Review article Eur J Dermatol 2013; 23(5): 592-9
Xiaolu HUANGa Safety and efficacy of hyaluronic acid for the
Yimin LIANGa
Qingfeng LI
Department of Plastic & Reconstructive
Surgery,
Shanghai Ninth People’s Hospital,
Shanghai Jiao Tong University School of
Medicine,
639 Zhizaoju Road,
Shanghai 200011, P. R. China
Copyright © 2017 John Libbey Eurotext. Téléchargé par NYU LANGONE MED CTR SCH OF MED HEALTH SCIENCES LIBRARY le 08/03/2017.
a These two authors contributed equally to
this work as co-authors
Reprints: Q. Li
<dr.liqingfeng@shsmu.edu.cn>
Article accepted on 5/1/2013
S
oft-tissue augmentation of the face is an increas-
ingly popular cosmetic procedure. In recent years,
the number of available filling agents has also
increased dramatically, improving the range of options
available to physicians and patients. Understanding the vari-
ous characteristics, capabilities, risks, and limitations of the
available dermal fillers can help physicians improve patient
outcomes and reduce the risk of adverse events (AEs).
There are many types of dermal filler available on the mar-
ket, including fillers for non-permanent, semi-permanent
and permanent augmentation procedures. The most popular
fillers are those made from hyaluronic acid (HA). HA prepa-
rations of various products have been developed for facial
soft-tissue augmentation: Restylane, Perlane (Q-Med, Upp-
sala, Sweden); Juvéderm 18, Juvéderm 24, and Juvéderm
30 (including the High Viscosity (HV) formulations; Aller-
gan, Irvine, Calif., USA), and Captique (Allergan), etc.
Non-animal stabilized HA has been extensively used for
nasolabial fold correction, as the use of a non-animal source
reduces the likelihood of antigenic contamination and sub-
sequent hypersensitivity reactions [1].
Because a wide range of options for nasolabial fold cor-
rection are available to physicians and patients (different
brands, monophasic or biphasic filler, and the degree of
crosslink), the differences in efficacy and safety profiles
592
To cite this article: Huang X, Liang Y, Li Q. Safety and efficacy of hyaluronic acid for the correction of nasolabial folds: A meta-analysis. Eur J Dermatol 2013; 23(5): 592-9
doi:10.1684/ejd.2013.2151
correction of nasolabial folds: A meta-analysis
Background: Soft-tissue augmentation of the face is increasingly popu-
lar and the number of available filling agents has increased dramatically,
improving the range of options for hyaluronic acid (HA) fillers. How-
ever, their different efficacy and safety have not been systematically
compared. Objectives: To evaluate and compare the safety and efficacy
of different types of hyaluronic acid (HA) for nasolabial fold correction.
Methods & Materials: A literature search, using MEDLINE, PubMed
and Google Scholar, and a manual search of references for additional rel-
evant studies were performed. Randomized controlled trials (RCTs) and
clinical trials (CTs) with 0.5-24 months’ duration, evaluating efficacy
and safety after for HA augmentation therapy, were included. Results:
Overall, 18 RCTs (n = 2,521) and 7 CTs (n = 346) were included. Differ-
ent HA fillers for nasolabial fold correction were associated with various
efficacies. At the 6-month follow-up, the mean Wrinkle Severity Rating
Scale (WSRS) score change from the baseline for HA was 1.21. In sub-
group analysis, the JuvedermTM family achieved the best efficacy, while
their adverse event incidence was significantly higher than other HA
products. Monophasic fillers demonstrated a significantly better efficacy
than biphasic fillers over the 6 month follow-up period, while biphasic
fillers showed higher tolerance than monophasic fillers. Conclusion: Our
meta-analysis proved both safety and efficacy for HA fillers. JuvedermTM
family achieved the best efficacy, while the adverse event incidence for
JuvedermTM family was significantly higher than for other HA products.
Key words: dermal filler, hyaluronic acid, nasolabial folds
of these products have not been thoroughly reviewed and
investigated. The daily procedures of physicians are often
based on experience and commentary from experts, which
indicates limited evidence and subjectivity. The aim of this
meta-analysis was to investigate and compare the efficacy
and safety of the most commonly used HA products for
nasolabial fold correction and to provide physicians and
patients with information based on high-level evidence.
Methods
Study Selection
A systematic literature search for all relevant articles up
to July 2012 was conducted using MEDLINE (begin-
ning January 1950), PubMed and Google Scholar. The
search strategy combined Medical Subject Headings
doi:10.1684/ejd.2013.2151
and keywords, including “hyaluronic acid”, “nasolabial
fold” and “cosmetics” and the non-MeSH term “der-
mal filler”. For our MEDLINE search, we used the
Cochrane Collaboration’s Highly Sensitive Search Strategy
sensitivity-maximizing version for randomized controlled
trials (RCTs) [2]. A manual search of the references from
EJD, vol. 23, n◦ 5, September-October 2013
 reports of clinical trials or review articles was performed
to identify additional relevant studies. When applicable,
efforts were made to contact investigators for clarifica-
tion or additional data. Two investigators (Xiaolu Huang
and Yimin Liang) independently reviewed all potentially
relevant articles.
Trials with the following characteristics were included in
the analysis: (1) were RCTs or CTs; (2) used HA as
intervention procedures or placebo group for nasolabial
fold correction; (3) followed up participants for at least
2 weeks; (4) reported aesthetic outcomes by using Wrin-
kle Severity Rating Scale (WSRS) scores; or (5) reported
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adverse event incidence. The WSRS is a photograph-based
outcome instrument that is designed specifically for quan-
tifying facial folds. The scoring of fold severity is based
on the visual assessment of the length and apparent depth
of the nasolabial fold, without reference to the baseline or
pre-treatment appearance (table 1).
Validity Assessment
Validity assessment was performed by using the “Risk of
bias” tool [3], a tool for assessing risk of bias in each
included study recommended by Cochrane Collaboration.
This comprises a judgment and a support for the judgment
for each entry in a ‘Risk of bias’ table, where each entry
addresses a specific feature of the study. The judgment for
each entry involves assessing the risk of bias as ‘low risk’,
as ‘high risk’, or as ‘unclear risk’, with the last category
indicating either lack of information or uncertainty over the
potential for bias. All trials were independently reviewed
and graded by 2 investigators (Xiaolu Huang and Yimin
Liang). Disagreement was resolved through discussion.
Data Abstraction
By using a standardized tool, two investigators (Xiaolu
Huang and Yimin Liang) independently abstracted all data,
with disagreements resolved by discussion. The following
information was sought from each trial: (1) author identifi-
cation; (2) year of publication; (3) study design and method
quality; (4) sample size; (5) country in which the study
was conducted; (6) duration of follow-up; (7) treatment
schedule used; and (8) baseline characteristics (age, sex,
race, Fitzpatrick skin type, previous augmentation). The end
points examined included the mean change in WSRS, the
incidence of adverse events and touch-up volume. Detailed
unpublished data were obtained by contacting the author
of the original article if necessary. For literature discussed
Table 1. The Wrinkle Severity Rating Scale.
The Wrinkle Severity Rating Scale
5 Extreme: Extremely deep and long folds, detrimental to facial appearance; 2–4 mm visible V-shaped fold when stretched. Unlikely
to have satisfactory correction with injectable implant alone.
4 Severe: Very long and deep folds; prominent facial feature. Less than 2 mm visible fold when stretched. Significant improvement is
expected from injectable implant.
3 Moderate: Moderately deep folds; clear facial feature visible at normal appearance but not when stretched. Excellent correction is
expected from injectable implant.
2 Mild: Shallow but visible fold with a slight indentation; minor facial feature. Implant is expected to produce a slight improvement
in appearance.
1 Absent: No visible fold; continuous skin line.
EJD, vol. 23, n◦ 5, September-October 2013
with wide indications (facial rejuvenation, etc), we only
collected data for nasolabial fold correction in the meta-
analysis.
Statistical Analysis
Traditional meta-analyses, analyzing changes in WSRS as
continuous variables for augmentation procedures at dif-
ferent follow-up time points, were performed by using
weighted mean differences (WMDs) as effect size. WMDs
were calculated by using Revman 5.0 and visualized by
STATA (version 10.1). Separate analyses were conducted
for each class of augmentation procedure. Total AE inci-
dences were pooled to conduct a safety comparison among
the various augmentation procedures by using R software
(version 2.15.0, package META). In all cases, WMDs and
associated 95% confidence intervals (CIs) were calculated
using a DerSimonian and Laird random-effects model [4].
Pooled AE incidences were calculated based on the Logit
transformation method by using a random-effects model.
To assess the potential confounding effect on our results
of heterogeneity, subgroup analyses were performed on
the changes in WSRS scores at all follow-up points and
on AE incidence, in which trials were stratified by differ-
ent types of dermal filler (biphasic fillers vs monophasic
fillers, highly cross-linked fillers vs others, large gel vs
small gels) were re-analyzed. To be specific, biphasic fillers
included Restylane® , Perlane® , Hylaform® and Hylaform®
plus, while monophasic fillers included JuvédermTM fam-
ily and Emervel® . Highly cross-linked fillers including
JuvédermTM family, Hylaform® and Hylaform® plus. Fur-
thermore, small gel practice referred to Restylane® and
large gel practice referred to Perlane® . Baseline wrinkle
severity was considered by performing subgroup analysis
according to the baseline WSRS score, evaluating trials with
baseline WSRS scores of less than 4 and those with base-
line WSRS scores of 4 or greater. Trials of shorter duration
(0.5-12 months inclusive) and those of longer duration (>13
months) were analyzed separately in subgroup analyses.
Results
Study characteristics and study quality
Of the 448 non-duplicate citations identified from the litera-
ture search, 43 full-text articles were screened for eligibility
(figure 1). The assessment of the full-text articles revealed
593
 448 Citations identified through database
search
43 full-text articles assessed for eligibility
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25 high-quality articles included in
meta-analysis
▪ 17 RCT
▪ 8 CT
Figure 1. Identification, Review, and Selection of Articles Included in the Meta-analysis.
Abbreviations: RCT, randomized controlled trial; CT, clinical trial.
“Risk of bias” scores of less than 3 in 12 articles and 6 arti-
cles which did not analyze changes in WSRS scores or AE
incidences. Thus, 25 articles [5-30] were eligible for inclu-
sion, representing 18 unique RCTs. A total of 18 RCTs
(n = 2,521) and 7 CTs (n = 346) met all of the inclusion cri-
teria and were included in our meta-analysis and systematic
review. The involved study characteristics are described in
table 2.
The “Risk of bias” quality assessment tool was used to eval-
uate each selected study involved in pooled WSRS changes
and preference RD analysis (figures 2-3). Six bias risks were
taken into consideration as potential factors influencing
the impact quality of the RCTs involved. The existence of
selection bias (random sequence generation and allocation
concealment) was noted in over 50% of involved RCTs. In
contrast, 100% studies indicated low risks of reporting bias
(figure 2). Figure 3 demonstrates the detailed information
of the quality assessment on each RCT level.
Changes in WSRS scores
Figure 4 demonstrates the WMDs in WSRS for HA filler
interventions. WMDs was an effect size which was utilized
to evaluate the WSRS difference between the start and finish
(certain follow-up time point) values. For HA, at baseline,
improvements were noted on the HA-treated sides of the
face, with patients typically displaying a one- or two-grade
change in WSRS score with each treatment, and at the 6th
month, the WMD in WSRS score for HA decrease to 1.21.
After the 6th month, repeated injections with HA were per-
formed, at the 24th month of follow-up, the WMD in the
WSRS score for HA from baseline was 1.1.
Subgroup analysis
In subgroup analysis, we investigated several influence fac-
tors that we assumed would affect the outcomes of effect
594
405 were excluded after
reviewing the title and
abstract.
18 were excluded from study :
▪ 12 articles “Risk of bias”
score less than 3 points.
▪ 6 articles did not consist of
changes of WSRS score or AEs
incidence.
size and AE incidence. The influence factors involved were
as follows: (1) local analgesia or not; (2) race (Caucasian or
not); (3) Fitzpatrick skin type (I-VI); (4) large gel or small
gel HA; (5) highly cross-linked HA vs other HA products;
(6) baseline wrinkle severity; (7) duration of follow-up; (8)
monophasic versus biphasic fillers; (9) different type of HA
products.
The results indicated that dermal fillers formulated with
local analgesics are effective at reducing procedural pain
during the correction of facial wrinkles and folds, while
maintaining a similar safety and effectiveness profile as the
fillers without local analgesics. Patients with Fitzpatrick
skin types I-III were more likely to develop AEs, such
as swelling, redness, pain and pruritus (p<0.05), and no
difference was found in treatment efficacy. A large or
small gel did not affect either the efficacy or safety out-
comes. Neither baseline wrinkle severity, nor duration of
follow-up significantly affected safety or efficacy. Differ-
ent types of HA product demonstrated distinct efficacy,
the efficacy of JuvédermTM family indicated significantly
better results compared with Hylaform® , Emervel® and
Restylane® , while Emervel® and Restylane® demonstrated
competitive results for efficacy within a 6-month follow up
(figure 5A). As for monophasic fillers and biphasic fillers,
monophasic fillers demonstrated a superior efficacy ver-
sus biphasic fillers during the whole 6 month follow-up
period (figure 5B). Highly cross-linked HA fillers showed
a superior efficacy to other HA fillers (figure 5C).
AE incidence
The overall AE incidence for dermal fillers is shown in
table 3. The most common short-term AE (diminished
in one or two weeks after injection, with no intervention
required) was swelling (37.3%), and the second most com-
mon AE was redness (28.7%). The most common long-term
EJD, vol. 23, n◦ 5, September-October 2013
 Copyright © 2017 John Libbey Eurotext. Téléchargé par NYU LANGONE MED CTR SCH OF MED HEALTH SCIENCES LIBRARY le 08/03/2017.

Table 2. The characteristic of randomized controlled trails and clinical trials involved in systematic review and meta-analysis.

Author Publication Study Design Location/ Caucasian Sex Age, y No. of Cases products Outcome(s)
Year Follow-up, M (%) (women, %) (Participants) (assessment)
Hyaluronic acid
Amada Pinzon 2003 CT Panama/9 NA 22 (73.3) 52 30 Perfectha Derm® Subskin vs control GAIS&WSRS
Narins RS 2003 CS, DB, MC, RCT American/6 89 128 (93.4) 54.3 138 Restylane® vs Zyplast.® GAIS&WSRS

EJD, vol. 23, n◦ 5, September-October 2013

Lindqvist C 2004 CS, MC, RCT Sweden/9 100 65 (95.6) 49.4 68 Perlane® vs Zyplast® GAIS&WSRS
® ®
Carruthers A 2005 DB, MC, RCT Canada/6 93 140 (93.3) 51.9 150 Restylane Perlane vs Hylaform GAIS&WSRS
Narins RS 2007 CS, MC, RCT American/6 93 92 56 164 Dermicol-P35 vs Restylane® MFWS
Antonino Di Pietro 2007 CT Italy/6 NA 21 (95.5%) 48.4±11.7 22 HA GAIS&WSRS
Beer K 2007 CS, RCT American /6 86.7 15 (100) 53±12 15 Restylane vs Hylaform® plus gel GAIS&WSRS
Baumann LS 2007 CS, DB, MC, RCT American /6 74 404 (92) 49 439 J30 vs 24HV vs 30HV WAS
Lupo MP 2007 CS, MC, RCT American/6 62 79 (91) 49 87 24HV vs Zyplast WAS
Goldman MP 2007 RCT American/1.5 92 33 (91.7) 50±10 36 Restylane® vs laser+ Restylane® GAIS&WSRS
Narins RS 2008 CS, MC, RCT American/18 67 70 (93) 53.8±8.41 75 Restylane® GAIS&WSRS
®
Narins RS 2008 CS, MC, RCT American/12 92.6 137 (91.9) 55.7±8.3 164 Dermicol-P35 vs Restylane MFWS
Dover JS 2009 CS, MC, RCT American/6 79.8 266 (93.9) 53.7±9.0 283 Restylane® vs Perlane® WSRS
Hoffmann K 2009 CT Germany/0.5 NA 64 (91) 50 70 JuvédermTM GAIS
Weinkle SH 2009 CT American/0.5 78 69(96) 53 72 JuvédermTM with or without lidocaine WSRS
Carruthers A 2010 CS, MC, RCT American /6.5 82 90(100) 48.1±5.1 90 Restylane® vs onabotulinumtoxinA GAIS
Monheit GD 2010 CS, MC, RCT American/9 70 135 (96.4) 52.7±9.3 140 Restylane® vs DGE GGS
Heden P 2010 CS, CT Sweden/12 100 40 (95) 54 42 Restylane® with or without lidocaine WSRS
Narins RS 2010 CS, MC, RCT American/12 88.6 287 (91.1) 54.6±9.33 315 Restylane® WAS& GAIS
Narins RS 2010 CS, RCT American /18 97.9 88 (92.6) 53.0 95 Belotero® WAS& GAIS
Taylor SC 2010 CS, MC, RCT American /6 0 93.3 18-75 150 Restylane® vs Perlane® WSRS
®
Turlier V 2010 MC, CT France/12 NA 37 (78.7) 55.7±3.7 47 Glytone LS
Rzany B 2011 CS, RCT Germany/6 100 51 (98.1) 50.6±10.1 52 Emervel® vs Restylane® WSRS
Nast A 2011 CS, DB, RCT Switzerland/7 NA 52 (86.7) 54.8±8.8 60 Restylane® vs Perlane® WAS& GAIS
Narins RS 2011 CT American /18 66.7 70 (93.3) 53.8±8.4 63 Restylane® GAIS&WSRS
Abbreviations RCT Randomized Controlled Trail; CT, Clinical Trail; CS, Comparison Study; MC, Multi-Center; DB, Double Blind; HA, Hyaluronic Acid; GAIS, The Global Aesthetic Improvement Scale; WSRS,
The Wrinkle Severity Rating Scale; MFWS, Modified Fitzpatrick Wrinkle Scale; WAS, Wrinkle Assessment Scale LS, Lemperle scale; NA, Not Available.

595
 Random sequence generation (selection bias)
Allocation conoealment (selection bias)
Blinding of participants and personnel (performance bias)
Blinding of outcome assessment (detection bias)
Incomplete outcome data (attrition bias)
Selective reporting (reporting bias)

0% 25% 50% 75% 100%

Low risk of bias Unclear risk of bias High risk of bias

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Figure 2. Risk of bias graph: review authors’ judgements about each risk of bias item presented, as percentages across all included
studies.

2007-Goldman MP
2010-Carruthers A

2005-Carruthers A
2007-Baumaan LS
2010(2)-Narins RS

2010(1)-Narins RS

2008(2)-Narins RS

2008(1)-Narins RS
2009-Weinkle SH

2004-Lindqvist C

2003-Narins RS
2007-Lupo MP
2009-Dover JS
2010-Monheit
2011-Rzany B

2007-Beer K
2011-Nast A

+ + + + + Random sequence generation (selection bias)

−

−
+ + + + + + + Allocation concealment (selection bias)
−

+ + + + + + + + + Binding of participants and personnel (Performance bias)

−
−

−
−

+ + + + + + + + + + + + + + + Binding of outcome assessment (detection bias)

−

+ + + + + + + + + + + + + + + + Incomplete outcome data (attrition bias)

−

+ + + + + + + + + + + + + + + + + Selective reporting (reporting bias)

Figure 3. Risk of bias summary: review authors’ judgments about each risk of bias item for each included study. Red dots
indicated high risk of bias whereas green dots indicated low risk of bias.

AE (occurring 2 weeks after injections) was skin induration 13.8 million in 2011 [32]. Because the patient population
(11.5%). In the HA subgroup, including various HA prod- is increasing worldwide, the extensive array of fillers avail-
ucts, the subgroup analysis indicated that the AE incidences able for nasolabial fold correction requires that physicians
of Juvéderm were significantly higher than for other HA develop and maintain a thorough understanding of each
products (including pain, bruising, injection site nodules, product that they use with regard to the capabilities, limi-
pruritus, skin induration and skin discoloration), (p<0.01). tations and risk-benefit profiles. However, the efficacy and
Monophasic fillers demonstrated a significantly higher AE safety amongst different dermal fillers have not been sys-
incidence rate than biphasic fillers (p<0.0001). No signif- tematically compared. Our study investigated the efficacy
icant difference was observed between the small gel group and safety profiles of different dermal augmentation pro-
and the large gel group AE incidence. Compared with other cedures for nasolabial fold correction from the published
HA fillers, highly cross-linked fillers were proven to have literature, with the help of a meta-analysis and systematic
more chance of developing AEs (p<0.0001). Although we review.
generalized the pooled AE incidence, most of the follow The pooled HA efficacy was determined in the present
up periods were not longer than 24 weeks, so the long study, the results indicate that, by using HA as dermal
term safety profiles cannot be ascertained. A pharmacovig- fillers for nasolabial fold correction, the WSRS changes
ilance or adverse event reporting system would be required from baseline, decreasing from 1.87 to 1.21 in the first
to capture this data in further studies. 6 months after augmentation procedures and maintains
the efficacy by touch up in 24 months. Although the
combined HA efficacy was determined, different HA
products varied from each other with their different for-
Discussion mulations, phases and degree of cross-link, hence we
are continuing to conduct sub-group analyses to evalu-
Nasolabial fold correction with fillers is both an art and a ate if these variations can impact either efficacy or safety
science [31]. Soft tissue fillers constitute a growing cate- profiles. The results indicated that HA products with a
gory of minimally invasive therapies for the treatment of higher cross-link degree (like JuvédermTM family and
age-related changes in the face and the number of aesthetic Hylaform® , etc) achieve significantly better efficacy than
procedures performed in the United States has risen dra- other products. Such an outcome is in line with expecta-
matically, from approximately 2 million in 1997 to almost tions, since the cross-link technique was initially designed

596 EJD, vol. 23, n◦ 5, September-October 2013

 2
Investigator WSRS change from baseline
1.5
1
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.5
0

0 5 10 15 20 25
Time after HA injection (month)

Figure 4. Pooled WSRS changes over a 24-month period after cosmetic correction with HA (repeat injections were involved
after 6th month). Size of circle is proportional to sample size.
Abbreviations: WSRS, the Wrinkle Severity Rating Scale; HA, hyaluronic acid.

A B C
Mean investigator wsrs changes from baseline

Mean investigator wsrs changes from baseline

Mean investigator wsrs changes from baseline

2
2
2.5

1.8
1.5
2

1.6
1.5

1.4
1
1

1.2
.5
.5

0 5 10 15 20 25 0 5 10 15 20 25 0 5 10 15 20 25

Juve’derm Restylane
Hylan B plus Juve’derm ultra plus
Juve’derm ultra Emervel Monophasic fillers Biphasic fillers Highly cross-linked HA fillers Other HA fillers

Figure 5. Pooled WSRS changes over a 24-week period after cosmetic correction with HA (A). Comparison amongst different
HA products (B). Monophasic fillers vs Biphasic fillers (C). Comparison between highly cross-linked HA fillers and other HA
fillers.
Size of circle is proportional to sample size.Abbreviations: WSRS, the Wrinkle Severity Rating Scale; HA, hyaluronic acid.

for better maintenance and resistance to degradation. Other potentially confounding factors were investigated
Monophasic HA fillers were proven to be more effective in the subgroup analysis and sensitivity analysis. Because
than biphasic HA fillers, the result is consistent with for- pain is a common patient complaint during dermal filler
mer literature comparing the efficacy differences between injections, the application of local analgesia needs to be
monophasic HA fillers and biphasic HA fillers [28]. addressed. The combined results from the meta-analysis
The evidence-based conclusion for our study is based on a demonstrated that the application of local analgesia was
variety of RCTs and CTs. The quality of RCTs involved is effective in reducing procedural pain during the correction
crucial to the reliability and robustness of the conclusions of facial wrinkles and folds, while maintaining a similar
derived from the meta-analysis. With the help of the “risk safety and effectiveness profile. Several RCTs examined
of bias” quality assessment tool, we were able to reveal this issue and revealed similar findings. Weinkle SH et al.
the distribution of bias within the RCTs involved. Most reported a multi-center, double-blind, randomized, con-
studies did not pay a lot attention to controlling selection trolled study of the safety and effectiveness of Juvéderm
bias, which includes random sequence generation methods injectable gel with and without lidocaine, and their results
and allocation concealment performance and description. were consistent with our pooled results in the meta-analysis.
Further RCTs should be aware of bias control, especially The Fitzpatrick skin type scale is a numerical classifica-
for selection bias which is crucial for randomization. tion schema for the color of skin. It was developed in 1975

EJD, vol. 23, n◦ 5, September-October 2013 597

 Table 3. Pooled adverse events incidence of dermal fillers. Abbreviations: AE, Adverse events; HA, hyaluronic acid; DGE,
Dermal Gel Extra.

AE Incidence Redness Swelling Bruising Pruritus Skin induration Tenderness Skin discoloration Pain
HA 0.287 0.373 0.247 0.115 0.115 0.151 0.041 0.213
Biphasic fillers vs Monophasic fillers
Biphasic fillers 0.181 0.198 0.178 0.025 0.025 0.054 0.012 0.062
Monophasic fillers 0.803 0.816 0.511 0.266 0.726 0.003 0.313 0.818
p-value <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001
Highly cross-linked fillers vs others
Highly cross-linked 0.654 0.669 0.361 0.195 0.491 0.007 0.242 0.6553
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others 0.194 0.214 0.204 0.021 0.029 0.061 0.013 0.0636

p-value 0.06 0.02 0.16 <0.0001 <0.0001 0.01 <0.0001 0.00
Different type of HA
DGE 0.214 0.557 0.250 0.079 0.086 0.004 0.004 0.436
Hylaform 0.080 0.073 0.027 0.040 0.003 0.013 0.003 0.053
Juvéderm family 0.907 0.872 0.603 0.358 0.887 0.003 0.356 0.890
Perlane 0.066 0.047 0.096 0.012 0.016 0.029 0.017 0.015
Restylane 0.207 0.185 0.213 0.015 0.031 0.035 0.010 0.049
Restylane Perlane 0.410 0.700 0.327 0.033 0.040 0.323 0.008 0.204
p-value <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001
Small gel vs large gel
small gel 0.207 0.185 0.213 0.015 0.031 0.035 0.010 0.049
large gel 0.066 0.047 0.096 0.012 0.016 0.029 0.017 0.015
p-value 0.05 0.05 0.28 0.88 0.44 0.86 0.66 0.14

by T. B. Fitzpatrick. Previously published literature rarely
focused on the differences in the efficacy and safety pro-
files of dermal fillers for patients with varying skin types.
Our results showed that there is a significantly greater pos-
sibility of patients with a lighter skin color (skin types I-III)
developing AEs (swelling, redness, bruising and pain) than
patients with a darker skin color (skin types IV-VI) after
injection procedures. By reviewing previously published
studies, we found that the relationship between skin pig-
ment and hypersensitivity reactions has been extensively
reviewed and has yielded conflicting evidence. Lemperle
et al. [33] concluded by clinical observation that lighter skin
is more prone to allergic reactions than darker complexions,
while the study by Farage et al. [34] yielded a controversial
result after they reviewed various articles focusing on this
topic. More population-based epidemiology surveys should
be undertaken to reveal whether darker skin type is a risk
factor for developing allergic reactions.
All fillers are associated with the risk of both early and
late complications. Early side effects, such as swelling,
redness and bruising occur after intradermal or subdermal
injections. Late adverse events also include immunological
phenomena, such as late-onset allergies and non-allergic
foreign body granuloma. In general, most adverse events
were transient and mild in nature; the majority of events
were associated with the injection process, such as swelling,
bruising and redness. The injection site nodule formation
pooled incidence (HA: 9.3%; BC: 11.0%) was higher than
previously reported (less than 5%), [34, 35]. The incidence
of skin induration was relatively lower than other AE, but
it significantly reduced patients’ satisfaction with treat-
ment outcomes. In subgroup analysis, highly cross-linked
HA were observed to have more chance of developing
skin induration than other HA products. The potential
reason for the phenomenon may be because highly cross-
linked HA fillers are less elastic and more cohesive, which
makes it harder to disperse them intradermally. Except
for product-related nodule formation, nodules and some
other bumps (non-inflammatory) are generally technique-
dependent. These lumps can result from excess product
being injected into an area (over-correction) or from inject-
ing too superficially [36].
Our meta-analysis had the limitations typically observed
in traditional meta-analyses, such as variations in treat-
ment regimens or populations (heterogeneity). Although
estimates from the meta-analysis cannot be simply assumed
to be accurate, we think that the reliability and robustness
of our results are supported by (1) well-defined and strict
inclusion criteria, (2) observed goodness of model fit. One
limitation of our study is that some of the data from the
original studies were inadequate, which increased the level
of difficulty when performing a subgroup analysis. Fur-
ther investigations with more detailed documents should
be performed.
Based on the best available evidence, our meta-analysis
showed that amongst various HA fillers, JuvédermTM
family achieved the best efficacy, while the adverse
event incidence for JuvédermTM was significantly higher
than for other HA products. This systematic review and
meta-analysis provide evidence that AEs after HA filler
augmentation are associated with specific risk factors, such
as skin type, injection products, etc. The data regarding
pooled AE incidences were also summarized.

Disclosure. Financial support: none. Conflict of interest:
none.

598 EJD, vol. 23, n◦ 5, September-October 2013


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