Letters

RESEARCH LETTER Table. Characteristics of Patients Who Received an Intramuscular

Vitamin B12 Prescriptiona
Prevalence of Inappropriateness of Parenteral
Patients, No. (%)
Vitamin B12 Administration in Ontario, Canada Characteristics (n = 146 850)
Randomized clinical trials demonstrate that treating vitamin B12 Age, y
(cobalamin, or hereinafter B12) deficiency with oral supplemen- Mean (SD) 76.5 (8.1)
tation substantially increases serum B12 levels compared with Median (IQR) [range] 76 (14.0)
[65-110]
intramuscular injections, with no difference in hematologic or
Age categorized, y
neuropsychiatric outcomes.1 Despite this, some primary care phy- 65-69 36 866 (25.1)
sicians still inappropriately administer B12 injections to elderly 70-74 28 196 (19.2)
patients.2 To our knowledge, there is no published literature char- 75-79 28 014 (19.1)
acterizing prescribing patterns of intramuscular B12 using labo- 80-84 26 055 (17.7)
ratory data to document patient serum levels. In this study, we 85-89 18 384 (12.5)
assessed the prevalence of inappropriate B12 supplementation ≥ 90 9335 (6.4)
using population-based databases and estimated the associated Sex
cost. Male 60 037 (40.9)
Female 86 813 (59.1)
Methods | We performed a population-based, retrospective co- Location of residence
hort study using health system administrative databases within Rural 12 692 (8.6)
ICES, formerly the Institute for Clinical Evaluative Sciences, in Urban 124 359 (84.7)
Ontario, Canada. Data sets were linked using unique, encoded Neighborhood income quintile
identifiers and analyzed at ICES. All persons 65 years or older who Q1 (lowest) 32 905 (22.4)

received at least 1 intramuscular B12 prescription from January Q2 32 230 (22.0)

Q3 29 828 (20.3)
1, 2011, to September 30, 2015 (data on B12 levels were not avail-
Q4 27 679 (18.9)
able until January 1, 2010), were included. Data were analyzed
Q5 (highest) 23 573 (16.1)
from July 26, 2019, to November 22, 2019. The primary outcome
Comorbidities
was the proportion of inappropriate B12 supplementation, defined
Crohn disease, ulcerative colitis, and malabsorption 9309 (6.3)
as persons with either a normal serum B12 level (≥ 221 pmol/L),
Pernicious anemia 40 908 (27.9)
or without a documented B12 level in the 12 months prior to their
ADG comorbidity classification scheme
first intramuscular B12 prescription. Vitamin B12 supplementa-
Low scores (0-5) 24 135 (16.4)
tion was considered appropriate when persons had at least 1 Moderate scores (6-9) 51 920 (35.4)
documented level of marginal B12 deficiency (≤ 221 pmol/L) in High scores (≥ 10) 70 795 (48.2)
the year prior to receiving their first B12 injection. Annual cost of Dementia 14 844 (10.1)
inappropriate, once-monthly injections was estimated in Cana- Neuropathy 2471 (1.7)
dian dollars using the amount paid for a physician visit ($33.70),
Abbreviations: ADG, Aggregated Diagnosis Group; IQR, interquartile range.
intramuscular injection ($3.89), and prescription cost ($6.74). a
Some totals may not add up owing to missing data.
Sunnybrook Health Sciences Centre’s research ethics board ap-
proved this study and waived patient written informed consent
for deidentified data.
timated annual cost of inappropriate B12 prescribing was $45.6
Results | A total of 405 469 intramuscular B12 prescriptions were million, assuming a 64% inappropriate prescription rate. Finally,
dispensed to 146 850 persons (Table); the majority (63.7%; n = only 1.7% (n = 2498) of persons prescribed intramuscular B12
93 615) of these were inappropriate (Figure). In the year preced- demonstrated any deficiency with a malabsorptive indication.
ing persons’ first intramuscular B12 injection, 25.5% (n = 37 487)
had a normal B12 level, whereas 38.2% (n = 56 128) did not have Discussion | Most parenteral B12 in Ontario was prescribed to per-
a B12 level documented. Findings were similar over a 24-month sons without evidence of deficiency in the year preceding their
look-back period (data not shown). Only 43.1% (n = 24 175) of the first B12 prescription. Potential drivers of this include patient de-
56 128 people without a B12 level documented in the year preced- mands and poor physician awareness of the evidence informing
ing their first B12 prescription had ever had one measured. This B12 supplementation.3,4 It is also questionable whether paren-
was performed a mean (SD) 1033.5 (488.1) days prior to their first teral supplementation is required over oral supplementation be-
prescription (range, 366-2801 days). Only 35.3% (n = 8539) of cause oral B12 raises B12 serum levels and improves sequelae of
these 24 175 persons had marginally deficient B12 levels. The es- deficiency as well as, if not better than, intramuscular B12, even

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 Letters
Figure. Prevalence of Inappropriate Intramuscular Vitamin B12 Prescribing in Ontario From January 1, 2011, to September 30, 2015
146 850 Patients ≥65 y who received an intramuscular
vitamin B12 prescription from January 1, 2011,
to September 30, 2015
93 615 Inappropriate
56 128 No documented vitamin 37 487 Vitamin B12 levels
B12 levels in the past 12 mo >221 pmol/L
24 175 Vitamin B12 levels
documented >12 mo
prior to prescription
15 631 Vitamin B12 levels 8539 Vitamin B12 levels
>221 pmol/L <221 pmol/L
for pernicious anemia.1 Plausible reasons why physicians pre-
fer parenteral B12 include low quality of evidence supporting oral
B12, society guidelines recommending intramuscular B12 for all
patients, poor physician understanding of how to prescribe oral
B12, and physician misperception that patients prefer parenteral
over oral B12.1,3,5,6
Our study’s limitations include only looking 2 years be-
fore a person’s first documented prescription; using this
abridged period might have misclassified persons undergo-
ing treatment for chronic B12 deficiency, and so with normal
B12 levels, as receiving inappropriate supplementation. We were
also unable to access information on oral B12, and could not
understand why B12 was prescribed without laboratory evi-
dence of deficiency. Further studies should examine this is-
sue, to inform quality improvement initiatives aimed at re-
ducing this unnecessary care.
William K. Silverstein, MD
Yulia Lin, MD, FRCPC
Christoffer Dharma, MSc
Ruth Croxford, MSc
Craig C. Earle, MD, MSc, FRCPC
Matthew C. Cheung, MD, SM, FRCPC
Author Affiliations: Department of Medicine, University of Toronto, Toronto,
Ontario, Canada (Silverstein, Lin, Earle, Cheung); Division of Medical Oncology
& Hematology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
(Lin, Earle, Cheung); Department of Laboratory Medicine & Molecular
Diagnostics, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
(Lin); Department of Laboratory Medicine and Pathobiology, University of
Toronto, Toronto, Ontario, Canada (Lin); ICES, Toronto, Ontario, Canada
(Dharma, Croxford, Earle, Cheung).
Accepted for Publication: April 20, 2019.
Corresponding Author: William K. Silverstein, MD, Core Internal Medicine,
Faculty of Medicine, University of Toronto, Department of Medicine, University
Health Network, 200 Elizabeth St, Eaton Building 14-217, Toronto, Ontario M5G
2C4, Canada (william.silverstein@mail.utoronto.ca).
Published Online: July 15, 2019. doi:10.1001/jamainternmed.2019.1859
Author Contributions: Drs Cheung, Croxford, and Dharma had full access to all of
the data in the study and take responsibility for the integrity of the data and the
E2 JAMA Internal Medicine Published online July 15, 2019 (Reprinted)
© 2019 American Medical Association. All rights reserved.
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53 235 Appropriate
27 200 Vitamin B12 levels 6035 Vitamin B12 levels
149-221 pmol/L <148 pmol/L
1461 Patients with malabsorptive 1037 Patients with malabsorptive
disorders disorders
accuracy of the data analysis. Drs Lin and Cheung contributed equally as
co–senior authors to this study.
Study concept and design: Silverstein, Lin, Dharma, Cheung.
Acquisition, analysis, or interpretation of data: Lin, Dharma, Croxford,
Earle, Cheung.
Drafting of the manuscript: Silverstein, Cheung.
Critical revision of the manuscript for important intellectual content: Lin,
Dharma, Croxford, Earle, Cheung.
Statistical analysis: Dharma, Croxford, Cheung.
Obtained funding: Cheung.
Administrative, technical, or material support: Silverstein, Dharma, Cheung.
Study supervision: Lin, Cheung.
Conflict of Interest Disclosures: Dr Lin reported that she was a consultant for
Pfizer and that she was on the advisory board of Amgen. No other disclosures
were reported.
Funding/Support: This study was supported by research funding from the
Sunnybrook Hospital Foundation. This study was also supported by ICES, which
is funded by an annual grant from the Ontario Ministry of Health and Long-Term
Care (MOHLTC).
Role of the Funder/Sponsor: The funders had no role in the design and conduct
of the study; collection, management, analysis, and interpretation of the data;
preparation, review, or approval of the manuscript; and decision to submit the
manuscript for publication.
Disclaimer: No endorsement by ICES or the Ontario MOHLTC is intended or
should be inferred. Parts of this material are based on data and information
compiled and provided by the Canadian Institute for Health Information (CIHI).
The opinions, results and, conclusions reported in this article are those of the
authors and are independent from the funding sources and CIHI.
Additional Contributions: We thank IMS Brogan Inc for use of their Drug Infor-
mation Database. No contributors received compensation for their assistance.
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