Prévia do material em texto

Official reprint from UpToDate
www.uptodate.com © 2024 UpToDate, Inc. and/or its affiliates. All Rights Reserved.
Treatment of vitamin B12 and folate deficiencies
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:
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:
®
�������: Robert T Means, Jr, MD, MACP, Kathleen M Fairfield, MD, DrPH
������� ������: Clifford M Takemoto, MD
������ �������: Jennifer S Tirnauer, MD, Han Li, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Aug 2024.
This topic last updated: Jun 05, 2024.
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".)
●
Symptomatic anemia or neurologic or neuropsychiatric findings, due to the risk of
adverse events and irreversibility of neurologic deficits
●
https://www.uptodate.com/
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/1
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/contributors
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/contributors
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/contributors
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/contributors
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/contributors
https://www.uptodate.com/home/editorial-policy
https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-vitamin-b12-and-folate-deficiency?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-vitamin-b12-and-folate-deficiency?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/causes-and-pathophysiology-of-vitamin-b12-and-folate-deficiencies?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/causes-and-pathophysiology-of-vitamin-b12-and-folate-deficiencies?search=vitamina%20b12&topicRef=7154&source=see_link
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 RBC transfusion in adults".)
Route of administration — Vitamin B12 and folic acid can be administered orally or
parenterally.
The choice of route is discussed in sections below; the following general principles apply:
Pregnancy, as the developing fetus may be affected●
Neonates and infants, whose development may be impacted●
Vitamin B12 – Formulations are available for intramuscular/deep subcutaneous
injection and oral, sublingual, and nasal administration. We do not use timed release,
intranasal, transdermal, or intravenous routes. (See 'Treatment of vitamin B12
deficiency' below.)
●
Folic acid – Formulations are available for intravenous, intramuscular, and
subcutaneous use, as well as oral administration. (See 'Treatment of folate deficiency'
below.)
●
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 [PA],
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.)
●
https://www.uptodate.com/contents/image?imageKey=HEME%2F131424&topicKey=HEME%2F7154&search=vitamina%20b12&rank=2%7E150&source=see_link
https://www.uptodate.com/contents/image?imageKey=HEME%2F131424&topicKey=HEME%2F7154&search=vitamina%20b12&rank=2%7E150&source=see_link
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/2,3
https://www.uptodate.com/contents/folic-acid-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/red-blood-cell-transfusion-in-infants-and-children-indications?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/red-blood-cell-transfusion-in-infants-and-children-indications?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/indications-and-hemoglobin-thresholds-for-rbc-transfusion-in-adults?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/indications-and-hemoglobin-thresholds-for-rbc-transfusion-in-adults?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/folic-acid-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/folic-acid-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/1,2
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:
Other terms used for the physiologic forms of vitamin B12 and folate are presented
separately. (See "Clinical manifestations and diagnosis of vitamin– Individuals at risk for vitamin B12 deficiency
(eg, strict vegan or vegetarian diet, gastric or bariatric surgery, pregnancy or lactating
with limited intake of foods from animals) should receive oral vitamin B12 supplements
( table 1). Patients with other risk factors may either use supplementation or periodic
monitoring with treatment if deficiency occurs. (See 'Prevention of vitamin B12
deficiency' above.)
●
Treatment of vitamin B12 deficiency – Vitamin B12 deficiency may be treated with
oral or parenteral vitamin B12, as summarized in the algorithm ( algorithm 1). The
table discusses considerations in the choice of route ( table 3).
●
https://www.uptodate.com/contents/vitamin-b12-deficiency-and-folate-deficiency-the-basics?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/vitamin-b12-deficiency-and-folate-deficiency-the-basics?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/pernicious-anemia-the-basics?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/how-to-plan-and-prepare-for-a-healthy-pregnancy-the-basics?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/how-to-plan-and-prepare-for-a-healthy-pregnancy-the-basics?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/epilepsy-and-pregnancy-the-basics?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/epilepsy-and-pregnancy-the-basics?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/nutrition-before-and-during-pregnancy-the-basics?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/nutrition-before-and-during-pregnancy-the-basics?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/vitamin-supplements-the-basics?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/vitamin-supplements-the-basics?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/inflammatory-bowel-disease-and-pregnancy-beyond-the-basics?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/inflammatory-bowel-disease-and-pregnancy-beyond-the-basics?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/nausea-and-vomiting-of-pregnancy-beyond-the-basics?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/nausea-and-vomiting-of-pregnancy-beyond-the-basics?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/image?imageKey=HEME%2F142028&topicKey=HEME%2F7154&search=vitamina%20b12&rank=2%7E150&source=see_link
https://www.uptodate.com/contents/image?imageKey=HEME%2F142028&topicKey=HEME%2F7154&search=vitamina%20b12&rank=2%7E150&source=see_link
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/image?imageKey=HEME%2F131424&topicKey=HEME%2F7154&search=vitamina%20b12&rank=2%7E150&source=see_link
https://www.uptodate.com/contents/image?imageKey=HEME%2F131424&topicKey=HEME%2F7154&search=vitamina%20b12&rank=2%7E150&source=see_link
https://www.uptodate.com/contents/image?imageKey=HEME%2F142051&topicKey=HEME%2F7154&search=vitamina%20b12&rank=2%7E150&source=see_link
https://www.uptodate.com/contents/image?imageKey=HEME%2F142051&topicKey=HEME%2F7154&search=vitamina%20b12&rank=2%7E150&source=see_link
Route and dose for concerning symptoms – 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 adherence, although improvements
in anemia and neuropsychiatric findings may be equivalent with oral administration
( table 3). (See 'Treatment of vitamin B12 deficiency' above.)
•
The dose is 1000 mcg by deep subcutaneous or intramuscular injection. For
concerning symptoms, this is given three times per week or up to daily for the first
week, followed by once weekly for one month, followed by 1000 mcg once per
month. The monthly dosing after initial replacement can be given by
intramuscular/deep subcutaneous injection or orally. If oral vitamin B12 is used in
individuals with impaired absorption, the dose is 1000 to 2000 mcg daily.
•
Route and dose (no significant anemia or associated symptoms) – For patients
with vitamin B12 deficiency identified on laboratory testing and without significant
anemia or associated symptoms, repletion should begin within a few weeks. During
pregnancy, treatment should be started as soon as possible as the developing fetus
may be affected. Intramuscular/deep subcutaneous or oral/sublingual routes are
reasonable. If oral vitamin B12 is used in individuals with impaired absorption, the
dose is 1000 to 2000 mcg daily.
•
Duration of treatment – Pernicious anemia (PA) and other chronic causes of
deficiency are treated indefinitely. For reversible causes, supplementation can be
discontinued if the underlying cause no longer exists, such as a diet, medication, or
reversible cause of malabsorption.
•
Other testing – All individuals with vitamin B12 deficiency should have the cause
determined because some causes such as pernicious anemia (PA) carry additional
risks, some causes are reversible with treatment, and some causes require lifelong
supplementation. Individuals with PA are at increased risk for gastrointestinal
malignancy, and 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 "Preconception and
prenatal folic acid supplementation".)
●
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/grade/6?title=Grade%202C&topicKey=HEME%2F7154
https://www.uptodate.com/contents/image?imageKey=HEME%2F142051&topicKey=HEME%2F7154&search=vitamina%20b12&rank=2%7E150&source=see_link
https://www.uptodate.com/contents/image?imageKey=HEME%2F142051&topicKey=HEME%2F7154&search=vitamina%20b12&rank=2%7E150&source=see_link
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/folic-acid-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/preconception-and-prenatal-folic-acid-supplementation?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/preconception-and-prenatal-folic-acid-supplementation?search=vitamina%20b12&topicRef=7154&source=see_link
ACKNOWLEDGMENTS
UpToDate gratefully acknowledges Stanley L Schrier, MD, who contributed as Section Editor
on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in
Hematology.
The UpToDate editorial staff also acknowledgesthe extensive contributions of William C
Mentzer, MD, to earlier versions of this and many other topic reviews.
Use of UpToDate is subject to the Terms of Use.
REFERENCES
1. Devalia V, Hamilton MS, Molloy AM, British Committee for Standards in Haematology.
Guidelines for the diagnosis and treatment of cobalamin and folate disorders. Br J
Haematol 2014; 166:496.
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 reticulocytosis within three to four days, initial
increase in hemoglobin over one to two weeks, and 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".)
●
https://www.wolterskluwer.com/en/know/clinical-effectiveness-terms
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/1
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/1
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/1
https://www.uptodate.com/contents/folic-acid-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/folic-acid-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/causes-and-pathophysiology-of-vitamin-b12-and-folate-deficiencies?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/causes-and-pathophysiology-of-vitamin-b12-and-folate-deficiencies?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-vitamin-b12-and-folate-deficiency?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-vitamin-b12-and-folate-deficiency?search=vitamina%20b12&topicRef=7154&source=see_link
2. Carmel R. How I treat cobalamin (vitamin B12) deficiency. Blood 2008; 112:2214.
3. Stabler SP. Clinical practice. Vitamin B12 deficiency. N Engl J Med 2013; 368:149.
4. Sugrue A. Author's reply to Charkin. BMJ 2014; 349:g5391.
5. Kim YI. Folate and cancer: a tale of Dr. Jekyll and Mr. Hyde? Am J Clin Nutr 2018; 107:139.
6. Valera-Gran D, Navarrete-Muñoz EM, Garcia de la Hera M, et al. Effect of maternal high
dosages of folic acid supplements on neurocognitive development in children at 4-5 y of
age: the prospective birth cohort Infancia y Medio Ambiente (INMA) study. Am J Clin
Nutr 2017; 106:878.
7. Vitamin B12: fact sheet for health professionals. National Institutes of Health Office of Di
etary Supplements. Available at: https://ods.od.nih.gov/factsheets/VitaminB12-HealthPr
ofessional/#h1 (Accessed on August 22, 2022).
8. Balcı YI, Ergin A, Karabulut A, et al. Serum vitamin B12 and folate concentrations and the
effect of the Mediterranean diet on vulnerable populations. Pediatr Hematol Oncol
2014; 31:62.
9. Carmel R, Mallidi PV, Vinarskiy S, et al. Hyperhomocysteinemia and cobalamin deficiency
in young Asian Indians in the United States. Am J Hematol 2002; 70:107.
10. Antony AC. Vegetarianism and vitamin B-12 (cobalamin) deficiency. Am J Clin Nutr 2003;
78:3.
11. Centers for Disease Control and Prevention (CDC). Neurologic impairment in children
associated with maternal dietary deficiency of cobalamin--Georgia, 2001. MMWR Morb
Mortal Wkly Rep 2003; 52:61.
12. Grattan-Smith PJ, Wilcken B, Procopis PG, Wise GA. The neurological syndrome of
infantile cobalamin deficiency: developmental regression and involuntary movements.
Mov Disord 1997; 12:39.
13. Renault F, Verstichel P, Ploussard JP, Costil J. Neuropathy in two cobalamin-deficient
breast-fed infants of vegetarian mothers. Muscle Nerve 1999; 22:252.
14. Green R. Vitamin B12 deficiency from the perspective of a practicing hematologist.
Blood 2017.
15. UK label for hydroxocobalamin https://www.medicines.org.uk/emc/product/4662/smpc/
print (Accessed on August 02, 2023).
16. Sezer RG, Akoğlu HA, Bozaykut A, Özdemir GN. Comparison of the efficacy of parenteral
and oral treatment for nutritional vitamin B12 deficiency in children. Hematology 2018;
23:653.
17. Carmel R, Watkins D, Rosenblatt DS. Megaloblastic anemia. In: Nathan and Oski's hemat
ology and oncology of infancy and childhood, 8th ed, Orkin SH, Fisher DE, Ginsburg D, et
al (Eds), Elsevier Saunders, Philadelphia 2015. Vol 1, p.308.
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/2
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/3
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/4
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/5
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/6
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/6
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/6
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/6
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/8
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/8
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/8
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/9
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/9
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/10
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/10
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/11
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/11
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/11
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/12
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/12
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/12
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/13
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/13https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/14
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/14
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/16
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/16
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/16
18. Hathcock JN, Troendle GJ. Oral cobalamin for treatment of pernicious anemia? JAMA
1991; 265:96.
19. Eussen SJ, de Groot LC, Clarke R, et al. Oral cyanocobalamin supplementation in older
people with vitamin B12 deficiency: a dose-finding trial. Arch Intern Med 2005; 165:1167.
20. Rajan S, Wallace JI, Brodkin KI, et al. Response of elevated methylmalonic acid to three
dose levels of oral cobalamin in older adults. J Am Geriatr Soc 2002; 50:1789.
21. Sezer RG, Bozaykut A, Akoğlu HA, Özdemir GN. The Efficacy of Oral Vitamin B12
Replacement for Nutritional Vitamin B12 Deficiency. J Pediatr Hematol Oncol 2018;
40:e69.
22. Chandelia S, Chandra J, Narayan S, et al. Addition of cobalamin to iron and folic acid
improves hemoglobin rise in nutritional anemia. Indian J Pediatr 2012; 79:1592.
23. Solomon LR. Oral vitamin B12 therapy: a cautionary note. Blood 2004; 103:2863.
24. Kuwata Y, Tsuruoka S, Ohkuchi A, et al. Serious adverse drug reaction in a woman with
hyperemesis gravidarum after first exposure to vitamin B complex containing vitamins
B1, B6 and B12. J Obstet Gynaecol Res 2009; 35:790.
25. Wang H, Li L, Qin LL, et al. Oral vitamin B12 versus intramuscular vitamin B12 for vitamin
B12 deficiency. Cochrane Database Syst Rev 2018; 3:CD004655.
26. Kuzminski AM, Del Giacco EJ, Allen RH, et al. Effective treatment of cobalamin deficiency
with oral cobalamin. Blood 1998; 92:1191.
27. Bolaman Z, Kadikoylu G, Yukselen V, et al. Oral versus intramuscular cobalamin
treatment in megaloblastic anemia: a single-center, prospective, randomized, open-label
study. Clin Ther 2003; 25:3124.
28. Butler CC, Vidal-Alaball J, Cannings-John R, et al. Oral vitamin B12 versus intramuscular
vitamin B12 for vitamin B12 deficiency: a systematic review of randomized controlled
trials. Fam Pract 2006; 23:279.
29. Glass GB, Skeggs HR, Lee DH. Hydroxocobalamin. V. Prolonged maintenance of high
vitamin B12 blood levels following a short course of hydroxocobalamin injections. Blood
1966; 27:234.
30. Delpre G, Stark P, Niv Y. Sublingual therapy for cobalamin deficiency as an alternative to
oral and parenteral cobalamin supplementation. Lancet 1999; 354:740.
31. Slot WB, Merkus FW, Van Deventer SJ, Tytgat GN. Normalization of plasma vitamin B12
concentration by intranasal hydroxocobalamin in vitamin B12-deficient patients.
Gastroenterology 1997; 113:430.
32. Hsing AW, Hansson LE, McLaughlin JK, et al. Pernicious anemia and subsequent cancer.
A population-based cohort study. Cancer 1993; 71:745.
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/18
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/18
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/19
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/19
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/20
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/20
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/21
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/21
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/21
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/22
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/22
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/23
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/24
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/24
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/24
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/25
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/25
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/26
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/26
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/27
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/27
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/27
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/28
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/28
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/28
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/29
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/29
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/29
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/30
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/30
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/31
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/31
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/31
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/32
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/32
33. Vannella L, Lahner E, Osborn J, et al. Systematic review: gastric cancer incidence in
pernicious anaemia. Aliment Pharmacol Ther 2013; 37:375.
34. Murphy G, Dawsey SM, Engels EA, et al. Cancer Risk After Pernicious Anemia in the US
Elderly Population. Clin Gastroenterol Hepatol 2015; 13:2282.
35. Talley NJ, Chute CG, Larson DE, et al. Risk for colorectal adenocarcinoma in pernicious
anemia. A population-based cohort study. Ann Intern Med 1989; 111:738.
36. Boursi B, Mamtani R, Haynes K, Yang YX. Pernicious anemia and colorectal cancer risk -
A nested case-control study. Dig Liver Dis 2016; 48:1386.
37. Minoli G, Prada A, Gambetta G, et al. The ASGE guidelines for the appropriate use of
upper gastrointestinal endoscopy in an open access system. Gastrointest Endosc 1995;
42:387.
38. Pritchard DM, Hooper M. Letter: gastric cancer and pernicious anaemia--only a minority
of UK pernicious anaemia patients have had a gastroscopy. Aliment Pharmacol Ther
2016; 43:1106.
39. From Dr. Takemoto 8/10/2022: There is a link we could use as alternative https://ods.od.
nih.gov/factsheets/Folate-HealthProfessional/ (Accessed on August 22, 2022).
40. Turck D. Cow's milk and goat's milk. World Rev Nutr Diet 2013; 108:56.
41. Alférez MJ, Rivas E, Díaz-Castro J, et al. Folic acid supplemented goat milk has beneficial
effects on hepatic physiology, haematological status and antioxidant defence during
chronic Fe repletion. J Dairy Res 2015; 82:86.
42. Selhub J, Morris MS, Jacques PF. In vitamin B12 deficiency, higher serum folate is
associated with increased total homocysteine and methylmalonic acid concentrations.
Proc Natl Acad Sci U S A 2007; 104:19995.
43. Dhar M, Bellevue R, Carmel R. Pernicious anemiawith neuropsychiatric dysfunction in a
patient with sickle cell anemia treated with folate supplementation. N Engl J Med 2003;
348:2204.
44. Vasconcelos OM, Poehm EH, McCarter RJ, et al. Potential outcome factors in subacute
combined degeneration: review of observational studies. J Gen Intern Med 2006;
21:1063.
45. Healton EB, Savage DG, Brust JC, et al. Neurologic aspects of cobalamin deficiency.
Medicine (Baltimore) 1991; 70:229.
Topic 7154 Version 83.0
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/33
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/33
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/34
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/34
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/35
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/35
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/36
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/36
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/37
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/37
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/37
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/38
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/38
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/38
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/40
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/41
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/41
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/41
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/42
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/42
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/42
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/43
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/43
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/43
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/44
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/44
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/44
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/45
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/45
GRAPHICS
Treatment of vitamin B12 deficiency in adults
Refer to a separate algorithm for diagnosis of vitamin B12 deficiency, including use of the MMA level
in people with borderline vitamin B12 levels. If not known, the cause of vitamin B12 deficiency must
be determined as it has implications for the route of administration, duration of therapy, and other
testing or treatments that may be indicated. Intranasal, transdermal, and oral "timed release"
formulations of vitamin B12 are not recommended, and vitamin B12 is not given intravenously.
Refer to UpToDate for pediatric dosing.
Vitamin B12 administration should lead to a reticulocytosis within several days, improvement in the
hemoglobin in 1 to 2 weeks, and normalization of the hemoglobin and MCV within 4 to 8 weeks.
Neurologic symptoms may resolve or stabilize without complete resolution. Refer to UpToDate for
details.
CBC: complete blood count; IM: intramuscular; MCV: mean corpuscular volume; MMA: methylmalonic
acid (increased in vitamin B12 deficiency); SL: sublingual.
* Malabsorption is classically due to pernicious anemia (PA; vitamin B12 deficiency caused by
autoantibodies to intrinsic factor or gastric parietal cells). Other causes may include bariatric, gastric,
or small intestinal surgery. Some experts will use oral vitamin B12 as initial therapy for individuals
with malabsorption if they do not have severe anemia or neurologic complications and if adherence
was assured. Refer to UpToDate for diagnostic testing for PA and other evaluations.
¶ Dose and frequency depend on the level of concern and the costs and burdens of therapy, with
shared decision making. For severe deficiency, daily dosing for the first week can be considered. If a
dose increase is needed due to insufficient response, it is reasonable to increase the dosing frequency
(eg, 1000 mcg IM every 2 weeks) and/or increase the dose (eg, 2000 mcg orally instead of 1000 mcg).
Lower doses are used for children (refer to UpToDate for details).
Graphic 131424 Version 10.0
Vitamin B12 deficiency: Risk factors and approach to prevention
Risk factor Preferred approach to prevention
Insufficient dietary intake:
Vegan or strict vegetarian diet
Pregnancy or lactating with limited intake of
animal protein
Neonate breastfed by mother with vitamin
B12 deficiency
Provide oral vitamin B12 supplementation:
2.4 mcg daily (adult RDA) or more is
sufficient for most patients
2.6 mcg daily for pregnancy
2.8 mcg daily for breastfeeding
Ensure that breastfeeding mothers are vitamin
B12 replete
Inability to release vitamin B12 from food proteins
(reversible causes):
Untreated chronic Helicobacter pylori
infection
Chronic anti-acid therapy:
Antacids
Proton pump inhibitors
Histamine receptor 2 blockers
Chronic excess alcohol use
Treat H. pylori infection
Review need for chronic anti-acid therapy
Reduce alcohol use
Monitoring or supplementation may be
appropriate for individuals who cannot reverse
the underlying cause
Gastric/bariatric surgery* Provide routine supplementation with either:
Oral vitamin B12 (350 to 1000 mcg daily)
or
IM (or deep subcutaneous) vitamin B12
1000 mcg per month (cyanocobalamin)
or
1000 mcg every two to three months
(hydroxocobalamin)
Inability to absorb vitamin B12-intrinsic factor
complex:
Metformin use
Pancreatic insufficiency
Small intestinal bacterial overgrowth
Small intestinal inflammation
Small intestinal surgery
Fish tapeworm infection
Treat reversible infections (bacterial
overgrowth, tapeworm) or inflammation
Monitor vitamin B12 levels (once a year is
reasonable, test at any time if symptoms
occur)
Some patients may reasonably choose to take
a supplement rather than undergo monitoring
Inactivation of vitamin B12 and inhibition of
cofactor function:
Nitrous oxide (inhalation anesthetic or
recreational use)
Avoid nitrous oxide in susceptible individuals
Perioperative monitoring of the CBC; maintain
a low threshold to evaluate any abnormalities
Maintain a low threshold for measuring
vitamin B12 levels when evaluating neurologic
or neuropsychiatric symptoms
¶
¶
Sometimes these individuals have normal
vitamin B12 levels but the vitamin is
dysfunctional, and testing of MMA is required
This table lists risk factors for which prevention and/or monitoring are appropriate; it does not
address treatment once vitamin B12 deficiency is diagnosed. A comprehensive discussion of the
causes of vitamin B12 deficiency (including pernicious anemia, heritable/genetic disorders, and
others) and their treatment is presented in UpToDate. All individuals with vitamin B12 deficiency
should have the cause determined, because some causes such as pernicious anemia carry additional
risks and require additional monitoring or testing, some causes are reversible with treatment, and
some causes requirelifelong supplementation.
For conditions with a variable risk of causing vitamin B12 deficiency, monitoring vitamin B12
levels is often preferred, but some individuals may reasonably choose supplementation.
For established vitamin B12 deficiency, correction of the deficiency followed by routine
supplementation is suggested.
CBC: complete blood count; IM: intramuscular; MMA: methylmalonic acid; RDA: recommended dietary
allowance.
* May also be associated with decreased or absent intrinsic factor.
¶ The mechanism of metformin-induced vitamin B12 deficiency involves decreased intestinal calcium.
The mechanism of nitrous oxide is inactivation of functional vitamin B12.
Graphic 142028 Version 2.0
Micronutrient management after bariatric surgery
  Preoperative
prevalence
Postoperative
prevalence
Symptoms of
deficiency
RDA Supple
Vitamin
A
Up to 17% 8 to 11% after
RYGB
70% after
BPD/DS
Early signs:
Night blindness
Bitot's spots
Hyperkeratinization
of skin
Loss of taste
Advanced signs:
Corneal damage
Blindness
Men: 900
mcg (3000
IU)
Women:
700 mcg
(2300 IU)
LAGB: 5
RYGB or
10,000 I
BPD/DS
daily
Vitamin D 85% 63% Hypocalcemia, tetany,
tingling, cramping,
metabolic bone disease,
muscle pain
General:
600 IU
Pregnancy,
lactation,
or over 71
years of
age: 800
IU
3000 IU
from all
maintai
level of 
Vitamin E 2.2% Uncommon Neuromuscular
disorders and hemolysis
General:
15 mg
(22.4 IU)
Lactation:
19 mg
(28.4 IU)
Adults a
adolesc
older: 1
IU) daily
Lactatio
(28.4 IU
Vitamin K Uncommon Uncommon Impaired coagulation 90 to 120
mcg
LAGB, R
90 to 12
BPD/DS
daily
[1]
[2]
[1,3]
[3]
[4] [4]
Vitamin
B1
(Thiamine)
7% 19% at 3
months, 9% at 6
months, 6% at
12 months
Numbness, tingling in
extremities, gait ataxia,
edema, vomiting,
confusion
Wernicke-Korsakoff
syndrome:
Encephalopathy
Ataxia
Oculomotor
dysfunction
Confabulation
Impaired memory
Impaired learning
Beriberi:
Neuropathy
Pain
Paresthesia
Loss of reflexes
1.5 mg >12 mg 
preferab
mg daily
complex
With IV 
100 mg 
should b
the solu
not con
if Werni
encepha
suspect
Vitamin
B12
0 to 18% 33% after RYGB;
4 to 20% after
SG
Macrocytic
(megaloblastic) anemia,
mild pancytopenia,
neuropsychiatric
findings (eg, depression,
neuropathy)
2.4 mcg Oral dos
1000 mc
1000 mc
monthly
spray
Folate 0 to 54% Up to 65% after
RYGB; 18% after
SG
Macrocytic
(megaloblastic) anemia,
mild pancytopenia,
neural tube defects
400 mcg General
mcg dai
multivit
Women
childbea
800 to 1
daily
Should 
mg per 
Iron 15% 17%, 25% after
RYGB, 12% after
SG
Anemia
Pica
Impaired learning
Men ages
19 and
older and
women
ages 51
and older:
8 mg per
day
Women
between
Males, p
menopa
and pat
history o
mg of ir
multivit
Menstru
women 
women 
undergo
[5]
[5]
[6]
[6]
the ages
of 19 to
50: 18 mg
per day
SG, or B
to 60 m
element
from all
Zinc 24 to 28%
overall; 9 to
74% seeking
BPD/DS
70% after
BPD/DS, 40%
after RYGB, 19%
after SG, 34%
after LAGB
Growth retardation,
delayed sexual maturity,
impotence, impaired
immune function
Women: 8
mg
Men: 11
mg
BPD/DS
(200% R
RYGB: 8
(100 to 2
SG or LA
mg (100
Maintai
to 15 m
1 mg of
Copper 68% in women
seeking BPD
90% after
BPD/DS, 10 to
20% after RYGB
Anemia, neutropenia,
ataxia
900 mcg BPD/DS
mg daily
SG or LA
daily (10
Maintai
to 15 m
1 mg of
Selenium 2% 14 to 22% after
RYGB and
BPD/DS
Skeletal muscle
dysfunction and
cardiomyopathy, mood
disorder, impaired
immune function,
macrocytosis
55 mcg Unknow
higher t
mcg/da
Calcium 1 to 10% 3.6% after
bariatric surgery
(1.9% after
RYGB, 9.3% after
SG, and 10%
after BPD/DS)
Bone disease, secondary
hyperparathyroidism
1000 to
1200 mg
RYGB, S
1200 to 
daily in 
doses
BPD/DS
2400 mg
divided 
Plus vita
supplem
(refer to
BPD/DS: biliopancreatic diversion with duodenal switch; IM: intramuscular; IU: international unit; IV:
intravenous; LAGB: laparoscopic adjustable gastric band; RDA: Recommended Daily Allowance; RYGB:
Roux-en-Y gastric bypass; SG: sleeve gastrectomy; SQ: subcutaneous.
[9]
References:
1. Mechanick JI, Apovian C, Brethauer S, et al. Clinical practice guidelines for the perioperative nutrition, metabolic, and
nonsurgical support of patients undergoing bariatric procedures - 2019 update: Cosponsored by American Association
of Clinical Endocrinologists/American College of Endocrinology, The Obesity Society, American Society for Metabolic &
Bariatric Surgery, Obesity Medicine Association, and American Society of Anesthesiologists. Surg Obes Relat Dis 2020;
16:175.
2. U.S. Department of Health and Human Services and U.S. Department of Agriculture. 2015–2020 Dietary Guidelines for
Americans, 8th Edition, December 2015. Available at: https://health.gov/our-work/food-nutrition/previous-dietary-
guidelines/2015 (Accessed on April 7, 2021).
3. Stein J, Stier C, Raab H, Weiner R. Review article: The nutritional and pharmacological consequences of obesity surgery.
Aliment Pharmacol Ther 2014; 40:582.
4. Giustina A, di Filippo L, Facciorusso A, et al. Vitamin D status and supplementation before and after bariatric surgery:
Recommendations based on a systematic review and meta-analysis. Rev Endocr Metab Disord 2023; 24:1011.
5. Karimi Behnagh A, Eghbali M, Abdolmaleki F, et al. Pre- and post-surgical prevalence of thiamine deficiency in patients
undergoing bariatric surgery: A systematic review and meta-analysis. Obes Surg 2024; 34:653.
6. Enani G, Bilgic E, Lebedeva E, et al. The incidence of iron deficiency anemia post-Roux-en-Y gastric bypass and sleeve
gastrectomy: A systematic review. Surg Endosc 2020; 34:3002.
7. Institute of Medicine (U.S.). Panel on Dietary Antioxidants and Related Compounds. Dietary Reference Intakes for
Vitamin C, Vitamin E, Selenium, and Carotenoids, National Academy Press, Washington DC 2000.
8. Al-Matary A, Hussain M, Ali J. Selenium: a brief review and a case report of selenium responsive cardiomyopathy. BMC
Pediatr 2013; 13:39.
9. Shah M, Sharma A, Wermers RA, et al. Hypocalcemia after bariatric surgery: Prevalence and associated risk factors.
Obes Surg 2017.
Graphic 114101 Version 6.0
https://health.gov/our-work/food-nutrition/previous-dietary-guidelines/2015
https://health.gov/our-work/food-nutrition/previous-dietary-guidelines/2015
Advantages and disadvantages of oral and intramuscular (IM) vitamin B12
Route Advantages Disadvantages
Oral Outpatient visit not required
Preferred for dietary deficiency
Equal efficacy to intramuscular
therapy
Adherence may not be assured
Higher doses required for any
condition that interferes with
absorption
For initial repletion of severe or
symptomatic deficiency, there may
be a concern about rapid and
sufficient repletion; however, oral
repletion can be effective for
maintenance therapy if needed
Intramuscular Adherence is assured (especially
important for severe or
symptomatic deficiency)
Opportunity to interact with the
medical team*
Preferred for altered
gastrointestinal anatomy or
impaired absorption
Less-frequent dosing after
deficiency is corrected
May require outpatient visit
(including nurse time, wait time,
travel)
Higher cost, which includes co-pay
for visit and possibly a facility fee
Extremely rare reports of
hypersensitivity
Vitamin B12 to prevent or treat deficiency can be given orally (tablets, sublingual) or intramuscularly.
The oral dose used to overcome impaired absorption is 1000 to 2000 mcg daily. The initial IM dose
(can also be given as a deep subcutaneous injection) for adults is 1000 mcg daily, every other day, or
weekly, depending on the severity of deficiency and clinical concern, followed by once monthly
(cyanocobalamin) or once every two to three months (hydroxocobalamin). All patients should have an
evaluation for the underlying cause.
Other routes are generally not used:
Intravenous – Not used due to concerns about excretion (mostly excreted in urine) and
anaphylaxis, with rare exceptions such as in total parenteral nutrition.
Intranasal – Generally not used due to discomfort; oral route is likely to provide more consistent
absorption.Transdermal – Generally not used due to lack of data for efficacy.
IM: intramuscular.
* Some individuals have a strong placebo effect from the intramuscular injection and feel an
immediate burst of energy; they may prefer to continue intramuscular injections.
¶ The requirement for outpatient visits and higher cost can be avoided by self-administration of B12
injections, which may be possible for some patients with appropriate training.
Graphic 142051 Version 3.0
¶
Dietary Reference Intakes (DRIs): Recommended dietary allowances and
adequate intakes of several vitamins in children
 
Source
of
goal*
Child
1 to 3
Female
4 to 8
Male
4 to 8
Female
9 to 13
Male
9 to
13
Female
14 to
18
Male
14 to
18
Vitamins
Vitamin A,
mcg RAE
RDA 300 400 400 600 600 700 900
Vitamin E, mg
AT
RDA 6 7 7 11 11 15 15
Vitamin D,
international
units
RDA 600 600 600 600 600 600 600
Vitamin C, mg RDA 15 25 25 45 45 65 75
Thiamin, mg RDA 0.5 0.6 0.6 0.9 0.9 1 1.2
Riboflavin,
mg
RDA 0.5 0.6 0.6 0.9 0.9 1 1.3
Niacin, mg RDA 6 8 8 12 12 14 16
Vitamin B6,
mg
RDA 0.5 0.6 0.6 1 1 1.2 1.3
Vitamin B12,
mcg
RDA 0.9 1.2 1.2 1.8 1.8 2.4 2.4
Choline, mg AI 200 250 250 375 375 400 550
Vitamin K,
mcg
AI 30 55 55 60 60 75 75
Folate, mcg
DFE
RDA 150 200 200 300 300 400 400
RAE: retinol activity equivalents; RDA: recommended dietary allowance; AT: alpha-tocopherol; AI:
adequate intake; DFE: dietary folate equivalents.
* 14 g fiber per 1000 kcal = basis for AI for fiber.
References:
1. Institute of Medicine. Dietary Reference Intakes: The essential guide to nutrient requirements. Washington (DC): The
National Academies Press, 2006.
2. Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D. Washington (DC): The National Academies
Press, 2010.
Reproduced from: U.S. Department of Health and Human Services and U.S. Department of Agriculture. 2015–2020 Dietary
Guidelines for Americans, 8th Edition, December 2015. Available at: https://health.gov/our-work/food-nutrition/previous-
dietary-guidelines/2015 (Accessed on April 7, 2021).
https://health.gov/our-work/food-nutrition/previous-dietary-guidelines/2015
https://health.gov/our-work/food-nutrition/previous-dietary-guidelines/2015
Graphic 106207 Version 6.0
Contributor Disclosures
Robert T Means, Jr, MD, MACP Consultant/Advisory Boards: Affinergy [Iron-related diagnostic tests].
All of the relevant financial relationships listed have been mitigated. Kathleen M Fairfield, MD,
DrPH No relevant financial relationship(s) with ineligible companies to disclose. Clifford M Takemoto,
MD Grant/Research/Clinical Trial Support: Daiichi Sankyo [Thrombosis]; Novo Nordisk [Sickle cell
disease]; Pfizer [Sickle cell disease]. Consultant/Advisory Boards: Genentech [Hemophilia]; Merck
[Anticoagulants]; Novartis [DSMB – Aplastic anemia]. All of the relevant financial relationships listed
have been mitigated. Jennifer S Tirnauer, MD No relevant financial relationship(s) with ineligible
companies to disclose. Han Li, MD No relevant financial relationship(s) with ineligible companies to
disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these
are addressed by vetting through a multi-level review process, and through requirements for
references to be provided to support the content. Appropriately referenced content is required of all
authors and must conform to UpToDate standards of evidence.
Conflict of interest policy

https://www.uptodate.com/home/conflict-interest-policyB12 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 [PA]). 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:
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.
●
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 [4].
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.
●
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.
●
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/3
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-vitamin-b12-and-folate-deficiency?sectionName=TERMINOLOGY&search=vitamina%20b12&topicRef=7154&anchor=H3792687810&source=see_link#H3792687810
https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-vitamin-b12-and-folate-deficiency?sectionName=TERMINOLOGY&search=vitamina%20b12&topicRef=7154&anchor=H3792687810&source=see_link#H3792687810
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/folic-acid-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/hydroxocobalamin-vitamin-b12a-supplement-and-cyanide-antidote-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/4
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/1,2
https://www.uptodate.com/contents/folic-acid-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/leucovorin-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/methotrexate-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
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 [5,6]. 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 "Preconception and
prenatal folic acid supplementation".)
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 [7]:
(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.)
●
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●
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/1,2
https://www.uptodate.com/contents/folic-acid-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/5,6
https://www.uptodate.com/contents/vitamin-intake-and-disease-prevention?sectionName=TOXICITY%20AT%20HIGH%20DOSES&search=vitamina%20b12&topicRef=7154&anchor=H74132982&source=see_link#H74132982
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/folic-acid-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/preconception-and-prenatal-folic-acid-supplementation?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/preconception-and-prenatal-folic-acid-supplementation?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/causes-and-pathophysiology-of-vitamin-b12-and-folate-deficiencies?sectionName=Dietary%20sources%20and%20RDI&search=vitamina%20b12&topicRef=7154&anchor=H2089813338&source=see_link#H2089813338https://www.uptodate.com/contents/causes-and-pathophysiology-of-vitamin-b12-and-folate-deficiencies?sectionName=Dietary%20sources%20and%20RDI&search=vitamina%20b12&topicRef=7154&anchor=H2089813338&source=see_link#H2089813338
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/7
https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-vitamin-b12-and-folate-deficiency?sectionName=POST-DIAGNOSTIC%20TESTING&search=vitamina%20b12&topicRef=7154&anchor=H4095866104&source=see_link#H4095866104
https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-vitamin-b12-and-folate-deficiency?sectionName=POST-DIAGNOSTIC%20TESTING&search=vitamina%20b12&topicRef=7154&anchor=H4095866104&source=see_link#H4095866104
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. The table
summarizes these causes of vitamin B12 deficiency ( table 1).
These include:
Pregnancy – 2.6 mcg per day●
Lactation – 2.8 mcg per day●
Vegan or vegetarian diet – Vitamin 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 [8,9]. 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. Post-bariatric surgery supplementation of vitamin
B12 can be provided by many routes, as listed in the table ( table 2) 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
●
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/causes-and-pathophysiology-of-vitamin-b12-and-folate-deficiencies?sectionName=Vitamin%20B12%20absorption%20and%20body%20stores&search=vitamina%20b12&topicRef=7154&anchor=H618258678&source=see_link#H618258678
https://www.uptodate.com/contents/causes-and-pathophysiology-of-vitamin-b12-and-folate-deficiencies?sectionName=Vitamin%20B12%20absorption%20and%20body%20stores&search=vitamina%20b12&topicRef=7154&anchor=H618258678&source=see_link#H618258678
https://www.uptodate.com/contents/image?imageKey=HEME%2F142028&topicKey=HEME%2F7154&search=vitamina%20b12&rank=2%7E150&source=see_link
https://www.uptodate.com/contents/image?imageKey=HEME%2F142028&topicKey=HEME%2F7154&search=vitamina%20b12&rank=2%7E150&source=see_link
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/8,9
https://www.uptodate.com/contents/vegetarian-diets-for-children?sectionName=Vitamin%20B12&search=vitamina%20b12&topicRef=7154&anchor=H19&source=see_link#H19
https://www.uptodate.com/contents/healthy-diet-in-adults?sectionName=Plant-based%20and%20vegetarian%20diets&search=vitamina%20b12&topicRef=7154&anchor=H1862857268&source=see_link#H1862857268
https://www.uptodate.com/contents/healthy-diet-in-adults?sectionName=Plant-based%20and%20vegetarian%20diets&search=vitamina%20b12&topicRef=7154&anchor=H1862857268&source=see_link#H1862857268
https://www.uptodate.com/contents/image?imageKey=SURG%2F114101&topicKey=HEME%2F7154&search=vitamina%20b12&rank=2%7E150&source=see_link
https://www.uptodate.com/contents/image?imageKey=SURG%2F114101&topicKey=HEME%2F7154&search=vitamina%20b12&rank=2%7E150&source=see_link
https://www.uptodate.com/contents/bariatric-surgery-postoperative-nutritional-management?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-vitamin-b12-and-folate-deficiency?sectionName=Vitamin%20B12%20normal%20ranges&search=vitamina%20b12&topicRef=7154&anchor=H2652234191&source=see_link#H2652234191
https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-vitamin-b12-and-folate-deficiency?sectionName=Vitamin%20B12%20normal%20ranges&search=vitamina%20b12&topicRef=7154&anchor=H2652234191&source=see_link#H2652234191
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 [14].
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.
The table summarizes advantages and disadvantages of parenteral (intramuscular or deep
subcutaneous) versus oral/sublingual vitamin B12 ( table 3).
An approach to decision-making regarding formulation, dose, and frequency is summarized
in the algorithm ( algorithm 1).
if exclusively breastfed [10-13]. 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 (N O) 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 vitaminB12
are borderline. This occurs because N O chemically inactivates the vitamin B12-derived
methylcobalamin molecule at the active site of methionine synthase [14]. This can lead
to rapid neuropsychiatric deterioration and/or other complications.
●
2
2
In individuals with known vitamin B12 or folate deficiency undergoing anesthesia with
N O, 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'.)
2
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/14
https://www.uptodate.com/contents/metformin-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/causes-and-pathophysiology-of-vitamin-b12-and-folate-deficiencies?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/causes-and-pathophysiology-of-vitamin-b12-and-folate-deficiencies?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/image?imageKey=HEME%2F142051&topicKey=HEME%2F7154&search=vitamina%20b12&rank=2%7E150&source=see_link
https://www.uptodate.com/contents/image?imageKey=HEME%2F142051&topicKey=HEME%2F7154&search=vitamina%20b12&rank=2%7E150&source=see_link
https://www.uptodate.com/contents/image?imageKey=HEME%2F131424&topicKey=HEME%2F7154&search=vitamina%20b12&rank=2%7E150&source=see_link
https://www.uptodate.com/contents/image?imageKey=HEME%2F131424&topicKey=HEME%2F7154&search=vitamina%20b12&rank=2%7E150&source=see_link
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/10-13
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/nitrous-oxide-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/nitrous-oxide-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/14
https://www.uptodate.com/contents/causes-and-pathophysiology-of-vitamin-b12-and-folate-deficiencies?sectionName=Nitrous%20oxide&search=vitamina%20b12&topicRef=7154&anchor=H2925831930&source=see_link#H2925831930
https://www.uptodate.com/contents/causes-and-pathophysiology-of-vitamin-b12-and-folate-deficiencies?sectionName=Nitrous%20oxide&search=vitamina%20b12&topicRef=7154&anchor=H2925831930&source=see_link#H2925831930
General principles regarding the route of administration are discussed above. (See 'Route of
administration' above.)
Intramuscular – It is never incorrect to initiate treatment of vitamin B12 deficiency by
intramuscular administration; intramuscular administration is very strongly
recommended for patients who are symptomatic or with adherence or access
challenges. (See 'Special populations (neuropsychiatric symptoms, issues with access or
adherence)' below.)
●
Adults – The typical dose of intramuscular vitamin B12 for adults is 1000 mcg
intramuscularly once per week until the deficiency is corrected and then once per
month (cyanocobalamin) or once every other month (hydroxocobalamin) [15].
•
If there are symptoms of anemia and/or neurologic symptoms, 1000 mcg can be
administered daily for three doses or every other day for a week (some experts
suggest two weeks), to replete deficiency and then transition to the typical monthly
schedule. Daily dosing would be used more typically in the inpatient setting. (See
'Special populations (neuropsychiatric symptoms, issues with access or adherence)'
below.)
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
mcg 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].
•
Vitamin B12 is not given intravenously. (See 'Route of administration' above.)
Oral●
Adults – In adults with normal absorption, oral dosing is equally effective as
intramuscular 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) [14,18-20].
•
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/hydroxocobalamin-vitamin-b12a-supplement-and-cyanide-antidote-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/15
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/16
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/hydroxocobalamin-vitamin-b12a-supplement-and-cyanide-antidote-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/17
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/14,18-20
Evidence regarding the relative efficacy of intramuscular versus high-dose oral vitamin B12
comes from small randomized trials and observational studies.
The following describes common approaches to treating patients with different causes of
vitamin B12 deficiency:
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, two days a week
for two weeks, and then weekly for three months [21]. Another study used 125 mcg
for children 2 years for a total of eight weeks [22]. Both of these studies showed normalization
of vitamin B12 levels.
•
Routes that are not used (timed release, intranasal, transdermal, intravenous) –
Over-the-counter preparations of vitamin B12 designated as "timed release" should be
avoided [23]. We generally do not use the intranasal formulations because of their
variable absorption and higher cost; these formulations may also cause rhinorrhea.
●
Transdermal forms of vitamin B12 are available over the counter, but this route of
administration has not beenvalidated clinically in the setting of vitamin B12 deficiency
and should not be relied upon for treatment.
Vitamin B12 is not given intravenously; prescribing information notes that intravenous
use will result in urinary excretion of most of the vitamin B12. Concerns about
anaphylaxis have also been raised [24].
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 [25].
●
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 [26-28].
●
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
●
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/21
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/22
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/23
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/24
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/25
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/26-28
https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-vitamin-b12-and-folate-deficiency?sectionName=TERMINOLOGY&search=vitamina%20b12&topicRef=7154&anchor=H3792687810&source=see_link#H3792687810
https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-vitamin-b12-and-folate-deficiency?sectionName=TERMINOLOGY&search=vitamina%20b12&topicRef=7154&anchor=H3792687810&source=see_link#H3792687810
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
Special populations (neuropsychiatric symptoms, issues with access or adherence)
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 [28,29]. 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 intramuscular vitamin B12 since this ensures rapid
absorption and adherence.
However, data are limited as to whether correction of the deficiency occurs more
rapidly or long-term complications are reduced with intramuscular versus oral therapy,
as discussed below.
These individuals may be treated initially with 1000 mcg of vitamin B12 daily for at least
three days or every other day for a week (some experts suggest two weeks), followed
by administration once monthly (cyanocobalamin) or once every two to three months
(hydroxocobalamin) [1]. (See 'Treatment of vitamin B12 deficiency' above.)
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/28,29
https://www.uptodate.com/contents/causes-and-pathophysiology-of-vitamin-b12-and-folate-deficiencies?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/causes-and-pathophysiology-of-vitamin-b12-and-folate-deficiencies?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/vitamin-intake-and-disease-prevention?sectionName=VITAMIN%20B12%20%28COBALAMIN%29&search=vitamina%20b12&topicRef=7154&anchor=H45&source=see_link#H45
https://www.uptodate.com/contents/vitamin-intake-and-disease-prevention?sectionName=VITAMIN%20B12%20%28COBALAMIN%29&search=vitamina%20b12&topicRef=7154&anchor=H45&source=see_link#H45
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/hydroxocobalamin-vitamin-b12a-supplement-and-cyanide-antidote-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/1
The typical response and our approach to monitoring are discussed below. (See 'Assessing
and monitoring response to treatment' below.)
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:
Once the initial deficiency has been corrected, it would bereasonable 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 intramuscular administration or patient preference – Some
individuals may not have access to intramuscular 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 [2,30,31]. 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 [14].
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.
●
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
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/2,30,31
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/14
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/32
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/33
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/34
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/35,36
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/37
Individuals without documented vitamin B12 deficiency — With the exception of the
preventive use of vitamin B12 in certain populations, we do not advocate routine
administration of vitamin B12 to individuals without documented deficiency. (See 'Prevention
of vitamin B12 deficiency' above.)
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].
Vitamin B12 supplementation in pregnancy is discussed separately. (See "Nutrition in
pregnancy: Dietary requirements and supplements", section on 'Vitamin B12'.)
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]:
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".)
●
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●
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/3
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/nutrition-in-pregnancy-dietary-requirements-and-supplements?sectionName=Vitamin%20B12&search=vitamina%20b12&topicRef=7154&anchor=H993610633&source=see_link#H993610633
https://www.uptodate.com/contents/nutrition-in-pregnancy-dietary-requirements-and-supplements?sectionName=Vitamin%20B12&search=vitamina%20b12&topicRef=7154&anchor=H993610633&source=see_link#H993610633
https://www.uptodate.com/contents/causes-and-pathophysiology-of-vitamin-b12-and-folate-deficiencies?sectionName=Dietary%20sources%20and%20RDI&search=vitamina%20b12&topicRef=7154&anchor=H2089813338&source=see_link#H2089813338
https://www.uptodate.com/contents/causes-and-pathophysiology-of-vitamin-b12-and-folate-deficiencies?sectionName=Dietary%20sources%20and%20RDI&search=vitamina%20b12&topicRef=7154&anchor=H2089813338&source=see_link#H2089813338
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/39
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/38
https://www.uptodate.com/contents/evidence-based-approach-to-prevention?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/overview-of-preventive-care-in-adults?search=vitamina%20b12&topicRef=7154&source=see_link
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:
In these cases, oral folic acid at a dose of 1 mg dailyis typically sufficient to prevent
deficiency from developing.
Other considerations with risk for 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●
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
"Preconception and prenatal folic acid supplementation".)
●
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 and 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
●
https://www.uptodate.com/contents/causes-and-pathophysiology-of-vitamin-b12-and-folate-deficiencies?sectionName=Folate%20absorption%20and%20body%20stores&search=vitamina%20b12&topicRef=7154&anchor=H619653869&source=see_link#H619653869
https://www.uptodate.com/contents/causes-and-pathophysiology-of-vitamin-b12-and-folate-deficiencies?sectionName=Folate%20absorption%20and%20body%20stores&search=vitamina%20b12&topicRef=7154&anchor=H619653869&source=see_link#H619653869
https://www.uptodate.com/contents/folic-acid-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/folic-acid-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/folic-acid-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/folic-acid-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/preconception-and-prenatal-folic-acid-supplementation?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/folic-acid-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/40,41
https://www.uptodate.com/contents/dietary-recommendations-for-toddlers-and-preschool-and-school-age-children?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/dietary-recommendations-for-toddlers-and-preschool-and-school-age-children?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/methotrexate-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/folic-acid-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
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 4).
(See "Vitamin intake and disease prevention".)
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
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 adverse
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'.)
●
https://www.uptodate.com/contents/causes-and-pathophysiology-of-vitamin-b12-and-folate-deficiencies?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/causes-and-pathophysiology-of-vitamin-b12-and-folate-deficiencies?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/folic-acid-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/1
https://www.uptodate.com/contents/image?imageKey=PC%2F106207&topicKey=HEME%2F7154&search=vitamina%20b12&rank=2%7E150&source=see_link
https://www.uptodate.com/contents/image?imageKey=PC%2F106207&topicKey=HEME%2F7154&search=vitamina%20b12&rank=2%7E150&source=see_link
https://www.uptodate.com/contents/vitamin-intake-and-disease-prevention?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/folic-acid-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/folic-acid-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/folic-acid-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/leucovorin-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/major-adverse-effects-of-low-dose-methotrexate?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/major-adverse-effects-of-low-dose-methotrexate?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/therapeutic-use-and-toxicity-of-high-dose-methotrexate?search=vitamina%20b12&topicRef=7154&source=see_linkhttps://www.uptodate.com/contents/therapeutic-use-and-toxicity-of-high-dose-methotrexate?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/folic-acid-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/overview-of-the-management-and-prognosis-of-sickle-cell-disease?sectionName=NUTRITION&search=vitamina%20b12&topicRef=7154&anchor=H30509050&source=see_link#H30509050
https://www.uptodate.com/contents/overview-of-the-management-and-prognosis-of-sickle-cell-disease?sectionName=NUTRITION&search=vitamina%20b12&topicRef=7154&anchor=H30509050&source=see_link#H30509050
https://www.uptodate.com/contents/warm-autoimmune-hemolytic-anemia-aiha-in-adults?sectionName=Folic%20acid&search=vitamina%20b12&topicRef=7154&anchor=H2868624254&source=see_link#H2868624254
https://www.uptodate.com/contents/warm-autoimmune-hemolytic-anemia-aiha-in-adults?sectionName=Folic%20acid&search=vitamina%20b12&topicRef=7154&anchor=H2868624254&source=see_link#H2868624254
https://www.uptodate.com/contents/non-immune-coombs-negative-hemolytic-anemias-in-adults?sectionName=Folic%20acid%20for%20chronic%20hemolysis&search=vitamina%20b12&topicRef=7154&anchor=H853070955&source=see_link#H853070955
https://www.uptodate.com/contents/non-immune-coombs-negative-hemolytic-anemias-in-adults?sectionName=Folic%20acid%20for%20chronic%20hemolysis&search=vitamina%20b12&topicRef=7154&anchor=H853070955&source=see_link#H853070955
https://www.uptodate.com/contents/unstable-hemoglobin-variants?sectionName=Folic%20acid&search=vitamina%20b12&topicRef=7154&anchor=H4976432&source=see_link#H4976432
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:
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, we do not advocate routine administration of folic
acid to individuals without documented deficiency. (See 'Prevention of folate deficiency'
above.)
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".)
Folic acid supplementation in pregnancy is discussed separately. (See "Nutrition in
pregnancy: Dietary requirements and supplements", section on 'Folate/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]:
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.
●
Hemolysis markers – Day 1 to 2●
Reticulocytosis – Day 3 to 4●
Anemia – Week 1 to 2 (initial improvement) and week 4 to 8 (normalization)●
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/42
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/folic-acid-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/43
https://www.uptodate.com/contents/folic-acid-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/folic-acid-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/vitamin-intake-and-disease-prevention?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/vitamin-intake-and-disease-prevention?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/folic-acid-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/nutrition-in-pregnancy-dietary-requirements-and-supplements?sectionName=Folate%2Ffolic%20acid&search=vitamina%20b12&topicRef=7154&anchor=H717782123&source=see_link#H717782123
https://www.uptodate.com/contents/nutrition-in-pregnancy-dietary-requirements-and-supplements?sectionName=Folate%2Ffolic%20acid&search=vitamina%20b12&topicRef=7154&anchor=H717782123&source=see_link#H717782123
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/folic-acid-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/2,3
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/folic-acid-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/folic-acid-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/folic-acid-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/folic-acid-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
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 (PA) who have been treated, recovered, and then discontinued vitamin
B12 supplementation (eg, neurologic findings may return within six months, whereas
megaloblastic anemia may take yearsto 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:
Hypersegmented neutrophils – Day 10 to 14●
Leukopenia and/or thrombocytopenia – Week 2 to 4●
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.)
●
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/2
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/3
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/44
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/45
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies/abstract/3
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
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:
INFORMATION FOR PATIENTS
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.
Verify that the correct vitamin was taken.●
Switch from oral to parenteral therapy if there are concerns about absorption (eg,
possible PA 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".)
●
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-vitamin-b12-and-folate-deficiency?sectionName=DIFFERENTIAL%20DIAGNOSIS&search=vitamina%20b12&topicRef=7154&anchor=H4046378654&source=see_link#H4046378654
https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-vitamin-b12-and-folate-deficiency?sectionName=DIFFERENTIAL%20DIAGNOSIS&search=vitamina%20b12&topicRef=7154&anchor=H4046378654&source=see_link#H4046378654
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/cyanocobalamin-vitamin-b12-drug-information?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-vitamin-b12-and-folate-deficiency?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-vitamin-b12-and-folate-deficiency?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/approach-to-the-child-with-anemia?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/approach-to-the-child-with-anemia?search=vitamina%20b12&topicRef=7154&source=see_link
https://www.uptodate.com/contents/diagnostic-approach-to-anemia-in-adults?search=vitamina%20b12&topicRef=7154&source=see_link
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 5 to 6
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 10 to 12
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.)
SUMMARY AND RECOMMENDATIONS
th th
th th
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)")
●
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