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Treatment of vitamin B12 and folate deficiencies

Treatment of vitamin B12 and folate deficiencies
Authors:
Robert T Means, Jr, MD, MACP
Kathleen M Fairfield, MD, DrPH
Section Editor:
Clifford M Takemoto, MD
Deputy Editors:
Jennifer S Tirnauer, MD
Jane Givens, MD, MSCE
Literature review current through: Dec 2022. | This topic last updated: Aug 24, 2022.

INTRODUCTION — This topic reviews the treatment of vitamin B12 and folate deficiencies, including the route and duration of therapy, monitoring, and expected hematologic and neurologic response.

Separate topic reviews discuss the clinical manifestations, diagnosis, causes, and pathophysiology of these deficiencies:

Clinical presentation and diagnosis – (See "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency".)

Causes and pathophysiology – (See "Causes and pathophysiology of vitamin B12 and folate deficiencies".)

GENERAL PRINCIPLES OF TREATMENT — All individuals with documented vitamin B12 and/or folate deficiency should be treated, unless there is a strong reason not to do so (eg, palliative care setting or patient refusal). A number of general principles apply to both vitamin B12 and folate deficiency. These are outlined below and in a 2014 guideline on the diagnosis and treatment of vitamin B12 and folate deficiency from the British Committee for Standards in Haematology [1].

Urgency of correction — Most individuals with vitamin B12 or folate deficiency present asymptomatically with an incidental laboratory finding or with the slow development of symptoms. Repletion of the deficient vitamin can be instituted over a period of weeks in these instances. However, in certain cases it may be prudent to intervene more urgently:

Symptomatic anemia or neurologic or neuropsychiatric findings, due to the risk of adverse events and irreversibility of neurologic deficits

Pregnancy, as the developing fetus may be affected

Neonates and infants, whose development may be impacted

In these cases, more urgent correction of the deficiency and more intensive monitoring are indicated, as illustrated in the algorithm (algorithm 1). However, there is no evidence of benefit from using a higher dose. Consultation with a specialist may be appropriate if there is a question about the cause of the symptoms or the deficiency.

In extremely rare cases of severe deficiency with hemodynamic compromise due to severe anemia, blood transfusion may be given [2,3]. Vitamin B12 and/or folic acid should also be administered as appropriate, but these cannot be relied on for emergency therapy because improvements in red blood cell production take several days to take effect. (See "Red blood cell transfusion in infants and children: Indications" and "Indications and hemoglobin thresholds for red blood cell transfusion in the adult".)

Route of administration — Vitamin B12 and folic acid can be administered orally or parenterally. For vitamin B12, formulations are available for intramuscular/deep subcutaneous injection and oral, sublingual, and nasal administration. For folic acid, formulations are available for intravenous, intramuscular, and subcutaneous use, as well as oral ingestion.

Symptomatic patients – Initial parenteral administration (vitamin B12 or folic acid) is suggested for those who have severe symptomatic anemia or any neurologic findings associated with deficiency. If appropriate, these individuals can be switched to oral therapy after symptoms resolve. (See 'Treatment of vitamin B12 deficiency' below and 'Treatment of folate deficiency' below.)

Impaired absorption – Parenteral vitamin B12 replacement is often used for those who do not have the capacity to absorb oral replacement (eg, pernicious anemia, intestinal blind loop). The parenteral route is usually well-tolerated, and medication adherence is assured. However, high-dose oral (or sublingual) vitamin B12 therapy can also be effective for those with impaired absorption, provided that the dose is sufficient, medication adherence is good, and a response is documented [1,2]. Evidence showing equivalence of parenteral and high-dose oral therapy is presented below. (See 'Treatment of vitamin B12 deficiency' below.)

We generally do not use the intranasal formulations because of their variable absorption and higher cost; these formulations may also cause rhinorrhea. Over-the-counter preparations of vitamin B12 designated as "timed release" should be avoided [4].

Dietary deficiency – Oral replacement (vitamin B12 or folic acid) is appropriate for those whose deficiency is due to reduced dietary intake and who have the capacity to ingest and absorb oral supplements.

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 [3].

Available therapeutic preparations — The following formulations are available:

Vitamin B12 (also called cobalamin) is available as cyanocobalamin, which contains a cyanide (CN) group introduced during chemical synthesis and hydroxocobalamin. Cyanocobalamin is predominantly used in the United States and hydroxocobalamin is predominantly used in Europe; both are effective in treating vitamin B12 deficiency [5]. Of note, pharmacokinetics differ between these formulations, and as a result, maintenance doses of cyanocobalamin are administered monthly; maintenance hydroxocobalamin is administered less frequently (once every two to three months) [1,2].

Folic acid is also called vitamin B9 and is the synthetic form of the vitamin, whereas folate is the form found naturally in food. Folinic acid (also called leucovorin) is a naturally occurring form of reduced folate that is primarily used to prevent toxicities of methotrexate; it is more expensive, and while it is effective for treating folate deficiency, it not typically used for folate repletion in patients without a specific indication.

Other terms used for the physiologic forms of vitamin B12 and folate are presented separately. (See "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency", section on 'Terminology'.)

Duration of therapy — The duration of therapy depends on whether the initial cause of the deficiency persists. Lifelong replacement is necessary for individuals with a condition that is not reversed (eg, gastric bypass surgery, autoantibodies to intrinsic factor [pernicious anemia]). If the cause of the deficiency can be treated or eliminated (eg, excessively restrictive diet, drug-induced deficiency, reversible cause of malabsorption), supplementation can be discontinued after the deficiency is corrected.

Need for additional testing — Individuals with dietary deficiency of vitamin B12 and folate require education to ensure that their diet and/or supplements contain sufficient vitamin levels but do not require additional testing. The following additional testing may be appropriate once the diagnosis of vitamin B12 and/or folate deficiency has been established:

For individuals for whom the cause of deficiency is not clear, additional testing to determine the cause is almost always indicated. This evaluation is presented separately. (See "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency", section on 'Post-diagnostic testing'.)

Individuals with pernicious anemia appear to have an increased risk of gastrointestinal malignancy and may have a higher prevalence of autoimmune disorders. We suggest increased surveillance and have a lower threshold for evaluating gastrointestinal or other symptoms in these individuals. (See 'Additional considerations for pernicious anemia' below.)

Adverse effects/overdose — Vitamin B12 and folate are water-soluble vitamins that are excreted when stores are adequate. Rare cases of hypersensitivity or acneiform eruptions with vitamin B12 have been reported [1,2]; we have not seen these in our practice. Reports of serious adverse effects from administration or intake of greater-than-recommended doses have not been observed. However, associations have been reported between high folic acid intake and cancer risk, and between preconception folate supplementation higher than 1 mg/d and incidence of developmental delay in newborns [6,7]. While association does not prove causation, in the absence of a clinical indication it is prudent to avoid folate or B12 supplementation at levels significantly greater than the recommended daily allowance. (See "Vitamin intake and disease prevention", section on 'Toxicity at high doses'.)

We also do not advocate routine administration of vitamin B12 or folic acid supplements to groups of individuals without documented deficiency who eat a varied diet. This practice is likely to incur excess costs and burdens and could potentially mask underlying disorders. An exception is women who may become pregnant, for whom routine folic acid supplementation is used to reduce the risk of neural tube defects. (See "Folic acid supplementation in pregnancy".)

Certain populations are treated with routine supplementation due to their high risk of deficiency. (See 'Prevention of vitamin B12 deficiency' below and 'Prevention of folate deficiency' below.)

VITAMIN B12

Normal vitamin B12 requirements — Dietary sources of vitamin B12 are discussed separately. (See "Causes and pathophysiology of vitamin B12 and folate deficiencies", section on 'Dietary sources and RDI'.)

The following recommended dietary allowances apply [8]:

Birth to 6 months – 0.4 mcg per day

Children and adolescents – Increase to 2.4 mcg per day by 14 to 18 years of age

Adults – 2.4 mcg per day

Pregnancy – 2.6 mcg per day

Lactation – 2.8 mcg per day

Body stores in adults range from 1 to 5 mg. Intrinsic factor from gastric parietal cells is required for vitamin B12 delivery to the small intestine. The terminal ilium is the site of vitamin B12 absorption. (See "Causes and pathophysiology of vitamin B12 and folate deficiencies", section on 'Vitamin B12 absorption and body stores'.)

Prevention of vitamin B12 deficiency — Specific interventions to prevent vitamin B12 deficiency are unnecessary in the vast majority of individuals who consume a varied diet. However, certain settings are associated with an increased risk of deficiency:

Vegan or vegetarian dietVitamin B12 is present in many animal-based foods but not in plant-derived foods. Some vitamin B12 may be ingested from soil present on plants or from milk or eggs. However, individuals who consume a vegan or strict vegetarian diet generally should take supplemental vitamin B12 to ensure adequate stores. This is especially important in females who are pregnant or may become pregnant, since the developing fetus also requires adequate vitamin B12. Other non-vegetarian diets, such as a primarily plant-based Mediterranean diet, may not contain sufficient vitamin B12 in some cases [9,10]. Daily requirements and recommended intake are discussed above and in more detail separately. (See 'Normal vitamin B12 requirements' above and "Vegetarian diets for children", section on 'Vitamin B12' and "Healthy diet in adults", section on 'Plant-based and vegetarian diets'.)

Gastric or bariatric surgery – Many individuals who have had bariatric or other gastric surgery (eg, subtotal gastrectomy for ulcer disease) will develop clinically significant vitamin B12 deficiency because they have insufficient levels of intrinsic factor, which is produced by gastric parietal cells. Vitamin B12 supplementation can be provided by many routes, as listed in the table (table 1) and discussed separately. (See "Bariatric surgery: Postoperative nutritional management".)

Disorders of the small intestine – Disorders of the small intestine may be associated with vitamin B12 deficiency, depending on their chronicity and severity, because the vitamin B12-intrinsic factor complex is absorbed in the distal ileum. Typically, individuals with these conditions are monitored periodically for vitamin B12 deficiency rather than given routine supplementation. (See "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency", section on 'Vitamin B12 normal ranges'.)

Neonates born to vitamin B12-deficient mothers – Infants born to mothers with vitamin B12 deficiency are at risk for being born deficient and/or of becoming deficient if exclusively breastfed [11-14]. The best means of preventing neonatal deficiency is to ensure that the mother is vitamin B12 replete during the pregnancy and breastfeeding. If the neonate is discovered to be vitamin B12-deficient at birth, rapid correction is indicated. (See 'Treatment of vitamin B12 deficiency' below.)

Nitrous oxide exposure – Individuals with prolonged or high-dose exposure to nitrous oxide (N2O) gas, either as an inhalant anesthetic or as a drug of abuse, can develop rapid onset of vitamin B12 deficiency, especially if their baseline levels of vitamin B12 are borderline. This occurs because N2O chemically inactivates the vitamin B12-derived methylcobalamin molecule at the active site of methionine synthase [15]. This can lead to rapid neuropsychiatric deterioration and/or other complications.

In individuals with known vitamin B12 or folate deficiency undergoing anesthesia with N2O, we suggest close monitoring with a complete blood count (CBC) perioperatively, along with evaluation of macrocytosis and/or anemia as rapidly as is feasible to avoid this complication. (See "Causes and pathophysiology of vitamin B12 and folate deficiencies", section on 'Nitrous oxide'.)

As noted above, oral supplementation is likely to be appropriate in these individuals. (See 'Route of administration' above.)

Aging is not always associated with an increased risk for vitamin B12 deficiency. However, some older individuals, particularly those with little dietary variation, may be near the threshold for deficiency and may be at increased risk if they have gastric dysfunction or regularly use medications including histamine-2 receptor antagonists or proton pump inhibitors, which reduce gastric acid needed for optimal vitamin B12 absorption [15]. Metformin has also been associated with decreased vitamin B12 absorption.

Additional discussion of pathophysiology and other less common conditions that predispose to vitamin B12 deficiency are discussed separately. (See "Causes and pathophysiology of vitamin B12 and folate deficiencies".)

Treatment of vitamin B12 deficiency — Vitamin B12 is available in several formulations and can be administered by several routes, including intramuscular, deep subcutaneous, oral, or sublingual. An approach to decision-making regarding formulation, dose, and frequency is summarized in the algorithm (algorithm 1). (See 'Route of administration' above.)

Parenteral

Adults – The typical dose for adults is 1000 mcg parenterally once per week until the deficiency is corrected and then once per month (cyanocobalamin) or once every other month (hydroxocobalamin). If there are symptoms of anemia and/or neurologic symptoms, 1000 mcg can be administered one to three times per week or daily, followed by once weekly.

Children – There are limited data for the optimal dosing and schedule for vitamin B12 replacement in children. Dosing 100 mcg per day for one week followed by 1000 mg every other day for one week, followed by twice per week, and then once weekly, has been shown to be safe and effective in repleting vitamin B12 in symptomatic children [16]. While doses of 1000 mcg parentally are appropriate in adolescents, some experts have suggested that in infants and young children, parenteral doses of 50 to 100 mcg are sufficient. Once deficiency is corrected, maintenance dosing can be given once per month (cyanocobalamin) or once every other month (hydroxocobalamin) if the underlying cause of the deficiency persists [17].

Oral

Adults – In adults with normal absorption, oral dosing is equally effective as intravenous dosing when given at a dose of 1000 mcg orally once per day. For individuals with impaired absorption of vitamin B12, therapy with very high oral doses of oral vitamin B12 (eg, 2000 mcg daily) will be effective as long as the dose is high enough to provide absorption via a mechanism that does not require intrinsic factor or a functioning terminal ileum (ie, passive diffusion/mass action) [15,18-20].

Children – In children without neurologic symptoms or severe anemia who have normal vitamin B12 absorption, oral dosing may be safe and effective to treat vitamin B12 deficiency. In a study of children 6 months to 18 years, 1000 mcg orally was given daily for a week, followed by every other day for a week, 2 days a week for 2 weeks, and then weekly for 3 months [21]. Another study used 125 mcg for children <1 year, 250 mcg for children 1 to 2 years, and 500 mcg for children >2 years for a total of 8 weeks [22]. Both of these studies showed normalization of vitamin B12 levels.

Intranasal and transdermal – The intranasal route 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.

Evidence regarding the relative efficacy of parenteral versus high-dose oral vitamin B12 comes from small randomized trials and observational studies.

A 2018 Cochrane review that included three small trials (153 participants in total) comparing oral versus intramuscular vitamin B12 in individuals with vitamin B12 deficiency suggested that both routes were effective in raising vitamin B12 levels [23].

A 2006 systematic review found data from two randomized trials (108 participants) that compared oral versus intramuscular vitamin B12 and found that oral vitamin B12 at these doses was equivalent to or better than intramuscular vitamin B12 for raising serum vitamin B12 levels, correcting anemia, and in one case, resolving neuropsychiatric findings [24-26].

The following describes common approaches to treating patients with different causes of vitamin B12 deficiency:

Pernicious anemia – Pernicious anemia (PA; vitamin B12 deficiency due to autoantibodies that inhibit vitamin B12 absorption (see "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency", section on 'Terminology')) is a potentially lifelong condition that prevents vitamin B12 absorption and thus is usually treated with parenteral vitamin B12, which is typically administered by intramuscular or deep subcutaneous injection at an initial dose of 1000 mcg (1 mg) once per week for four weeks, followed by 1000 mcg once per month. These doses have been found to be effective in observational studies [26,27]. Therapy is continued indefinitely. As noted above, high-dose oral vitamin B12 (1000 to 2000 mcg [1 to 2 mg] daily) is also an option, provided there are no acute symptoms of anemia or neurologic complications and adherence is assured.

Altered gastrointestinal anatomy – Alterations in gastrointestinal anatomy that affect production of intrinsic factor or absorption of the intrinsic factor-vitamin B12 complex include bariatric surgery, gastrectomy, ileal loop syndrome, and others. (See "Causes and pathophysiology of vitamin B12 and folate deficiencies".)

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. We often check the level three or four times during the first year off of therapy. (See 'Intensity of and duration of monitoring' below.)

Dietary deficiency – Individuals with diets that lack vitamin B12 (eg, 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. (See "Vitamin intake and disease prevention", section on 'Vitamin B12 (cobalamin)'.)

Concerning symptoms – Some individuals with symptomatic anemia, neurologic or neuropsychiatric findings, or pregnancy (in which the developing fetus may be deprived of vitamin B12) may benefit from more aggressive repletion. For these symptomatic patients or those with greater urgency for correction, we suggest initial administration of parenteral vitamin B12 since this ensures rapid absorption and compliance. However, data are limited as to whether correction of the deficiency occurs more rapidly or long-term complications are reduced with parenteral versus oral therapy, as discussed below. These individuals may be treated with 1000 mcg of vitamin B12 every other day initially for approximately two weeks, followed by administration once monthly (cyanocobalamin) or once every two to three months (hydroxocobalamin) [1]. Once the initial deficiency has been corrected, it would be reasonable to switch to oral administration if the patient preferred the oral route, as long as individuals with impaired absorption are given high enough doses to ensure adequate serum levels.

Lack of access to parenteral administration or patient preference – Some individuals may not have access to parenteral vitamin B12, particularly those residing in resource-limited settings, and some individuals may prefer to use an oral or sublingual vitamin B12 preparation. In these cases, it is reasonable to use the formulation that is available or that the patient prefers, as long as the dose is appropriate. Sublingual vitamin B12 replacement has not been studied extensively, but data from small studies suggest that therapy is effective as long as the dose is sufficient [2,28,29]. We often check vitamin B12 levels three to four times during the first year of therapy. Some experts will give the initial dose parenterally to ensure absorption [15].

Possible issues with medication adherence – Some individuals may have more difficulty adhering to daily oral medication. In these cases, monthly vitamin B12 injections ensures adequate adherence.

The typical response and our approach to monitoring are discussed below. (See 'Assessing and monitoring response to treatment' below.)

COVID-19 pandemic — Many individuals are avoiding in-person visits to their health care providers during the coronavirus disease 2019 (COVID-19) pandemic.

For individuals on maintenance vitamin B12 replacement therapy administered at the provider's practice, missing one or more office visits may pose a risk of relapse or of progression of symptoms related to vitamin B12 deficiency [30]. Such patients can switch to taking their maintenance therapy orally at a dose of 2000 mcg daily, or they can be instructed to self-administer cobalamin or hydroxycobalamin subcutaneously [30,31]. If necessary, such instruction could be provided using video teleconferencing technology.

Additional considerations for pernicious anemia — In addition to lifelong treatment of vitamin B12 deficiency (see 'Treatment of vitamin B12 deficiency' above), individuals with pernicious anemia (PA) may require additional evaluations and/or a lower threshold for evaluating symptoms of related conditions:

Gastrointestinal malignancy – PA is associated with an increased risk of gastrointestinal malignancy (carcinoma, carcinoid tumors) for which screening may be appropriate [32]. In a 2013 systematic review that included 27 studies on the association of PA with gastric cancer, the pooled incidence rate for gastric cancer was 0.27 percent per patient-year; the relative risk compared with individuals without PA was 6.8 (95% CI 2.6-18.1) [33]. A 2015 population-based case control study of older individuals (ages 66 to 69 years) in the United States found increased odds ratios (ORs) for gastric adenocarcinoma (OR 2.2, 95% CI 1.9-2.5); gastric carcinoid (OR 11.4, 95% CI 8.9-14.7); small intestinal cancer (OR 1.6, 95% CI 1.3-2.0); and some non-gastrointestinal malignancies [34]. The association of PA with gastrointestinal malignancies outside the stomach (eg, colon) is less clear [35,36].

A 1995 American Society of Gastrointestinal Endoscopy guideline has recommended that individuals with PA should undergo upper gastrointestinal endoscopy soon after PA diagnosis and/or if they develop gastrointestinal symptoms [37]. This is consistent with our practice. However, a support-group-based survey of patients with PA found that only approximately one-fourth had undergone endoscopic screening [38]. There are insufficient data to support routine surveillance with upper endoscopy following an initial screening in the absence of symptoms or to alter the patient's schedule for colon cancer screening based on the diagnosis of PA.

Other autoimmune disorders – There may be higher prevalence of other autoimmune disorders in individuals with PA, although there is very little high-quality evidence regarding such a risk. We do not specifically test for these conditions in the absence of symptoms, but we ensure that age-appropriate preventive care is performed and maintain a low threshold for considering autoimmune causes of symptoms and evaluating as appropriate. (See "Evidence-based approach to prevention" and "Overview of preventive care in adults".)

Individuals without documented vitamin B12 deficiency — With the exception of the preventive use of vitamin B12 in certain populations (see 'Prevention of vitamin B12 deficiency' above), we do not advocate routine administration of vitamin B12 to individuals without documented deficiency. We are aware that injections of vitamin B12 are used in the absence of deficiency by some practitioners. There are no data to support this practice, and it represents low-value care. Despite our skepticism, some experts have advocated possible supplementation in healthy adults [3].

FOLATE

Normal folate requirements — Dietary sources of folate include both plant and animal products. (See "Causes and pathophysiology of vitamin B12 and folate deficiencies", section on 'Dietary sources and RDI'.)

The following recommended daily allowances apply [39]:

Birth to 6 months – 65 mcg per day

Children and adolescents – Increase to 400 mcg per day by 14 to 18 years of age

Adults – 400 mcg per day

Pregnancy – 600 mcg per day

Lactation – 500 mcg per day

Total body stores are approximately 5 mg. The small intestine is the site of absorption, primarily in the jejunum. (See "Causes and pathophysiology of vitamin B12 and folate deficiencies", section on 'Folate absorption and body stores'.)

Prevention of folate deficiency — Several countries (eg, United States, Canada, Costa Rica, Chile, South Africa) have required manufacturers to enrich cereals and grain products with folic acid to reduce the risk of neural tube defects.

Thus, folate deficiency has become uncommon in individuals in these countries that provide routine fortification. However, individuals with the following conditions may be at increased risk of developing folate deficiency:

Gastrointestinal disorders that prevent absorption of dietary folates in the duodenum (eg, bariatric surgery)

Severe malnutrition, restrictive diets, or reduced oral intake

Chronic excessive alcohol use, which may be associated with chronic malnutrition and increased metabolic needs

Reduced intake of green leafy vegetables if residing in a country where cereals and grains are not routinely supplemented with folic acid

Chronic hemolytic anemia with increased red blood cell turnover

Other conditions associated with high cellular turnover such as severe eczema

In these cases, oral folic acid at a dose of 1 mg daily is typically sufficient to prevent deficiency from developing.

Other considerations with risk for folate deficiency

Neural tube defects – Folate is required during early embryogenesis for neural tube formation, and routine folic acid supplementation is used during pregnancy to reduce the risk of neural tube defects. This subject is discussed in detail separately. (See "Folic acid supplementation in pregnancy".)

Goat milk diet – Goat milk is low in folate, and infants fed exclusively goat milk may not receive adequate folic acid [40,41]. Some powdered goat milk is supplemented with folic acid, but use of a commercial infant formula is preferable. (See "Dietary recommendations for toddlers, preschool, and school-age children".)

Antimetabolites – Antimetabolites such as methotrexate act by reducing intracellular folates and cause a predictable megaloblastic anemia. In many cases, when these drugs are used to treat nonmalignant conditions, a source of folate is provided (eg, folic acid, folinic acid). Disease-specific prescribing information should be followed. Folinic acid (leucovorin) rescue after high-dose methotrexate for acute lymphoblastic leukemia and other hematologic malignancies is discussed separately. (See "Major side effects of low-dose methotrexate" and "Therapeutic use and toxicity of high-dose methotrexate".)

Sickle cell disease and other chronic hemolytic anemias – Because of increased red blood cell turnover, individuals with hemolytic anemia may be at risk for folate deficiency. There is no high quality evidence demonstrating the benefit of folate supplementation in these conditions. A common practice is to supplement with 1 mg of folic acid daily; however, in patients with sufficient dietary intake, some patients may reasonably elect to omit supplementation. (See "Overview of the management and prognosis of sickle cell disease", section on 'Nutrition' and "Warm autoimmune hemolytic anemia (AIHA) in adults", section on 'Folic acid' and "Non-immune (Coombs-negative) hemolytic anemias in adults", section on 'Folic acid for chronic hemolysis' and "Unstable hemoglobin variants", section on 'Folic acid'.)

Additional discussion of pathophysiology and other less common conditions that predispose to folate deficiency are discussed separately. (See "Causes and pathophysiology of vitamin B12 and folate deficiencies".)

Treatment of folate deficiency — Folate deficiency is typically treated with oral folic acid (1 to 5 mg daily) [1]. This dose is usually sufficient even if malabsorption is present, because it is considerably in excess of the 200 mcg (0.2 mg) recommended dietary allowance (table 2). (See "Vitamin intake and disease prevention", section on 'Folic acid'.)

For those with a reversible cause of deficiency, therapy is generally given for one to four months or until there is laboratory evidence of hematologic recovery. For those with a chronic cause of folate deficiency, such as chronic hemolytic anemia, therapy may be given indefinitely. (See 'Other considerations with risk for folate deficiency' above.)

Intravenous folic acid may be appropriate in certain settings, such as individuals who are unable to take an oral medication (eg, due to vomiting or obtundation) or those who have severe or symptomatic anemia due to folate deficiency and hence have a more urgent need for rapid correction.

It is important to be aware that administration of folic acid can partially reverse some of the hematologic abnormalities associated with vitamin B12 deficiency; however, the neurologic manifestations of vitamin B12 deficiency are not treated by folic acid. Thus, administration of folic acid to an individual with vitamin B12 deficiency can potentially mask untreated vitamin B12 deficiency or even worsen the neurologic complications (the latter for reasons that are not entirely clear) [42]. Because of this, testing for (and treatment of) vitamin B12 deficiency may be appropriate in certain patients being treated with folic acid:

Test for vitamin B12 deficiency in individuals with suspected folate deficiency, those with folate deficiency whose anemia and/or macrocytosis does not resolve with folic acid treatment, and/or those who develop new neurologic symptoms upon treatment with folic acid.

Administer vitamin B12 to individuals with megaloblastic anemia who are being treated with folic acid before results of vitamin B12 testing are available.

Administer vitamin B12 to individuals with folate deficiency who develop neurologic symptoms after treatment with folic acid. Ideally, testing for vitamin B12 deficiency is also sent, but administration of vitamin B12 should not be delayed while awaiting the results.

Some experts advocate repeat testing for vitamin B12 deficiency in patients receiving long-term folic acid, especially if hematologic (eg, macrocytic anemia, increasing levels of serum lactate dehydrogenase) and/or neurologic worsening occur [43].

Individuals without documented folate deficiency — With the exception of the preventive use of folic acid in certain populations (see 'Prevention of folate deficiency' above), we do not advocate routine administration of folic acid to individuals without documented deficiency.

The use (or avoidance) of folic acid supplementation to individuals without folate deficiency to reduce the risks of cancer and heart disease are discussed separately. (See "Vitamin intake and disease prevention", section on 'Folic acid'.)

ASSESSING AND MONITORING RESPONSE TO TREATMENT

Typical response — A hematologic response to vitamin B12 and/or folic acid should occur within a predictable timeframe as below, provided that the bone marrow is functioning normally and there are no other causes of anemia.

Laboratory markers improve in the following time scales [2,3]:

Hemolysis markers – Day 1 to 2

Reticulocytosis – Day 3 to 4

Anemia – Week 1 to 2 (initial improvement) and week 4 to 8 (normalization)

Hypersegmented neutrophils – Day 10 to 14

Leukopenia and/or thrombocytopenia – Week 2 to 4

Improvement in serum folate and/or vitamin B12 levels can be assayed to ensure correction, although this is not required, especially if hematologic and neurologic parameters improve as expected.-

Some individuals can develop hypokalemia during the initial week of treatment as there is marked potassium uptake during production of new blood cells, but this is unlikely to be clinically significant [2].

Neuropsychiatric improvement after treatment of vitamin B12 deficiency often occurs over a longer period of time (eg, starting within approximately three months and continuing to improve for as long as one year). Some experts report transient worsening of neurologic symptoms before improvement [3]. However, some neurologic findings may be irreversible, especially if they have been present for a long time before the deficiency was corrected [44]. In a 1991 series involving 121 individuals with vitamin B12 deficiency with neurologic findings, all had some neurologic improvement, to a degree that was inversely related to the extent and duration of disease [45]. Neurologic recovery was complete in 57 (47 percent), and only 7 (6 percent) had residual long-term moderate to severe neurologic disability.

Neurologic findings may recur more rapidly than hematologic findings in individuals with pernicious anemia who have been treated, recovered, and then discontinued vitamin B12 supplementation (eg, neurologic findings may return within six months, whereas megaloblastic anemia may take years to recur) [3].

Intensity of and duration of monitoring — The intensity of monitoring for hematologic and/or neurologic improvement depends on the severity of symptoms and other considerations. As examples:

For a person with concerning neurologic or neuropsychiatric findings or symptoms related to cytopenias (eg, shortness of breath from anemia, bleeding with thrombocytopenia), we monitor more aggressively so that we may intervene if the response is not occurring. This might involve daily testing of the complete blood count (CBC) for hospitalized patients and testing the vitamin B12 or folate level in one to two days.

For a pregnant individual with vitamin B12 or folate deficiency, concerns about fetal deficiency may warrant more rapid testing (eg, within a few days) to ensure that the vitamin has been absorbed. The urgency of correction is also greater during pregnancy. (See 'Urgency of correction' above.)

An individual with an incidental finding of deficiency presenting as mild macrocytosis and/or mild anemia could have a repeat CBC and measurement of the deficient vitamin (eg, vitamin B12 and/or folate level, methylmalonic acid [MMA] and/or homocysteine if appropriate) at two to four weeks.

If the individual is receiving oral therapy and there is concern about adequate absorption, it may be appropriate to monitor these parameters more frequently until it is clear that improvement is occurring.

Additional testing may be required if the individual reports lack of response (or worsening) in the expected time frame. This may include earlier testing of the CBC, vitamin B12 or folate level, or metabolites (MMA and homocysteine) and/or testing for other causes of anemia or neuropsychiatric findings. (See "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency", section on 'Differential diagnosis'.)

Monitoring should continue until a complete response has been documented. For those with a cause of deficiency that is known to have been eliminated, subsequent testing may not be necessary. However, it may be prudent to reevaluate the CBC and/or vitamin B12 or folate level within 3 to 12 months after stopping therapy.

Approach to lack of response — A delayed or incomplete response suggests that the vitamin was not taken or was not absorbed, or that the original diagnosis was inaccurate or incomplete. In cases in which the expected response is not seen, the following is appropriate:

Verify that the correct vitamin was taken.

Switch from oral to parenteral therapy if there are concerns about absorption (eg, possible pernicious anemia incorrectly diagnosed as dietary lack of vitamin B12) or adherence. (See 'Available therapeutic preparations' above.)

Repeat the diagnostic testing. (See "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency".)

Perform additional testing for other causes of anemia or other findings (eg, test for concomitant iron or copper deficiency, infection, hypothyroidism, and/or a myelodysplastic syndrome). The specific testing depends on the characteristics of the anemia and the patient history and examination. (See "Approach to the child with anemia" and "Diagnostic approach to anemia in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Vitamin B12 deficiency and folate deficiency (The Basics)" and "Patient education: Pernicious anemia (The Basics)" and "Patient education: How to plan and prepare for a healthy pregnancy (The Basics)" and "Patient education: Epilepsy and pregnancy (The Basics)" and "Patient education: Nutrition before and during pregnancy (The Basics)" and "Patient education: Vitamin supplements (The Basics)")

Beyond the Basics topics (see "Patient education: Inflammatory bowel disease and pregnancy (Beyond the Basics)" and "Patient education: Nausea and vomiting of pregnancy (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Indications for treatment – All individuals with documented vitamin B12 and/or folate deficiency should be treated. The urgency of correction depends on the severity of deficiency and associated symptoms. (See 'General principles of treatment' above.)

Prevention of vitamin B12 deficiency – Individuals at risk for vitamin B12 deficiency (eg, vegan or strict vegetarian diet, gastric or bariatric surgery) should receive oral vitamin B12 supplements. (See 'Prevention of vitamin B12 deficiency' above.)

Treatment of vitamin B12 deficiencyVitamin B12 deficiency may be treated with oral or parenteral vitamin B12, as summarized in the algorithm (algorithm 1).

For patients with vitamin B12 deficiency who have concerning symptoms (eg, severe or symptomatic anemia, neuropsychiatric findings), we suggest parenteral rather than oral vitamin B12 (Grade 2C). This ensures rapid absorption and compliance, although improvements in anemia and neuropsychiatric findings may be equivalent with oral administration. (See 'Treatment of vitamin B12 deficiency' above.)

The dose is 1000 mcg by deep subcutaneous or intramuscular injection once weekly for one month followed by 1000 mcg once per month.

Oral (or sublingual) vitamin B12 are effective alternatives if adherence is not a concern. If oral vitamin B12 is used in individuals with impaired absorption, the dose is 1000 to 2000 mcg daily.

Pernicious anemia (PA) and other chronic causes of deficiency are treated indefinitely. Individuals with PA are at increased risk for gastrointestinal malignancy. We perform a one-time upper gastrointestinal endoscopy soon after PA diagnosis and/or if the individual develops gastrointestinal symptoms. (See 'Additional considerations for pernicious anemia' above.)

Prevention of folate deficiency – Individuals at risk for folate deficiency (eg, malnutrition, chronic alcohol use, chronic hemolytic anemia) should receive folic acid supplementation (typical dose, 1 mg orally per day). We do not advocate routine folic acid supplementation for the general population. Folic acid supplementation in pregnancy is discussed separately. (See 'Prevention of folate deficiency' above and 'Individuals without documented folate deficiency' above and "Folic acid supplementation in pregnancy".)

Treatment of folate deficiency – Folate deficiency is typically treated with oral folic acid (1 to 5 mg daily). Therapy is generally given for one to four months or until there is laboratory evidence of hematologic recovery, or indefinitely for those with a chronic cause of folate deficiency. Intravenous folic acid may be appropriate for individuals who are unable to take an oral medication or those who require more urgent correction. Testing and/or treatment for vitamin B12 deficiency may be appropriate for some patients. (See 'Treatment of folate deficiency' above.)

Monitoring response to treatment – The typical response to correction of vitamin B12 and/or folate deficiency includes an initial reticulocytosis over one to two weeks followed by resolution of anemia in four to eight weeks. Resolution of neuropsychiatric changes in vitamin B12 deficiency may take longer and may be incomplete, especially in individuals with more severe and/or longstanding deficits. Monitoring for a response to therapy should be tailored to the patient's symptoms and other factors (eg, more intensive monitoring during pregnancy). If the expected response does not occur, additional testing for other causes of the patient's findings may be indicated. (See 'Assessing and monitoring response to treatment' above.)

Causes and diagnosis of vitamin B12 and folate deficiencies – Causes of vitamin B12 and folate deficiency and our approach to diagnostic testing are discussed in detail in separate topic reviews. (See "Causes and pathophysiology of vitamin B12 and folate deficiencies" and "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency".)

ACKNOWLEDGMENTS — We are saddened by the death of Stanley L Schrier, MD, who passed away in August 2019. The editors at UpToDate gratefully acknowledge Dr. Schrier's role as author on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Hematology, and his dedicated and longstanding involvement with the UpToDate program.

The UpToDate editorial staff also acknowledges the extensive contributions of William C Mentzer, MD, to earlier versions of this and many other topic reviews.

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