Comparison of Sublingual and Intramuscular Administration of Vitamin B12 for the Treatment of Vitamin B12 Deficiency in Children

Abstract

Background:
In most countries, contrary to some disadvantages, such as pain, relatively higher cost, and poor adherence to treatment, intramuscular (IM) route is still the primary treatment method for Vitamin B12 (VB12) deficiency. In recent years, because of these difficulties, new treatment methods are being sought for VB12 deficiency.

Objectives:
We aimed to compare sublingual (SL) and IM routes of VB12 administration in children with VB12 deficiency and to compare the efficacy of methylcobalamin and cyanocobalamin therapy in these children.

Methods:
This retrospective study comprised 129 patients with VB12 deficiency (serum Vitamin 12 level ≤ 200 pg/mL) aged 5-18 years. Based on the formulations of Vitamin 12, we divided the patients into three treatment groups as IM cyanocobalamin, SL cyanocobalamin, and SL methylcobalamin.

Results:
After Vitamin 12 therapy, serum Vitamin 12 levels increased significantly in all patients, and there was a statistically significant difference between the treatment groups (p < 0.05).

Conclusions:
SL cyanocobalamin and methylcobalamin were found as effective as IM cyanocobalamin for children with Vitamin 12 deficiency in correcting serum Vitamin 12 level and hematologic abnormalities.

Full text

3
REVISTA DE INVESTIGACIÓN CLÍNICA
Contents available at PubMed
www.clinicalandtranslationalinvestigation.com
Comparison of Sublingual and
Intramuscular Administration
of Vitamin B12 for the Treatment of
Vitamin B12 Deficiency in Children
Aş Tğ-K1*  Z Çğ-M2
1Division of Pediatric Neurology, Faculty of Medicine, Ankara University, Ankara; 2Department of Pediatrics,
Kütahya Parkhayat Hospital, Kütahya, Turkey
Received for publication: 07-05-2020
Approved for publication: 29-06-2020
DOI: 10.24875/RIC.20000208
ABSTRACT
Background: In most countries, contrary to some disadvantages, such as pain, relatively higher cost, and poor adherence to
treatment, intramuscular (IM) route is still the primary treatment method for Vitamin B12 (VB12) deficiency. In recent years,
because of these difficulties, new treatment methods are being sought for VB12 deficiency. Objectives: We aimed to compare
sublingual (SL) and IM routes of VB12 administration in children with VB12 deficiency and to compare the efficacy of methyl-
cobalamin and cyanocobalamin therapy in these children. Methods: This retrospective study comprised 129 patients with VB12
deficiency (serum Vitamin 12 level ≤ 200 pg/mL) aged 5-18 years. Based on the formulations of Vitamin 12, we divided the
patients into three treatment groups as IM cyanocobalamin, SL cyanocobalamin, and SL methylcobalamin. Results: After Vita-
min 12 therapy, serum Vitamin 12 levels increased significantly in all patients, and there was a statistically significant difference
between the treatment groups (p < 0.05). Conclusions: SL cyanocobalamin and methylcobalamin were found as effective as
IM cyanocobalamin for children with Vitamin 12 deficiency in correcting serum Vitamin 12 level and hematologic abnormalities.
REV INVEST CLIN. AHEAD OF PRINT
Key words: Cyanocobalamin. Intramuscular. Methylcobalamin. Sublingual. Vitamin B12.
*Corresponding author:
Ayşe Tuğba Kartal
E-mail: dratugbakartal@gmail.com
0034-8376 / © 2020 Revista de Investigación Clínica. Published by Permanyer. This is an open access article under the
CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
ORIGINAL ARTICLERev Invest Clin. (ahead of print)
INTRODUCTION
The estimated prevalence of Vitamin B12 (VB12) de-
ficiency in the general population varies between
1.5% and 15%1,2. The most common cause of VB12
deficiency in children is inadequate dietary intake3. As
VB12 cannot be produced by humans, it should be
obtained from animal-based foods, such as meat,
milk, eggs, and fish4,5. Therefore, vegetarianism and
low socioeconomic conditions are important risk fac-
tors for VB12 deficiency6. Other causes are pernicious
anemia, gastrectomy, bariatric surgery, gastritis,
drugs (proton-pump inhibitors, H2 receptor blockers,
antacids, etc.), and Imerslund-Gräsbeck syndrome7,8.
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REV INVEST CLIN. (ahead of print)
Intramuscular (IM) route is the primary choice of
treatment for VB12 deficiency in most countries; how-
ever, it has some disadvantages, such as pain, high
cost, and poor adherence to treatment9,10. In recent
years, because of these disadvantages, new methods
are being sought for treating VB12 deficiency.
Dietary VB12 gets absorbed through two different
pathways11. Through the first pathway, VB12 binds
intrinsic factor (IF), which is released by parietal cells
in the stomach, following which the VB12-IF complex
gets actively absorbed in the terminal ileum12. Ap-
proximately 60% of the absorption of dietary VB12
occurs through this biochemical mechanism12.
Through the second pathway, dietary VB12 gets ab-
sorbed by simple diffusion (without binding to IF)
along the entire intestine or it gets directly absorbed
by sublingual (SL) capillaries13. Therefore, SL route for
treating VB12 deficiency has several advantages, in-
cluding potentially good adherence to treatment,
safety, and low cost1. In addition, this route enables
the treatment of VB12 deficiency in patients with
swallowing disorders or malabsorption syndrome (in-
flammatory intestinal diseases, intestinal surgery,
short bowel syndrome, etc.)14,15. In recent years, the
importance of SL route has been recognized; however,
few studies have evaluated this method, especially in
children1,13,16.
In the present study, we aimed to compare SL and
IM routes of VB12 administration in children with
VB12 deficiency and to compare the efficacy of
methylcobalamin and cyanocobalamin therapy in
these children.
METHODS
Study population
This retrospective study comprised 129 patients with
VB12 deficiency (126 inadequate dietary intake and
3 pernicious anemia) aged 5-18 years, and conducted
between January 2017 and December 2019. We ob-
tained the data from the electronic medical record
system and patient files at Parkhayat Hospital. Based
on the formulations of VB12, we divided the patients
into three treatment groups as IM cyanocobalamin,
SL cyanocobalamin, and SL methylcobalamin. The
study was approved by Kütahya University of Health
Sciences Ethics Committee and conducted in accor-
dance with the ethical principles described by the
Declaration of Helsinki (2020/05-12).
Inclusion criteria were as follows: (I) aged 5-18 years
and (II) VB12 deficiency (serum VB12 level ≤ 200 pg/
mL). Exclusion criteria were as follows: (I) patients
with chronic diseases that may affect hematologic
parameters (sideroblastic anemia, thalassemia, aplas-
tic anemia, etc.), (II) folate deficiency, (III) iron defi-
ciency, (IV) renal disease, (V) using drugs that may
affect the absorption of VB12 (metformin, proton
pump inhibitors, phenobarbital, etc.), and (VI) having
missing data.
Laboratory studies
Complete blood count was measured with automat-
ic blood count device LH 750 (Beckman Coulter, Inc.,
USA), and VB12 level was measured with automatic
biochemistry device Advia Centaur® XPT (Siemens,
Berlin, Germany). The lower level of hemoglobin
(Hb), white blood cell (WBC), and platelet was de-
termined as follows: < 11 g/dL, < 4000/mm3, and
< 150.000/mm3, respectively. VB12 level ≤ 200 pg/mL
was described as a deficiency. According to the pro-
tocol that is applied in our hospital, the treatment
response of VB12 is reevaluated after 4 weeks in
every patient.
Treatment protocols
IM route
A 1000 mcg every other day for 1 week, then week-
ly for 3 weeks (Dodex® ampule, 1000 mcg/1 ml cya-
nocobalamin).
SL route
A 1000 mcg once daily for 7 days, then every other
day for 3 weeks (SL cyanocobalamin: Solgar® 1000
mcg SL tablet; SL methylcobalamin: Ocean Methyl
B12 1000 mcg 10 mL spray).
Statistical analysis
The statistical analyses were performed using SPSS
version 21 software. Continuous variables were calcu-
lated as mean ± standard deviation (SD). A one-way
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analysis of variance and Chi-square tests were used
to assess comparisons between the treatment groups.
Post hoc analysis was carried out by Tukey test. The
independent t-test was used to compare pre-treat-
ment and post-treatment values. p < 0.05 was con-
sidered as statistically significant.
RESULTS
A total number of 129 children with VB12 deficiency
were included in this retrospective study (the treat-
ment groups; IM cyanocobalamin group [n = 47], SL
cyanocobalamin group [n = 43], and SL methylco-
balamin group [n = 39]). Female/male ratio of IM
cyanocobalamin, SL cyanocobalamin, and SL methyl-
cobalamin groups was 21/26, 23/20, and 19/20,
respectively (p > 0.05), and mean age of the groups
was 12.7 ± 5.1, 12.3 ± 2.1, and 11.9 ± 5.6 years,
respectively (p > 0.05). The demographic and labora-
tory characteristics of the study participants are sum-
marized in Table 1.
After VB12 therapy, serum VB12 levels increased sig-
nificantly in all patients, and there was a statistically
significant difference between the treatment groups (p
< 0.05). Mean pre-treatment VB12 levels of IM cyano-
cobalamin, SL cyanocobalamin, and SL methylcobala-
min groups were found as 147.5 ± 37.7, 137.2 ± 36.5,
and 146.7 ± 40.5 pg/mL, respectively (p > 0.05), and
after the therapy, the levels were detected as 602.0 ±
156.1, 483.4 ± 144.8, and 565.5 ± 108.1 pg/mL,
respectively (p < 0.05) (Table 1 and Fig. 1). In addition,
mean ± SD difference between serum VB12 levels be-
fore and after VB12 therapy of the treatment groups
was found as 454.5 ± 118.4, 346.2 ± 108.3, and
418.8 ± 67.6, respectively (p < 0.05) (Table 1).
Mean ± SD difference between serum VB12 levels
before and after VB12 therapy was found as in IM
cyanocobalamin group versus SL cyanocobalamin
group (454.5 ± 118.4 vs. 346.2 ± 108.3, p < 0.05);
in IM cyanocobalamin group versus SL methylcobala-
min group (454.5 ± 118.4 vs. 418.8 ± 67.6, p < 0.05);
and in SL cyanocobalamin group versus SL methylco-
balamin group (346.2 ± 108.3 vs. 418.8 ± 67.6,
p < 0.05) (Table 2).
Out of 129 patients, 76 (58.9%) were found to have
anemia (Hb < 11 g/dL) before VB12 treatment. After
the 1st month of the treatment, the improvement
ratios in anemia of the treatment groups (IM cyano-
cobalamin group, SL cyanocobalamin group, and SL
methylcobalamin group) were detected as 13
(46.4%)/28, 7 (30.4%)/23, and 9 (36%)/25, res-
pectively (p > 0.05). In addition, WBC and platelet
counts did not change significantly either after VB12
therapy or between the treatment groups.
DISCUSSION
IM injection is a traditional choice of treatment for
VB12 deficiency due to inadequate dietary intake,
pernicious anemia, gastrectomy, ileal resection, or
malabsorption syndrome17,18. However, IM method is
associated with some disadvantages, such as pain,
high cost, poor adherence to treatment, and bleeding
in patients with coagulation disorders19. Considering
these issues, SL route is now being considered for
VB12 administration. SL method enables direct ab-
sorption of VB12 under the tongue, bypassing intes-
tinal absorption14. Moreover, this method has several
advantages, for example, it is less costly, results in
high patient satisfaction, does not require a hospital
visit, is not painful, and does not result in injection-
related injury16. However, few studies have evaluated
the efficacy of SL administration of VB12 and com-
pared it with that of IM administration.
Bensky et al. compared the efficacy of SL and IM
administration of VB12 in terms of normalizing se-
rum cyanocobalamin levels. In their study, 3451 pa-
tients received SL VB12 (1000 µg/day for 6 months)
and 830 patients received 1000 µg/dose IM VB12
(every other day for 2 weeks, followed by once a
week for 4 weeks). Pre-treatment mean values of
serum cyanocobalamin level were increased from
298 ng/L to 551 ng/L in the SL group, whereas in
the IM group, mean value increased from 234 pg/mL
to 452 ng/L. The post-treatment values significantly
differed between the two groups (p < 0.001). The
authors concluded that SL route should be the first-
line choice of treatment in patients with VB12 defi-
ciency13. Sharabi et al. compared SL and oral routes
in a randomized prospective study of 30 adults with
VB12 deficiency. Participants were given one tablet
daily of 500 µg cyanocobalamin orally or sublingually
or two tablets daily of a VB12 complex (250 µg co-
balamin, 100 mg thiamine, and 250 mg pyridoxine)
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for 8 weeks. After 4 weeks, VB12 level normalized,
and serum cyanocobalamin levels were increased
from 108 to 286 pmol/L, 94 to 288 pmol/L, and 98
to 293 pmol/L, in SL, oral, and oral B-complex groups,
respectively (p = 0.0001). The authors reported that
SL route is as effective as the oral route in treating
VB12 deficiency20. In a prospective open-labeled
study, Delpre et al. tested 18 patients with VB12 defi-
ciency. In their study, the patients received VB12
(2000 µg/day for 7-12 days) by SL route, and
Table 1. The demographic and laboratory characteristics of the study participants
IM cyanocobalamin
group
(n = 47)
SL cyanocobalamin
group
(n = 43)
SL methylcobalamin
group
(n = 39)
p
Mean ± SD
Age, year 12.7 ± 5.1 12.3 ± 2.1 11.9 ± 5.6 0.463
Gender, n 21/26 23/20 19/20 0.139
Female
Male
Serum vitamin B12, pg/mL
Pre-treatment 147.5 ± 37.7 137.2 ± 36.5 146.7 ± 40.5 0.153
Post-treatment 602.0 ± 156.1 483.4 ± 144.8 565.5 ± 108.1
p< 0.001 < 0.001 < 0.001 –
∆sVB12 levels before
and after treatment
454.5 ± 118.4 346.2 ± 108.3 418.8 ± 67.6 < 0.001
Hb, gr/dl
Pre-treatment 10.1 ± 1.3 10.4 ± 1.5 10.3 ± 1.6 0.154
Post-treatment 11.8 ± 1.2 11.3 ± 1.3 11.6 ± 1.4 0.142
p< 0.001 < 0.001 < 0.001 –
MCV, fL
Pre-treatment 82.6 ± 10.8 81.1 ± 6.8 82.3 ± 7.1 0.332
Post-treatment 78.7 ± 10.2 80.1 ± 6.8 79.3 ± 15.9 0.591
p< 0.001 0.023 < 0.001 –
Anemia, n
Pre-treatment 28 (59.5%) 23 (53.4%) 25 (64.1%) 0.417
Post-treatment 15 (31.9%) 16 (37.2%) 16 (41%) 0.351
WBC count, /mm3
Pre-treatment 7266.6 ± 1556.5 8612.1 ± 1012.7 7877.5 ± 1890.2 0.211
Post-treatment 8924.4 ± 1015.4 8904.1 ± 2534.1 7351.2 ± 1199.9 0.124
p0.131 0.342 0.457 –
Platelet count, /mm3
Pre-treatment 290.833 ± 57.314 296.920 ± 95.949 291.374 ± 116.925 0.927
Post-treatment 272.142 ± 57.616 304.187 ± 89.928 299.333 ± 66.525 0.573
P0.531 0.742 0.757 –
Hb: hemoglobin; IM: intramuscular; MCV: mean corpuscular volume; SL: sublingual; sVB12: serum Vitamin B12; WBC: white blood cell.
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A. Atici, Et Al.: THE ROLE OF
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serum VB12 level normalized rapidly and signifi-
cantly in all the patients14.
To the best of our knowledge, this is the first study
to compare two treatment methods (SL and IM)
and two cobalamin types (cyanocobalamin and
methylcobalamin) simultaneously in children with
VB12 deficiency. Our results are consistent with
those of previous studies. We found that SL cyano-
cobalamin and methylcobalamin were as effective
as IM cyanocobalamin in treating VB12 deficiency
in children. The serum VB12 level normalized in all
the patients after 4 weeks. The mean VB12 level
was found to be the highest in IM cyanocobalamin
group and the lowest in SL cyanocobalamin group
after the treatment.
Hematologic response time and degree to VB12
treatment vary according to the basal VB12 level of
patients21. Anemia (Hb and mean corpuscular volume
[MCV]) usually begins to improve in 1-2 weeks and
normalizes within 6-8 weeks21,22. Sezer et al. treated
135 children (aged between 1 month and 18 years)
with VB12 deficiency. Treatment protocols were as
follows: IM cyanocobalamin group “100 µg/day for
1 week, then 1000 µg on alternate days for a week,
then 1000 µg 2 times a week for a week and finally
once a week” and oral group “one B-complex tablet
(50 mg thiamin, 250 mg pyridoxine, and 1000 µg
cyanocobalamin) per day up to 1 month.” After the 1st
month of treatment, Hb levels normalized and MCV
decreased in 34% of patients in IM group and 19%
of patients in the oral group23. Verma et al. carried
out a prospective study in 28 children (aged between
6 months and 18 years) with macrocytic anemia,
and oral methylcobalamin was given at a dosage of
30 µg/kg/day for 1 month. After the treatment, Hb
levels normalized in 85.7% of the patients24. In an-
other study conducted by Andres et al., 30 patients
were treated with oral VB12 (250-1000 µg/day) for
>1 month. After the 1st month of treatment, ane-
mia improved in only 54% of the patients25.
Figure 1. Serum Vitamin B12 levels of the treatment groups.
Table 2. Tukey’s post hoc analysis of the groups
IM
cyanoco-
balamin
group
(n = 47)
SL
cyanoco-
balamin
group
(n = 43)
p IM
cyanoco-
balamin
group
(n = 47)
SL
methylco-
balamin
group
(n = 39)
p SL
cyanoco-
balamin
group
(n = 43)
SL
methylco-
balamin
group
(n = 39)
p
Mean ± SD Mean ± SD Mean ± SD
∆sVB12 levels
before
and after
treatment
454.5
± 118.4
346.2
± 108.3
< 0.001 454.5
± 118.4
418.8
± 67.6
0.032 346.2
± 108.3
418.8
± 67.6
<0.001
sVB12: serum Vitamin B12; IM: intramuscular; SL: sublingual.
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REV INVEST CLIN. (ahead of print)
Our results were in line with previous studies. After
the 1st month of the treatment, the improvement in
anemia was mostly detected in IM cyanocobalamin
group (46.4%), whereas the least improvement was
observed in SL cyanocobalamin group (30.4%). How-
ever, there was no statistical difference between the
three groups. We thought that these differences be-
tween the studies were probably because of the case
selection, follow-up time, treatment method, and
drug selection.
The retrospective design is the most limiting factor
of the study. Therefore, we did not investigate meth-
ylmalonic acid and homocysteine levels. In addition,
short follow-up period and relatively small sample size
are another limitations of the study.
In conclusion, SL cyanocobalamin and methylcobala-
min are as effective as IM cyanocobalamin in correct-
ing serum VB12 levels and hematologic abnormalities
in children with VB12 deficiency. However, SL formu-
lations, which are cheaper, safer, painless, and practi-
cal, have been less used than IM formulations for
decades. Our results suggest that SL formulations
can be used as the first-line treatment in children
with VB12 deficiency.
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