refer to a gastroenterologist if:
    • Malabsorption or an inflammatory bowel disorder is suspected.  
    • The person has pernicious anaemia and gastrointestinal symptoms, especially if there is a suspicion of gastric cancer (for example co-existing iron deficiency).
      • If gastric cancer is suspected, refer urgently using a suspected cancer pathway referral (for an appointment within 2 weeks). 
  • Consider referral to a dietician if vitamin B12 or folate deficiency is thought to be due to a poor diet.

Basis for recommendation

The recommendations on when to refer are based on expert opinion in a narrative review Vitamin B12 deficiency [Hunt, 2014], the National Institute for Health and Care Excellence (NICE) guideline Suspected cancer: recognition and referral [NICE, 2021],  a chapter on Macrocytic anaemias in the medical textbook ABC of Clinical Haematology [Hoffbrand, 2023], and are also pragmatic, based on what CKS considers to be good clinical practice.

What monitoring is required after treatment for vitamin B12 or folate deficiency has started?

  • Perform a full blood count and reticulocyte count:
    • Within 7–10 days of starting treatment.
      • A rise in the haemoglobin level and an increase in the reticulocyte count to above the normal range indicates that treatment is having a positive effect.
      • If there is no improvement following initial B12 treatment, check serum folate level (if this has not been done already).
    • After 8 weeks of treatment.
      • Blood counts and mean cell volume should have normalised.
      • At this point, also measure iron and folate levels in people being treated for B12 deficiency to ensure that other deficiencies have not been masked.
    • On completion of folic acid treatment to confirm a response.
  • At each follow-up appointment, ask the person if their symptoms have improved or worsened, or if they are experiencing new symptoms that could be linked to vitamin B12 deficiency.
  • For people taking oral vitamin B12 replacement: 
    • Check they are taking the correct dosage. 
    • If symptoms have not sufficiently improved and they are still interfering with their normal daily activities, take into account their treatment preferences and either: 
      • Increase the oral dosage to the maximum licensed dosage, or
      • If they are already taking the maximum licensed dosage for oral treatment, switch to intramuscular vitamin B12 injections.
    • If the person has new or worsening symptoms, consider alternative diagnoses and do one of the following: 
      • Consider further testing with serum methylmalonic acid (MMA), or plasma homocysteine if this test is not available, and continue with existing treatment while waiting for the test result if the person did not have serum MMA or plasma homocysteine as an initial diagnostic test. 
      • If the person had serum MMA or plasma homocysteine as an initial diagnostic test, take into account their treatment preferences and either increase the oral dosage to the maximum licensed dosage, or if they are already taking the maximum licensed dosage for oral treatment, switch to intramuscular vitamin B12 injections.
    • If a further test to measure either serum MMA or plasma homocysteine suggests a vitamin B12 deficiency, or the result is uncertain, take into account the person's treatment preferences and either: 
      • Increase the oral dosage to the maximum licensed dosage.
      • Switch to intramuscular vitamin B12 injections if they are already taking the maximum licensed dosage for oral treatment.
      • Explore alternative diagnoses if the person still has symptoms but a further test to measure serum MMA or plasma homocysteine suggests they no longer have a vitamin B12 deficiency.
    • Continue with oral vitamin B12 replacement and agree a date for reassessment with the person if symptoms have resolved or improved, and:
      • The cause, or suspected cause, of the vitamin B12 deficiency has not been addressed (for example, the person is still taking a medicine that could affect vitamin B12 absorption), or
      • The cause of deficiency is unknown.
    • Consider stopping treatment if:
      • The person's symptoms have resolved or improved and the cause, or suspected cause, of the vitamin B12 deficiency has been addressed (for example, the person has increased their dietary intake of the vitamin).
    • If stopping treatment, advise the person to come back if symptoms get worse, reappear or they get new symptoms.
  • For people receiving intramuscular vitamin B12 replacement: 
    • Do not repeat the initial diagnostic test in people who are having intramuscular vitamin B12 replacement.
    • If symptoms have got worse or have not sufficiently improved so they are still interfering with their normal daily activities, or they have new symptoms of vitamin B12 deficiency:
      • Increase the frequency of injections if needed, in line with the summary of product characteristics, and 
      • Think about alternative diagnoses, and
      • Agree a date for reassessment of the person's symptoms.
    • If a person has, or is suspected of having, an irreversible cause of vitamin B12 deficiency:
      • Continue with lifelong intramuscular injections, even if their symptoms have improved or are no longer present, and
      • Advise them to come back if symptoms get worse, reappear, or they get new symptoms.
    • If the person's symptoms have improved, or are no longer present, and they have either a reversible cause of vitamin B12 deficiency that has not been addressed, or the cause is unknown:
      • Continue with intramuscular injections, and
      • Agree a date for their next follow up.
    • If the cause, or suspected cause, of vitamin B12 deficiency has been resolved and the person's symptoms have improved, or are no longer present:
      • Consider stopping or reducing the frequency of the intramuscular injections, and
      • Advise them to come back if their symptoms get worse, reappear, or they get new symptoms.
  • Measuring cobalamin levels is unhelpful as levels increase with treatment regardless of how effective it is, and retesting is not usually required. 
    • However, cobalamin can be measured 1–2 months after starting treatment if there is no response. 
  • Neurological recovery may take some time — improvement begins within one week and complete resolution usually occurs between six weeks and three months.
  • Ongoing monitoring is unnecessary unless a lack of compliance with treatment is suspected, anaemia recurs, or neurological symptoms do not improve, or progress.

Basis for recommendation

The recommendations on monitoring during and after treatment for B12 or folate deficiency anaemia are based on the National Institute for Health and Care Excellence (NICE) guideline Vitamin B12 deficiency in over 16s: diagnosis and management [NICE, 2024], expert opinion in a narrative review article Vitamin B12 deficiency [Hunt, 2014] and the BMJ Best Practice guidelines Folate deficiency [BMJ Best Practice, 2021] and Vitamin B12 deficiency [BMJ Best Practice, 2022].

Monitoring intervals
  • Expert opinion is that iron and folate levels should be measured after 8 weeks of treatment for a B12 deficiency as co-existing deficiency is often obscured in B12 deficiency [Hunt, 2014].
  • NICE recommends offering an initial follow-up for people having B12 replacement 3 months after they started treatment, or earlier depending on the severity of symptoms, or 1 month after treatment starts if they are pregnant or breastfeeding [NICE, 2024]. 

Prescribing information

Important aspects of prescribing information relevant to primary healthcare are covered in this section specifically for the drugs recommended in this CKS topic. For further information on contraindications, cautions, drug interactions, and adverse effects, see the electronic Medicines Compendium (eMC), or the British National Formulary (BNF).

Cyanocobalamin

Cautions and contraindications

  • There are no listed contraindications or cautions for cyanocobalamin [ABPI, 2021a].

Adverse effects

  • Adverse effects of cyanocobalamin include:
    • Sensitisation (rarely) — itching exanthema, or exceptionally as anaphylactic shock. 
    • Acneform and bullous eruptions.

[ABPI, 2021a] 

Drug interactions

  • Absorption of cyanocobalamin from the GI tract may be reduced by:
    • Aminoglycosides.
    • Aminosalicylic acid.
    • Anticonvulsants.
    • Biguanides.
    • Chloramphenicol.
    • Cholestyramine.
    • Cimetidine.
    • Methyldopa.
    • Omeprazole
    • Potassium salts.

The manufacturer states that the clinical relevance of many of these interactions is likely to be small.

[ABPI, 2021a]

Pregnancy and breastfeeding

  • Pregnancy — cyanocobalamin can be used in pregnancy to correct an established vitamin B12 deficiency.
  • Breastfeeding — cyanocobalamin is excreted in breastmilk, but is unlikely to be harmful.

[UKTIS, 2017; ABPI, 2021a]

Folic acid

Cautions and contraindications

  • Do not prescribe folic acid to people with:
    • Pernicious anaemia or undiagnosed megaloblastic anaemia (unless also prescribing vitamin B12) — use of folic acid alone may precipitate subacute combined degeneration of the spinal cord.
    • Malignant disease (unless megaloblastic anaemia caused by folate deficiency is an important complication).
  • Prescribe folic acid with caution to people: 
    • Who may have folate dependent tumours.

[ABPI, 2023; BNF, 2023]

Adverse effects

  • Rare adverse effects of folic acid include:
    • Gastrointestinal — abdominal distension, flatulence, anorexia, nausea.
    • Immune system — allergic reactions, including erythema, rash, pruritus, urticaria, dyspnoea, and anaphylactic reactions (including shock).

[ABPI, 2023; BNF, 2023]

Drug interactions

  • Drug interactions with folic acid include:
    • Carbamazepine — levels may be reduced if taken concurrently with folic acid. Monitor carbamazepine concentrations and adjust the dose accordingly.
    • Fluorouracil — levels may be increased producing toxicity. Avoid concurrent use with folic acid.
    • Fosphenytoin — levels may be reduced if taken concurrently with folic acid. Monitor fosphenytoin concentrations and adjust the dose accordingly.
    • Phenobarbital — levels may be reduced if taken concurrently with folic acid. Monitor phenobarbital concentrations and adjust the dose accordingly.
    • Phenytoin — levels may be reduced by 16–50% if taken concurrently with folic acid. Monitor phenytoin concentrations and adjust the dose accordingly.
    • Primidone —  levels may be reduced if taken concurrently with folic acid. Monitor primidone concentrations and adjust the dose accordingly.
    • Sulfasalazine — absorption of folic acid may be reduced. Monitor blood counts closely if folic acid is given concurrently with sulfasalazine.
  • Be aware that folic acid is removed by haemodialysis.

[ABPI, 2023; BNF, 2023; Preston, 2019]

Pregnancy and breastfeeding

  • Pregnancy — folic acid can be used during pregnancy.
  • Breastfeeding — folic acid is actively excreted in breastmilk. No adverse effects of folic acid supplementation have been observed in breastfed infants. 

[ABPI, 2023]

Hydroxocobalamin

Contraindications and cautions

  • Hydroxocobalamin should not be given until a vitamin B12 deficiency has been confirmed. 

[ABPI, 2021b; BNF, 2023]

Adverse effects

  • Adverse effects of hydroxocobalamin include:
    • Arrhythmias.
    • Chromaturia.
    • Fever, chills, hot flushes, dizziness, malaise, pain.
    • Initial hypokalaemia.
    • Reactive thrombocytosis.
    • Rash, itching, exanthema.
    • Injection site reactions. 
    • Headache, paraesthesia, tremor.
    • Nausea, vomiting, diarrhoea. 

[ABPI, 2021b; BNF, 2023]

Drug interactions

  • People using chloramphenicol may respond poorly to hydroxocobalamin.
  • Serum concentrations of hydroxocobalamin may be lowered by concurrent use of oral contraceptives. This interaction is unlikely to be clinically significant.

[ABPI, 2021b; BNF, 2023]

Pregnancy and breastfeeding

  • Pregnancy — hydroxocobalamin can be used in pregnancy to correct an established vitamin B12 deficiency.
  • Breastfeeding — hydroxocobalamin is excreted in breastmilk, but is unlikely to be harmful.

[UKTIS, 2017; ABPI, 2021a]

Supporting evidence

This CKS topic is based on expert opinion in medical textbooks, including a chapter on Macrocytic anaemias in the ABC of Clinical Haematology [Hoffbrand, 2023], Hoffbrand's essential haematology [Hoffbrand, 2019], and a chapter on Megaloblastic anaemia and miscellaneous deficiency anaemias in the Oxford textbook of medicine [Hoffbrand, 2020], as well as the British Journal of Haematology Guidelines for the diagnosis and treatment of cobalamin and folate disorders [Devalia, 2014],  a narrative review article Vitamin B12 deficiency [Hunt, 2014] and the BMJ Best Practice guidelines Folate deficiency [BMJ Best Practice, 2021] and Vitamin B12 deficiency [BMJ Best Practice, 2022].

The rationale for the individual recommendations is discussed in the basis for recommendation sections. CKS has not summarized the evidence for secondary care investigations and management as they are beyond the scope of this topic.

How this topic was developed

This section briefly describes the processes used in developing and updating this topic. Further details on the full process can be found in the About Us section and on the Clarity Informatics website.

Search strategy

A literature search was conducted for guidelines, systematic reviews and randomized controlled trials on primary care management of Anaemia - B12 and folate deficiency.

Search dates

March 2018 - March 2023

Key search terms

Various combinations of searches were carried out. The terms listed below are the core search terms that were used for EBSCO Medline.

  • (MH "Anemia, Macrocytic+")
  • (MH "Vitamin B 12 Deficiency+")
  • (MH "Folic Acid Deficiency")
  • AB ( ((anemi* or anaemi* or deficien*) N3 ((folate or folic acid or vitamin b9 or vitamin b12 or cobalamin or pernicious or macrocytic or nutritional)) ) OR TI ( ((anemi* or anaemi* or deficien*) N3 ((folate or folic acid or vitamin b9 or vitamin b12 or cobalamin or pernicious or macrocytic or nutritional)) ) 

Sources of guidelines

Sources of systematic reviews and meta-analyses

  • The Cochrane Library:
    • Systematic reviews
    • Protocols
    • Database of Abstracts of Reviews of Effects
  • Medline (with systematic review filter)
  • EMBASE (with systematic review filter)

Sources of health technology assessments and economic appraisals

Sources of randomized controlled trials

  • The Cochrane Library:
    • Central Register of Controlled Trials
  • Medline (with randomized controlled trial filter)
  • EMBASE (with randomized controlled trial filter)

Sources of evidence based reviews and evidence summaries

Sources of national policy

Patient experiences

Sources of medicines information

The following sources are used by CKS pharmacists and are not necessarily searched by CKS information specialists for all topics. Some of these resources are not freely available and require subscriptions to access content.

Stakeholder engagement

Our policy

The external review process is an essential part of CKS topic development. Consultation with a wide range of stakeholders provides quality assurance of the topic in terms of:

  • Clinical accuracy.
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  • Usability.

Principles of the consultation process

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  • Discussion with an individual or an organization about the CKS response to their comments is only undertaken in exceptional circumstances (at the discretion of the Clinical Editor or Editorial Steering Group).
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  • All reviewers are invited to be acknowledged on the website. All reviewers are given the opportunity to feedback about the external review process, enabling improvements to be made where appropriate.

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  • Key stakeholders identified by the CKS team are invited to comment on draft CKS topics. Individuals and organizations can also register an interest to feedback on a specific topic, or topics in a particular clinical area, through the Getting involved section of the Clarity Informatics website.
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Patient engagement

Clarity Informatics has enlisted the support and involvement of patients and lay persons at all stages in the process of creating the content which include:

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  • Second draft internal review
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Our lay and patient involvement includes membership on the editorial steering group, contacting expert patient groups, organizations and individuals.

Evidence exclusion criteria

Our policy

Scoping a literature search, and reviewing the evidence for CKS is a methodical and systematic process that is carried out by the lead clinical author for each topic. Relevant evidence is gathered in order that the clinical author can make fully informed decisions and recommendations. It is important to note that some evidence may be excluded for a variety of reasons. These reasons may be applied across all CKS topics or may be specific to a given topic.

Studies identified during literature searches are reviewed to identify the most appropriate information to author a CKS topic, ensuring any recommendations are based on the best evidence. We use the principles of the GRADE and PICOT approaches to assess the quality of published research. We use the principles of AGREE II to assess the quality of published guidelines.

Standard exclusions for scoping literature:

  • Animal studies
  • Original research is not written in English

Possible exclusions for reviewed literature:

  • Sample size too small or study underpowered
  • Bias evident or promotional literature
  • Population not relevant
  • Intervention/treatment not relevant
  • Outcomes not relevant
  • Outcomes have no clear evidence of clinical effectiveness
  • Setting not relevant
  • Not relevant to UK
  • Incorrect study type
  • Review article
  • Duplicate reference

Organizational, behavioural and financial barriers

Our policy

The CKS literature searches take into consideration the following concepts, which are discussed at the initial scoping of the topic.

  • Feasibility
    • Studies are selected depending on whether the intervention under investigation is available in the NHS and can be practically and safely undertaken in primary care.
  • Organizational and Financial Impact Analysis
  • Studies are selected and evaluated on whether the intervention under investigations may have an impact on local clinical service provision or national impact on cost for the NHS. The principles of clinical budget impact analysis are adhered to, evaluated and recorded by the author. The following factors are considered when making this assessment and analysis.
    • Eligible population
    • Current interventions
    • Likely uptake of new intervention or recommendation
    • Cost of the current or new intervention mix
    • Impact on other costs
    • Condition-related costs
    • In-direct costs and service impacts
    • Time dependencies
  • Cost-effectiveness or cost-benefit analysis studies are identified where available. 

We also evaluate and include evidence from NICE accredited sources which provide economic evaluations of recommendations, such as NICE guidelines. When a recommended action may not be possible because of resource constraints, this is explicitly indicated to healthcare professionals by the wording of the CKS recommendation.

Declarations of interest

Our policy

Clarity Informatics requests that all those involved in the writing and reviewing of topics, and those involved in the external review process to declare any competing interests. Signed copies are securely held by Clarity Informatics and are available on request with the permission of the individual. A copy of the declaration of interest form which participants are asked to complete annually is also available on request. A brief outline of the declarations of interest policy is described here and full details of the policy is available on the Clarity Informatics website. Declarations of interests of the authors are not routinely published, however competing interests of all those involved in the topic update or development are listed below. Competing interests include:

  • Personal financial interests
  • Personal family interest
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  • Non-personal financial gain or benefit

Although particular attention is given to interests that could result in financial gains or losses for the individual, competing interests may also arise from academic competition or for political, personal, religious, and reputational reasons. An individual is not obliged to seek out knowledge of work done for, or on behalf of, the healthcare industry within the departments for which they are responsible if they would not normally expect to be informed.

Who should declare competing interests?

Any individual (or organization) involved in developing, reviewing, or commenting on clinical content, particularly the recommendations should declare competing interests. This includes the authoring team members, expert advisers, external reviewers of draft topics, individuals providing feedback on published topics, and Editorial Steering Group members. Declarations of interest are completed annually for authoring team and editorial steering group members, and are completed at the start of the topic update and development process for external stakeholders.

Competing interests declared for this topic:

None.

References

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