Clinical Oral Investigations (2022) 26:109–117

https://doi.org/10.1007/s00784-021-04223-w

REVIEW

Effect and longevity of botulinum toxin in the treatment of gummy

smile: a meta‑analysis and meta‑regression
Aline Cristina Soares Zengiski1   · Isabela Bittencourt Basso2   · Bianca L. Cavalcante‑Leão3   ·
José Stechman‑Neto3   · Rosane Sampaio Santos3   · Odilon Guariza‑Filho4   · Bianca Simone Zeigelboim3   ·
Karinna Veríssimo Meira Taveira5   · Cristiano Miranda de Araujo3 

Received: 12 September 2021 / Accepted: 10 October 2021 / Published online: 15 October 2021
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2021

Abstract
Objective  The aim of this systematic review is to synthesize the evidence on the effectiveness and longevity of the botulinum
toxin in the treatment of individuals with excessive gingival exposure.
Methods  The search was adapted to six electronic databases and gray literature. The risk of bias was assessed using the
Cochrane Risk of Bias Assessment Tool for Non-Randomized and Randomized Studies of Interventions. Meta-analyses and
meta-regression were performed using random effects models.
Results  A total of 5247 articles were collected during the final search in the database, resulting in 17 articles included. There
was a mean decrease of 3.42 mm [95% CI = −4.50 to −2.34; I2 = 97%] in the level of gingival exposure 2 weeks after the
application of botulinum toxin. The application time explained 29.58% of the observed variance (p < 0.001), with a tendency
for the effect size to decrease from the second week of application onwards, with values returning close to baseline levels
in 24 weeks.
Conclusion  Botulinum toxin is an alternative technique considered effective for reducing gummy smile, especially for gummy
smiles up to 4 mm, with a longevity of at least 12 weeks, returning close to initial values within 24 weeks after application.
Clinical relevance  The knowledge about the longevity and effectiveness of botulinum toxin in the treatment of gummy smile
allows for a more adequate clinical planning for these cases, as well as for clinical decisions, as for prognostic factors.

Keywords  Botulinum toxins, Type A · Gummy smile · Longevity · Meta-analysis

* Cristiano Miranda de Araujo Karinna Veríssimo Meira Taveira

cristiano.araujo@utp.br karinnavm@hotmail.com
Aline Cristina Soares Zengiski 1
Undergraduate Dentistry Program, Tuiuti University
alinezengiski@icloud.com
of Paraná, Curitiba, Brazil
Isabela Bittencourt Basso 2
Postgraduate Program in Dentistry, Pontifícia Universidade
isabelabbasso@hotmail.com
Católica do Paraná, Curitiba, Paraná, Brazil
Bianca L. Cavalcante‑Leão 3
Postgraduate Program in Communication Disorders, Tuiuti
bianca.leao@utp.br
University of Paraná, Street Sydnei Antonio Rangel Santos,
José Stechman‑Neto 238 ‑ Santo Inacio, Curitiba, PR, Brazil
stechman1@gmail.com 4
Department of Orthodontics, Pontifícia Universidade
Rosane Sampaio Santos Católica do Paraná, Curitiba, Paraná, Brazil
rosane.santos2@utp.br 5
Department of Morphology ‑ Center of Biosciences,
Odilon Guariza‑Filho Federal University of Rio Grande do Norte,
odilongfilho@gmail.com Natal, Rio Grande do Norte, Brazil
Bianca Simone Zeigelboim
bianca.zeigelboim@utp.br

13
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110
Introduction
With advances in cosmetic dentistry, patients are increas-
ingly looking for an ideal smile through non-invasive pro-
cedures. The gummy smile is an aesthetic problem that
causes problems of socialization and self-esteem, consider-
ing that the ideal smile depends on the correct harmoniza-
tion between teeth, gums, and lips [1, 2]. Gummy smile is
characterized by the excessive display of maxillary gingival
tissue during the act of smiling [1, 3]. Its etiology may be
associated with excessive muscle contraction, hyperactive
upper lip elevator muscles, dentoalveolar extrusion, clinical
crown length, and vertical maxillary excess [3, 4]. Several
treatment techniques are currently available for correction
of the gummy smile, namely, orthognathic surgery, gingi-
vectomy, dental intrusion through orthodontic treatment,
osteotomy and bone resection, botulinum toxin injection,
crown lengthening, and lip repositioning procedures [1, 3].
Botulinum toxin (BTX) is a non-invasive treatment
alternative, being a neurotoxin derived from an anaerobic
bacterium which inhibits acetylcholine, thus inhibiting
the neurotransmitter responsible for muscle contraction
and causing a reduction in muscle tone in the region of
application [5, 6]. Botulinum toxin type A (BTX-A) is
the most powerful botulinum toxin and is used in clinical
practice, having great advantages for being a minimally
invasive, safe, and effective technique with fast onset of
action, being administered at small doses [3, 7].
A systematic review addressed the duration of the
effects of BTX-A in patients with gummy smile [3] and
included two clinical trials in their analysis, concluding
that BTX-A therapy provides a relevant gingival decrease
after its application and is a reversible treatment, decreas-
ing its outcome over time. However, only three databases
were used to search for articles and there was no quantita-
tive analysis regarding the longevity of the effect, besides
that new studies related to the treatment of gummy smile
with BTX-A were carried out, thus justifying the perfor-
mance of a new, more comprehensive systematic review
that allows for more robust evidence.
Thus, the aim of this systematic review is to synthe-
size the evidence on the effectiveness and longevity of
the botulinum toxin in the treatment of individuals with
excessive gingival exposure.
Methods
This systematic review was developed according to the
Preferred Reporting Items for Systematic Reviews and
Meta-Analyses (PRISMA) [8].
13
Clinical Oral Investigations (2022) 26:109–117
Eligibility criteria
Randomized, pseudo-randomized, or non-randomized
clinical studies, controlled or not, were included, in which
the population consisted of humans with a gummy smile
who had undergone intervention with botulinum toxin,
and whose effectiveness has been evaluated. There was
no exclusion of any study based on sex, ethnicity, or age
of the population.
The following exclusion criteria were applied:
(1) Observational studies, experimental studies with
animals, reviews, expert opinions, letters to the editor,
or any other descriptive study; (2) studies in which the
population does not present gummy smile, or in which the
sample contains patients with degenerative diseases or that
affect muscle function; (3) studies in which the interven-
tion was not performed using botulinum toxin, or in which
any cosmetic treatment associated with botulinum toxin
was performed.
Information sources and search strategy
Appropriate word combinations and truncations were
used and adjusted for each following electronic database:
Cochrane Library, EMBASE, Latin American and Car-
ibbean Health Science Literature (LILACS), PubMed/
Medline, Scopus, and Web of Science (online resource
1). Gray literature was also used as information source
through Google Scholar, MedvRix, Open Grey, and Pro-
quest Dissertations & Theses. In addition, a manual search
was performed in the references of the included studies
and an expert was consulted to verify any possible arti-
cle not included. The Endnote® software (EndNote® X7
Thomson Reuters, Philadelphia, PA) was used to remove
duplicate references. All searches were performed on
August 7, 2020, and updated on July 21, 2021.
Selection process
The articles were evaluated in two phases. In phase 1, two
reviewers (A.C.S.Z. and I.B.B.) separately reviewed the
titles and abstracts of all references. All articles that did
not meet the eligibility criteria were excluded. In phase
2, the same reviewers performed the full reading of the
selected articles, also independently. When there was disa-
greement that was not resolved through debate between the
first and second reviewers, a third reviewer (C.M.A.) was
included for the tie-breaking vote.
In order to blind the reading of references and allow this
to occur independently and confidentially in both phases,
Clinical Oral Investigations (2022) 26:109–117
the Rayyan website (http://​r ayyan.​q cri.​o rg) was used,
blinding all assessments. To ensure calibration between
both reviewers, the kappa coefficient of agreement was cal-
culated and the selection of studies only started when the
agreement value was > 0.8, indicating good agreement.
Data collection process
Two reviewers collected information from the included stud-
ies and this information was discussed. The following data
were collected: study characteristics (authors, year of publi-
cation, country, and study design), population characteristics
(sample size, sex, and age), clinical evaluation characteris-
tics (dosage, application point), characteristics of the results
(results presented in relation to the study), and conclusions.
When the data were incomplete, three attempts were made to
contact the authors (first and last author and corresponding
author) to obtain this information. When a response was not
obtained, the article was excluded.
Data items
Mean values (mm) and measures of variability (stand-
ard deviation) for the level of gingival exposure (distance
between the lower edge of the upper lip and the gingival
edge of the maxillary central incisor) were extracted from
the included studies. In addition, the evaluation period of
these values, in number of weeks, was also extracted. When
there was no report of the standard deviation as a measure
of variability and there was no possibility of obtaining the
standard deviation values either by mathematical calcula-
tion through another measure of dispersion or by the lack
of response by the author, the value of the study with the
highest standard deviation of the analysis was imputed [9].
Assessment of risk of bias
In order to assess the risk of bias of the selected randomized
clinical trials, the Cochrane Collaboration Tool for Assess-
ing Risk of Bias was used [10]. The understanding of the
risk of bias was based on references extracted from the
study, being grouped as having “high risk” or “low risk” of
bias. When the study was classified as a non-randomized
clinical trial, the Cochrane Risk of Bias Assessment Tool
for Non-Randomized Studies of Interventions (ROBINS-I)
was used [11], classifying each domain as having low, mod-
erate, or severe risk of bias. In studies where there were no
convincing details reported, the risk of bias was perceived as
“not clear” and the authors of the original study were asked
for further clarification.
Two reviewers carried out this process independently
(A.C.S.Z. and I.B.B.) and a third reviewer (C.M.A.) was
111
included when there was disagreement between them for
the tie-breaking vote.
Effect measures
The mean difference (MD) between the pre-intervention
period (baseline) and the different post-intervention evalua-
tion periods was calculated. Comparisons were then carried
out considering the baseline values (pre-intervention) as a
control.
Synthesis method
A meta-analysis with a random effects model using the
inverse-variance weighted method was performed through
the statistical software RStudio, version 1.2.1335 (RStudio
Inc, Boston, USA) and forest plots were generated. To cal-
culate the variance, expressed by the T­ au2 values, the Der-
Simonian-Laird estimator was used [12], and heterogeneity
was calculated using the inconsistency index (I2) [13]. To
determine the longevity of BTX, the influence of the covari-
ate post-application time on the observed effect size was
evaluated through meta-regression with a random effects
model, generating a bubble plot for analysis in the software
Stata version 16.0 (Stata Corp LLC, College Station, USA).
The significance level adopted was 5% and 95% confidence
intervals (95% CI) were generated for all analyses.
Reporting bias assessment
When there was the presence of heterogeneity in the analy-
sis, sensitivity analyses were performed to check whether
any study deemed to be at higher risk of bias changed the
estimates. Studies that obtained > 50% of the domains
assessed as having moderate or high risk of bias were con-
sidered as having greater bias. In addition, when extreme
effect sizes were found as a source of heterogeneity within
the analysis, the leave-one-out method was performed by
recalculating the global effect estimate k - 1 times with the
respective confidence intervals and the values of I2, omitting
one study at a time. Thus, whether the influence of any study
distorted the estimate of the combined effect was evaluated
[14].
When it was impossible to assess the occurrence of pub-
lication bias using the funnel plot or Egger’s test (n < 10),
strategies to reduce the probability of occurrence of this bias
were carried out.
Certainty of the evidence
To assess the level of certainty of the evidence generated, the
Grading of Recommendations, Assessment, Development
and Evaluation (GRADE) approach [15] was used, which
13
112
classifies the certainty of the evidence into the following
four levels: very low, low, moderate, and high, considering
five aspects for evaluating the evidence [16].
Results
Study selection
A total of 5247 articles were collected during the final data-
base search, leaving 2749 after duplicate removal. After
reading the titles and abstracts (phase 1), 16 articles were
selected for full reading (phase 2), out of which 3 were
excluded [17–19], resulting in 13 articles included (Fig. 1).
Four articles were included from the gray literature and
expert consultation, totaling 17 articles included for the
qualitative synthesis. No additional articles were included
after manually searching the references.
Study characteristics
Among the articles included, 16 were in English and only
1 was Portuguese-Brazilian, originating from the fol-
lowing countries: Brazil, China, Egypt, Germany, India,
Puerto Rico, Peru, Saudi Arabia, Syria, Turkey, and the
Fig. 1  Flowchart of literature search and selection criteria
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Clinical Oral Investigations (2022) 26:109–117
USA. The year of publication ranged from 2005 to 2021,
with the sample size of the studies ranging from 5 to 52
participants and age ranging from 15 to 70 years, and there
was a higher prevalence of females in the studies.
Most articles used standardized photographs before and
after the procedure as a way of measuring the result, with
the exception of one article [20], which used a question-
naire for evaluation. The dosage of BTX-A used in the
studies ranged from 2.5 to 8 IU. Information regarding
the characteristics of the included studies are provided in
online resource 2.
Risk of bias
The domains that presented the highest risk of bias for
non-randomized clinical trials were related to the lack of
control of confounding factors, either by appropriate sam-
pling techniques or statistical control with multivariate
analysis, and related to the selection of study participants,
with the establishment of well-defined eligibility criteria.
Randomized clinical trials showed a low risk of bias in
most of the domains evaluated (Fig. 2 and online resource
3).
Clinical Oral Investigations (2022) 26:109–117
Fig. 2  Comparison of the level of gingival exposure between the baseline and the 2-week post-intervention period after application of BTX-A.
Forest plot displaying the risk of bias judgement for each study included
Results of individual studies
All articles included showed a significant improvement in
gingival exposure after BTX-A injection, being considered a
safe treatment when used in appropriate dosages and settings
(online resource 2). Patients reported feeling a difference
when smiling on average 3–5 days after application [21], and
the result considered extremely satisfactory occurred after
14 days [22, 23]. Some patients reported mild side effects,
such as functional difficulties [20], spasms at the application
site, headache, and dizziness [6].
Longevity was considered satisfactory within 12 weeks
for correction of mild and moderate gummy smile [24],
while other studies have revealed that it can have a longev-
ity of 12 to 20 weeks [25]. It was found that even after 6
months of application, the gingival exposure did not return
to its baseline values [7]. It was also noted that gender and
baseline severity of gingival exposure may influence the
results [24]. No studies have evaluated the effect of BTX
on the muscles over the long term, after booster doses, or
recurrently.
Synthesis of results
Seven studies were included in the quantitative synthesis,
making it possible to perform the meta-analysis for the
following post-intervention periods: 2 weeks, 4 weeks, 12
weeks, and 24 weeks.
When the baseline is compared with the period 2 weeks
after application of BTX-A, there was a mean decrease of
3.42 mm [95% CI = −4.50 to −2.34; I2 = 97%] in the level
113
of gingival exposure (Fig. 2), maintaining proximity to these
values even after the removal of studies with higher pro-
pensity of bias [MD = −3.37; 95% CI = −4.83 to −1.90; I2
= 98%]. Likewise, the effect of BTX-A persisted for peri-
ods from 4 to 12 weeks, with a slight decrease in the effect
size and mean values of −2.47 for both evaluation periods.
Changes were only observed in the confidence interval,
which presented a longer range for 12 weeks [95% CI =
−4.10 to −0.83; I2 = 98%] (Fig. 3). Through the sensitivity
analysis, it was observed that the studies by Skaria et al. [2]
and Al Wayli et al. [26] were the main responsible for the
heterogeneity observed in the analysis of 4 and 12 weeks,
respectively. It was not possible to identify any evident con-
founding factor to justify this variance between the sizes of
effects involving these two studies. However, even with the
omission of these studies by the influence analysis, the sta-
tistical significance remained with values close to the initial
ones when considering 4 weeks [MD = −2.84; 95% CI =
−3.30 to −2.37; I2 = 0%] and with a slight decrease in effect
size for the 12-week evaluation [MD = −1.68; 95% CI =
−2.08 to −1.27; I2 = 45%].
Even after the 24-week period, the mean values did not
return to baseline values, maintaining a statistically signifi-
cant difference of −0.32 mm [95% CI = −0.54 to −0.09; I2
= 0%]. However, despite denoting statistical significance (p
< 0.05), the observed effect size was very small, consider-
ably approaching the initial values, thus not being clinically
significant (Fig. 4).
When considering all the analyzed results, the applica-
tion time explained 29.58% of the observed variance (p <
0.001) with a tendency towards decreasing the effect size
13
114 Clinical Oral Investigations (2022) 26:109–117

Fig. 3  Comparison of level of gingival exposure between baseline and post-intervention periods after the application of BTX-A: (A) 4 weeks;
(B) 12 weeks. Forest plot displaying the risk of bias judgement for each study included

Fig. 4  Comparison of the level of gingival exposure between baseline and the 24-week post-intervention period after application of BTX-A

13
Clinical Oral Investigations (2022) 26:109–117
Fig. 5  Bubble plot of the meta-regression of the observed values,
using the postoperative time measured in weeks after the application
of BTX-A as a covariate
from the second week of application, with an increase of
0.122 mm weekly (Fig. 5) in the level of gingival exposure
and tending to return to initial values in approximately 29
weeks, based on the values obtained by the regression line
[β = 0.1223341; intercept = −3.496247].
Reporting biases
Due to the lack of the minimum number of 10 studies, it
was not possible to assess the presence of publication bias
using the funnel plot and the Egger test. However, the use of
a broad search strategy in six databases and gray literature,
besides the inclusion of a database with a language other
than English (LILACS), decreased the probability of occur-
rence of this bias.
Certainty of the evidence
The certainty of the evidence was considered very low (12
weeks), low (2 and 4 weeks), and moderate (24 weeks) for
the evaluations performed. The domain related to inconsist-
ency was judged as serious or very serious in all analyses,
mainly due to high heterogeneity values (without detection
of the causative source) and few studies in the analysis, not
ensuring robustness to this domain (online resource 4).
Discussion
With the increasing demand for cosmetic dentistry, patients
are increasingly seeking a harmonious smile with minimally
invasive methods that do not involve surgical interventions
[7]. The aim of the present study was to evaluate the effect of
botulinum toxin in the treatment of gummy smile through a
115
systematic review. Based on the current existing literature on
the subject, BTX-A promotes a decrease in the level of gin-
gival exposure after a period of 2 weeks, with the result per-
sisting for up to 12 weeks and a tendency to return close to
baseline values in 24 weeks, with linear relationship between
the time after toxin application and the observed effect.
BTX should be considered the first-choice technique for
the treatment of gummy smile due to its easy application,
minimal side effects, and use of small doses, besides being
a reversible procedure when compared to other techniques
described in the literature, such as gingivoplasty, bone resec-
tion, orthognathic surgery through maxillary impaction, and
lip repositioning, which present a high cost and a painful
postoperative period [1, 5, 20]. In the present study, a mean
decrease of 3.42 mm was observed in the level of gingi-
val exposure, with maintenance of the result and a slight
decrease of up to 12 weeks, and approaching baseline val-
ues in 24 weeks. These data are in agreement with those
observed by Han et al. [27], where they reported that all
their cases showed a significant correction 2 weeks after
the application of BTX, with their result remaining up to
24 weeks. According to Hexsel et al. [24], even after 12
weeks of post-application, 80% of patients were satisfied or
very satisfied with the treatment, and would like to repeat
the treatment again. Based on the present result, and due
to its conservative character, effectiveness, and satisfaction
generated in the patient, BTX should be considered as a
treatment option [7], especially for cases with up to 4 mm
of gingival exposure.
When considering the longevity presented by BTX, the
results of the present study show that the decrease in the
level of gingival exposure was already present after the
2-week period, with a gradual increase in the values of
exposure over time. These data corroborate those observed
by Polo et al. [6], who reported that the gingival display
gradually increased from 2 weeks after the injection and
lasted for 24 weeks, but by the 24th week, the mean gingival
display had not yet returned to its baseline values [6]. Like-
wise, Al-Fouzan et al. [1] reported the maintenance of the
effect of BTX-A over a period ranging from 16 to 24 weeks
[1]. On the other hand, Mazzuco et al. [25] reported that the
effect had its maximum longevity from 16 to 20 weeks [25].
Based on the results of the meta-regression, the post-appli-
cation time proved to be a significant predictor for the level
of gingival exposure when using BTX, with the estimate
going back to the baseline of 29 weeks and explaining part
of the observed heterogeneity. However, most of the existing
heterogeneity could not be explained. Confounding factors
such as daily habits, the patient’s metabolism, and the brand
of product used can influence these results. Furthermore, it
was not possible to analyze the periods from 16 to 20 weeks
post-application due to the lack of studies that evaluated
these periods.
13
116
BTX has been used for several clinical situations
involving neurological, medical, and cosmetic conditions.
Although its use is considered safe and with good efficacy,
there is a report in the literature regarding the produc-
tion of antibodies mainly due to short intervals between
doses (booster injections) and higher dosages, in addition
to the property, formulation, manufacture, and storage of
this substance [28]. Before the diagnosis of failure in the
result induced by antibodies in the treatment with BTX, the
complete clinical history (dose, muscle applied to, product
used, frequency, and technique used) and complementary
exams must be performed [29]. In the present review, it was
observed that after 24 weeks of application, the values of the
level of gingival exposure returned close to the baseline val-
ues, with an estimate of return to initial values being verified
in the twenty-ninth week. No study included evaluated the
muscle effect of BTX application on a recurrent (long-term)
basis, so the values observed in this study should be viewed
with caution, as the results may be influenced by other con-
founding factors, such as the interval for a new application,
formulation, dosage, and storage of the product.
Some limitations of this systematic review must be con-
sidered. Most of the included studies did not carry out ade-
quate randomization processes, and there was no adequate
control of confounding factors either by statistical methods
or by adequate sampling techniques, a fact that generated
undetected sources of statistical heterogeneity. The absence
of control for these factors can influence the observed effect
estimate. Due to these factors, certainty ranged from very
low to moderate in the analyses performed. Thus, new stud-
ies should be carried out with adequate sampling and rand-
omization processes, thus allowing for greater certainty in
the evidence generated. Factors such as the long-term and
recurrent muscle effect in correcting gummy smile must be
evaluated in order to produce more robust clinical evidence.
Conclusions
The botulinum toxin proved to be effective for the treatment
of gummy smile, especially for cases with up to 4 mm of
gingival exposure, with evident results as early as 2 weeks
after its application, with a return close to the initial values
in 24 weeks.
Other information
The protocol was registered [30] on the PROSPERO website
(Prospective International Registry of Systematic Review -
Center for Comments and Disclosure of the University of
York) - under number CRD42020208814.
13
Clinical Oral Investigations (2022) 26:109–117
Supplementary Information  The online version contains supplemen-
tary material available at https://d​ oi.o​ rg/1​ 0.1​ 007/s​ 00784-0​ 21-0​ 4223-w.
Declarations 
Ethical approval  This article does not contain any studies with human
participants or animals performed by any of the authors.
Informed consent  For this type of study, formal consent is not required.
Conflict of interest  The authors declare no competing interests.
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