Quality of life in children with infantile hemangioma: a case control study
Wang et al. Health and Quality of Life Outcomes
Quality of life in children with infantile hemangioma: a case control study
Chuan Wang 1
Yanan Li 1
Bo Xiang 1
Fei Xiong 4
Kai Li 3
Kaiying Yang 1
Siyuan Chen 2
Yi Ji 1
0 37 Guo-Xue-Xiang , Chengdu, Sichuan Province 610041 , China
1 Division of Oncology, Department of Pediatric Surgery, West China Hospital of Sichuan University
2 Pediatric Intensive Care Unit, Department of Critical Care Medicine, West China Hospital of Sichuan University , Chengdu, Sichuan Province , China
3 Division of Oncology, Department of Pediatric Surgery, Children's Hospital of Fudan University , Shanghai , China
4 Department of Child Health, West China Second University Hospital, Sichuan University , Sichuan Province, Chengdu , China
Background: Infantile hemangioma (IH) is the most common vascular tumor in children. It is controversial whether IHs has effects on the quality of life (QOL) in patients of whom IH poses no threat or potential for complication. Thus, we conducted this study to evaluate the q QOL in patients with IH and find the predictors of poor QOL. Methods: The PedsQL 4.0 Genetic Core Scales and the PedsQL family information form were administered to parents of children with IH and healthy children both younger than 2-year-old. The quality-of-life instrument for IH (IH-QOL) and the PedsQL 4.0 family impact module were administered to parents of children with IH. We compared the PedsQL 4.0 Genetic Core Scales (GCIS) scores of the two groups. Multiple step-wise regression analysis was used to determine factors that influenced QOL in children with IH and their parents. Results: Except for physical symptom, we found no significant difference in GCIS between patient group and healthy group (P = 0.409). The internal reliability of IH-QOL was excellent with the Cronbach's alpha coefficient for summary scores being 0.76. Multiple step-wise regression analysis showed that the predictors of poor IH-QOL total scores were hemangioma size, location, and mother's education level. The predictors of poor FIM total scores were hemangioma location and father's education level. The predictors of poor GCIS total scores were children's age, hemangioma location and father's education level. Conclusion: The findings support the feasibility and reliability of the Chinese version of IH-QOL to evaluate the QOL in children with IH and their parents. Hemangioma size, location and education level of mother are important impact factors for QOL in children with IH and their parents.
Infantile hemangioma; Quality of life; QOL instrument for IH; Pediatric quality of life inventory; Hemangioma location
Infantile hemangioma (IH) is the most common vascular
tumor in children, with an estimated prevalence of 5 to
10%. IH usually presents at birth, develops rapidly in the
first few months and involutes gradually at last.
Depending on the appearance of IH and dictated by the depth,
location, and stage of growth, the lesions are
]. In most patients, the hemangioma lesions
are small and pose no threat or potential for scarring
and complication. However, in some cases, IHs can grow
dramatically, destroy tissues and organs, impair function,
or even threaten the patients’ lives [
]. Importantly, IHs
are also able to cause physical distress and emotional
concern to both children and their families, and all of
these eventually influence quality of life (QOL) [
Improvement in QOL of patients and their families is
one of the most significant outcomes of treatment in
pediatric tumors. QOL of patients and their families is
able to reflect the efficacy of treatment as well.
Previously, investigators did not have validated
diseasespecific instrument to evaluate the QOL in IH patients
and their families. As results, the authors could not
directly ask the patients and/or their parents about the
influence of IHs. Studies using the generic QOL
instruments have yielded conflicting results [
]. By using a
Dutch version of hemangioma-specific questionnaires,
Hoornweg et al. demonstrated that most patients’ QOL
was not affected by IH . However, the authors found
considerable psychosocial impact of IH on patients,
especially in those with complication or IH was visible
located. Until recently, an English version of QOL
instrument for IHs (IH-QOL) has been developed [
This instrument provides the required information
account for the physical, emotional, social and
cognitive development that takes place during the early
Until now, there is little information available on QOL
in IH patients younger than 2 years old - when most of
the IH growth has already occurred [
]. This is also the
period that patients are most likely to undergo
treatment, particularly in current ‘propranolol era’ [
]. It is
still controversial whether IHs has effects on QOL in
cases with small lesions. In addition, questions exist as
to which factors are associated with QOL in IH patients
and their parents.
The goal of the present study was to evaluate and
analyze QOL in IH patients younger than 2 years old,
with the aim to improve our understanding of the effects
of IH on QOL in children and their parents.
Participants and procedures
This study was approved by the Ethics Committee of the
West China Hospital of Sichuan University. All
procedures followed the research protocols approved by West
China Hospital of Sichuan University and West China
Second University Hospital of Sichuan University and
were conducted according to the Declaration of Helsinki.
All patients were recruited from August 2015 and June
2016, at Department of Pediatric Surgery, West China
Hospital of Sichuan University. The criteria for inclusion
were as follows: 1) The patients were less than 2 years of
age; 2) Patients were currently not received treatment;
and 3) Consent of parents. The exclusion criteria were: 1)
Patients were older than 2 year at the time of interview; 2)
Patients had hemangioma-unrelated comorbid disease or
major development disorders. Age and gender matched
control subjects were healthy children aged 0 to 2 years.
They were recruited from Department of Child Health,
West China Second Hospital of Sichuan University,
between August 2015 and June 2016.
Written informed consents were obtained from all
children’s parents. The location and size of hemangioma
were noted. In the case of multiple IHs, only the
clinically most important IH (typically the largest or visceral
involvement) was documented. The parents completed
the questionnaires during the patients’ outpatient
department visit. Questionnaires contained Chinese versions of
IH-QOL and the Pediatric Quality of Life Inventory™
(PedsQL™). PedsQL™ consisted of the PedsQL™ Family
Information Form (FIF), the pedsQL™ 4.0 Family Impact
Module (FIM), the PedsQL™ 4.0 Generic Core Infant
Scales (GCIS) 1–12 months and the PedsQL™ 4.0 Generic
Core Infant Scales 13–24 months. The parents of children
in patient group were required to complete the IH-QOL,
the PedsQL™ FIF, the pedsQL™ FIM and the PedsQL™ 4.0
GCIS. The parents of children in healthy group were
required to complete the PedsQL™ FIF and the PedsQL™
4.0 GCIS. The investigators were trained by the project
manager in order to guarantee the quality of the
investigation. If the parents had questions on semantic
or conceptual understanding, the investigators assisted
parents to complete the questionnaires. Besides, the
investigators were responsible to ensure there were
no missing data in questionnaires.
The PedsQL™ 4.0 GCIS 1–12 months and the PedsQL™
4.0 GCIS 13–24 months are brief, parent-proxy-reported
standardized questionnaires. They are widely used to
assess QOL in pediatric patients [
]. The module
encompasses 5 functional domains: physical functioning,
physical symptom, emotional functioning, social
functioning and cognitive functioning. The PedsQL™ 4.0
GCIS 1–12 months contains 36 items and the PedsQL™
4.0 GCIS 13–24 months contains 45 items. The Chinese
version of PedsQL™ 4.0 GCIS has been demonstrated to
have good internal consistency, as well as discriminant
and construct validity for other disease [
The PedsQL™ 4.0 FIF, which was cross-culturally
adapted into Chinese, is aimed at collecting a child’s
basic information, including date of birth, gender and
disease duration, as well as caregiver’s basic information
including marital status and education levels.
The PedsQL™ FIM, which was developed by Varni et
], applies to measuring the impact of pediatric
chronic disease on their family functioning. Chen et al.
have translated it cross-culturally into Chinese version
11, 12, 14
]. This instrument is composed of 9
dimensions (physical functioning, emotional functioning, social
functioning, cognitive functioning, communication,
worry, daily activities, family relationships and financial
issues) and 37 items. The FIM can stand alone, or be
integrated into the other measurement model, allowing an
overall assessment of QOL of children and their parents.
The IH-QOL, which was developed by Sarah L Chamlin
et al., is designed to measure the impact on IH patients
and their parents [
]. This module consists of 4 domains
(physical symptom of patient, social functioning of patient,
social and psychological functioning of caregiver, and
emotional functioning of caregiver) and 29 items. The
Chinese Mandarin Version of IH-QOL was translated
according to the standardized procedures and consisted of
4 steps: forward translation (Chinese), backward
translation (English), preliminary test and field test.
Likert-type scale responses are used in all
questionnaires: 0 = never a problem, 1 = almost never a problem,
2 = sometimes a problem, 3 = often a problem and 4 =
almost always a problem. Scores of each item were linearly
transformed into a 0 to 100 scale (0 = 100, 1 = 75,
2 = 50, 3 = 25, 4 = 0).
All analyses were conducted using SPSS 22.0 for
Windows (SPSS Inc., Chicago, USA). Chi-square (χ2) tests
were used to compare qualitative variables. Independent
sample t-test was used to analyze the continuous
variables. Pearson correlation coefficients were used to
evaluate the scaling success, with value ranging 0.6 to
0.8 presenting strong correlation, and ranging 0.4 to 0.6
presenting moderate correlation. Internal consistency
reliability of IH-QOL was determined by calculating
Cronbach’s alpha coefficient. For IH-QOL total score,
Cronbach’s alpha coefficient ranging from 0.7 to 0.8
presented good reliability, and from 0.65 to 0.7 presented
moderate reliability. For subscales, Cronbach’s alpha
coefficient ranging from 0.7 to 0.8 presented good
reliability, and from 0.6 to 0.7 presented moderate
reliability. Multiple step-wise regression analyses were used
to find out the main influencing factors for GCIS, FIM
and IH-QOL total scores [
]. Statistical significance
was set at P < 0.05.
Two hundred and seventeen children (76 male, 141
female) with IH were included. Ninety-five healthy
children (39 male, 56 female) were selected as the healthy
control group. Comparisons of demographic
characteristics in two groups are listed in Table 1. There were no
significant differences in demographic characteristics
between patient group and healthy children (P > 0.05).
The clinical characteristics and demographic details of
patient group are listed in Table 2. The craniofacial and
neck area (109) was the dominant location, representing
50% of all IHs, followed by the trunk (44), extremities
(36), visceral involvement (16) and diaper area (12).
Internal organ involvement in these children with IH
contained 14 liver involvement, and 2 subglottie
involvement. None of these 16 children developed complications.
n number of individuals, m month
a Values are presented as mean (range)
Patient group (mean ± SD)
84.79 ± 12.75
healthy group (mean ± SD)
89.68 ± 6.16
91.41 ± 9.01
90.29 ± 10.78
85.11 ± 15.44
91.95 ± 12.03
89.63 ± 13.92
Scores of each instrument and each dimension are
shown in Table 3. We found no significant difference in
GCIS total scores between patient group and healthy
group (P = 0.409). There were also no significant
differences between two groups in scores of physical
functioning (P = 0.872), emotional functioning (P = 0.734), social
functioning (P = 0.846) and cognitive functioning
(P = 0.835). However, there was significant difference in
scores of physical symptom dimension between two
groups (P = 0.021).
Table 4 demonstrates the internal reliability estimates
of IH-QOL summary scale and subscales. The
Cronbach’s alpha coefficient for IH-QOL summary scores
was 0.76. The Cronbach’s alpha coefficient for IH-QOL
subscale scores ranged from 0.65 to 0.75. Item-summary
correlation ranged from 0.482 to 0.686, which meant
IH-QOL total score was moderately related to GCIS
total score with Pearson correlation coefficient being
0.582 (P < 0.05) (Table 5). In addition, IH-QOL total score
was strongly related to FIM total score with Pearson
correlation coefficient being 0.713 (P < 0.05) (Table 6).
The outcomes of multiple step-wise regression
analyses for IH-QOL total scores are listed in Table 7. We
found the main influencing factors for IH-QOL total
scores included hemangioma location, hemangioma size
and mother’s education level. For GCIS total scores, the
main influencing factors included child’s age, hemangioma
location and father’s education level (Table 8). For FIM
total scores, the main influencing factors included
hemangioma location and father’s education level (Table 9).
As experience treating IHs with β-blockers increases, a
careful shift to more cosmetic indications is occurring.
However, in spite of its efficacy, use of β-blockers has
some risk [
]. This dilemma makes clinicians face
new and difficult challenges when deciding whether or
not to use β-blockers in small IHs when parents are
worried about their child’s visible lesion, particularly
present on the face. In this regard, QOL should be the
important measurement to resolve the challenges and to
evaluate the efficacy of treatment. Although several
scoring systems for IH have been described over the years,
there have been few studies describing QOL in IH
patients and their parents [
]. In addition, only a few
common instruments, like the PedsQL™, could be used
to assess the QOL in IH patients before IH-QOL
developed. There is an emerging perspective that both generic
and disease-specific instrument should be administered
to IH patients and their families. For this reason, we
chose to use both generic and disease-specific
instrument in current study.
PedsQL™ is thought to be a reliable valid modular
approach to evaluating QOL in children with or without
]. In the present study, we used the GCIS
to evaluate the QOL in IH patients. Our results
demonstrated that there was no significant difference in total
score between IH patients and healthy children. These
findings were inconsistent with report by Cohen-Barak
et al. , who showed that IH patients and their parents
even reported higher QOL than healthy children. In
addition, we found physical symptom scores in patient
group were significant lower than that of healthy
children. One explanation for these obvious discrepancies is
that Chinese parents seem to care more about the
physical effects of IH on their children. Second, we have
included patients with visceral IH. These patients can be
associated with comorbid diseases and are more
commonly to be managed aggressively with medical therapy
4, 25, 26
]. Third, it might attribute to the marked age
differences between two studies: in the present study,
our children were too young to report on their own
behalf. Only parent proxy-report was available. However,
although children-self-reporting is important,
perspective of parents also are critical. Furthermore, it is usually
parents’ perceptions of children’s QOL that influences
health care utilization [
On the other hand, our data suggested that PedsQL™
GCIS might not be able to accurately evaluate QOL in
IH patients alone. Hence, disease-specific instrument
should be used to evaluate the QOL in IH patients as
well. Our study showed Chinese version of IH-QOL can
be completed smoothly with few questions by most of
parents. The internal reliability for the IH-QOL
aValues denote Pearson correlation coefficients. The P values of all coefficients above are less than 0.05
summary and subscales scores was excellent, with a high
degree of internal consistency among all item scores. In
addition, our study found that IH-QOL was significantly
correlated with GCIS and FIM. These findings are
exciting, suggesting that these instruments can be used in
combination. The data from these standardized
instruments can provide more information than when they are
In keeping with the previous studies, our multiple
stepwise regression analyses demonstrated that hemangioma
location and size were related to QOL [
hemangioma location was the only factor influencing the
total scores of all three instruments. We found that
patient with IH in craniofacial and neck area had lower
IH-QOL score than those with IH in trunk, diaper area or
extremities. This finding is not surprising given
craniofacial and neck hemangiomas are visible and carry a high
risk of residua scar than in other sites . Many
craniofacial and neck lesions can leave residual scars, which may
have life-long effects [
]. In addition, we found that when
hemangioma size was >2 cm2, the IH-QOL total score
decreased significantly. Therefore, for craniofacial and
neck hemangioms with size >2 cm2, early intervention
may be justified to potentially arrest the growth of the
lesion, and avoid psychosocial concerns [
introduction of relatively safer topical agents (e.g., timolol)
now allows earlier and easier intervention in
appropriate cases [
It is noteworthy that parents with higher education
level reported significantly higher QOL values.
Currently, accurate information for IH is disseminated
widely via the Internet. Conceptually, parents with
higher education levels may spend more time learning
hemangioma characteristics by themselves. This finding
is interesting, indicating that parents who worry about
the QOL of their child can be reassured. In contrast,
parents with lower education levels may have poor
knowledge of IH. This in turn, causes the heightened
anxiety even for those IHs that are unlikely to cause
complication or leave scarring. On the other hand,
clinician may wish to counsel the parents regarding the
changes of IH, such as rapid growth, infection or
ulceration, and to establish with the parents a means to see
the child on short notice if such changes are observed
]. Furthermore, parental attitudes and beliefs are
critical factors in treatment selection, more so in elective
cases . Thus, parental education on IH will not only
directly improve the QOL, but may also indirectly
improve QOL by preventing functional and/or cosmetic
complications via early referral and timely intervention
during the ‘watchful waiting’ period.
In conclusion, this study emphasizes that IH can
influence the QOL in young patients and their parents. Our
results demonstrate that PedsQL GCIS may not be
sufficient to evaluate QOL in children with IH alone.
IHQOL, with excellent internal reliability, is significantly
associated with the PedsQL GCIS and FIM. In addition,
our study provides novel findings that children’s age,
hemangioma location and size, and parents’ education
level are important risk factors for poor QOL in patients
and their parents.
FIF: The PedsQL™ family information form; FIM: The pedsQL™ 4.0 family
impact module; GCIS: The PedsQL 4.0 genetic core scales; IH: Infantile
hemangioma; IH-QOL: The quality-of-life instrument for IH; PedsQL™: The
pediatric quality of life inventory™; QOL: Quality of life
This work was supported at collection, analysis, and interpretation of data
and in writing the manuscript stages by grants from the National Natural
Science Foundation of China (81401606 and 81400862), and the Science
Foundation for Excellent Youth Scholars of Sichuan University (2015SU04A15).
Availability of data and materials
The datasets used and analysed during the current study are available from
the corresponding author on reasonable request.
SYC and YJ contributed to the design of the study. CW and YJ reviewed the
data, interpreted the statistical analysis and drafted the manuscript. CW, YNL,
BX, FX, KYY and YJ performed the experiments. CW analyzed the data. All of
the authors read and approved the final manuscript.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of the West China Hospital
of Sichuan University and West China Second University Hospital of Sichuan
University. All procedures followed the research protocols approved by West
China Hospital of Sichuan University and West China Second University Hospital
of Sichuan University and conducted according to the Declaration of Helsinki.
Written informed consents were obtained from all children’s parents.
Consent for publication
All children’s parents had provided their consent regarding the publication
of this manuscript.
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
1. Munden A , Butschek R , Tom WL , Marshall JS , Poeltler DM , Krohne SE , et al. Prospective study of infantile haemangiomas: incidence, clinical characteristics and association with placental anomalies . Br J Dermatol . 2014 ; 170 : 907 - 13 .
2. Darrow DH , Greene AK , Mancini AJ , Nopper AJ . Diagnosis and management of infantile hemangioma . Pediatrics . 2015 ; 136 : e1060 - 104 .
3. Drolet BA , Esterly NB , Frieden IJ . Hemangiomas in children . N Engl J Med . 1999 ; 341 : 173 - 81 .
4. Ji Y , Chen S , Xiang B , Xu Z , Jiang X , Liu X , et al. Clinical features and management of multifocal hepatic hemangiomas in children: a retrospective study . Sci Rep . 2016 ; 6 : 31744 .
5. Zweegers J , van der Vleuten CJ . The psychosocial impact of an infantile haemangioma on children and their parents . Arch Dis Child . 2012 ; 97 : 922 - 6 .
6. Hoornweg MJ , Grootenhuis MA , van der Horst CM. Health-related quality of life and impact of haemangiomas on children and their parents . J Plast Reconstr Aesthet Surg . 2009 ; 62 : 1265 - 71 .
7. Cohen-Barak E , Rozenman D , Shani Adir A. Infantile haemangiomas and quality of life . Arch Dis Child . 2013 ; 98 : 676 - 9 .
8. Chamlin SL , Mancini AJ , Lai JS , Beaumont JL , Cella D , Adams D , et al. Development and validation of a quality-of-life instrument for infantile hemangiomas . J Invest Dermatol . 2015 ; 135 : 1533 - 9 .
9 . Chang LC , Haggstrom AN , Drolet BA , Baselga E , Chamlin SL , Garzon MC , et al. Growth characteristics of infantile hemangiomas: implications for management . Pediatrics . 2008 ; 122 : 360 - 7 .
10. Adams DM , Trenor CC 3rd, Hammill AM , Vinks AA , Patel MN , Chaudry G , et al. Efficacy and safety of sirolimus in the treatment of complicated vascular anomalies . Pediatrics . 2016 ; 137 : e20153257 .
11. Ji Y , Chen S , Li K , Xiao N , Yang X , Zheng S , et al. Measuring health-related quality of life in children with cancer living in Mainland China: feasibility, reliability and validity of the Chinese Mandarin version of PedsQL 4.0 generic core scales and 3.0 cancer module . Health Qual Life Outcomes . 2011 ; 9 : 103 .
12. Hao Y , Tian Q , Lu Y , Chai Y , Rao S . Psychometric properties of the Chinese version of the pediatric quality of life inventory 4.0 generic core scales . Qual Life Res . 2010 ; 19 : 1229 - 33 .
13. Varni JW , Sherman SA , Burwinkle TM , Dickinson PE , Dixon P . The PedsQL family impact module: preliminary reliability and validity . Health Qual Life Outcomes . 2004 ; 2 : 55 .
14. Chen R , Hao Y , Feng L , Zhang Y , Huang Z. The Chinese version of the Pediatric Quality of Life Inventory (PedsQL) family impact module: crosscultural adaptation and psychometric evaluation . Health Qual Life Outcomes . 2011 ; 9 : 1 - 10 .
15. Wang C , Shang L , Zhang Y , Tian J , Wang B , Yang X , et al. Impact of functional constipation on health-related quality of life in preschool children and their families in Xi'an, China . PLoS One . 2013 ; 8 : e77273 .
16. Frommelt P , Juern A , Siegel D , Holland K , Seefeldt M , Yu J , et al. Adverse events in young and preterm infants receiving topical timolol for infantile hemangioma . Pediatr Dermatol . 2016 ; 33 : 405 - 14 .
17. Frost G , Relic J . Dangers of propranolol in preterm infants . Australas J Dermatol . 2013 ; 54 : 237 - 8 .
18. Lawley LP , Siegfried E , Todd JL . Propranolol treatment for hemangioma of infancy: risks and recommendations . Pediatr Dermatol . 2009 ; 26 : 610 - 4 .
19. Leaute-Labreze C , Hoeger P , Mazereeuw-Hautier J , Guibaud L , Baselga E , Posiunas G , et al. A randomized, controlled trial of oral propranolol in infantile hemangioma . N Engl J Med . 2015 ; 372 : 735 - 46 .
20. Prey S , Voisard JJ , Delarue A , Lebbe G , Taieb A , Leaute-Labreze C , et al. Safety of propranolol therapy for severe infantile hemangioma . JAMA . 2016 ; 315 : 413 - 5 .
21. Haggstrom AN , Beaumont JL , Lai JS , Adams DM , Drolet BA , Frieden IJ , et al. Measuring the severity of infantile hemangiomas: instrument development and reliability . Arch Dermatol . 2012 ; 148 : 197 - 202 .
22. Janmohamed SR , van Oosterhout M , de Laat PC , van Rosmalen J , Madern GC , Oranje AP . Scoring the therapeutic effects of oral propranolol for infantile hemangioma: a prospective study comparing the Hemangioma Activity Score (HAS) with the Hemangioma Severity Scale (HSS) . J Am Acad Dermatol . 2015 ; 73 : 258 - 63 .
23. Kuhlthau KA , Pulsifer MB , Yeap BY , Rivera Morales D , Delahaye J , Hill KS , et al. Prospective study of health-related quality of life for children with brain tumors treated with proton radiotherapy . J Clin Oncol . 2012 ; 30 : 2079 - 86 .
24. Varni JW , Seid M , Rode CA. The PedsQL: measurement model for the pediatric quality of life inventory . Med Care . 1999 ; 37 : 126 - 39 .
25. Orlow SJ , Isakoff MS , Blei F . Increased risk of symptomatic hemangiomas of the airway in association with cutaneous hemangiomas in a “beard” distribution . J Pediatr . 1997 ; 131 : 643 - 6 .
26. Drolet BA , Pope E , Juern AM , Sato T , Howell B , Puttgen KB , et al. Gastrointestinal bleeding in infantile hemangioma: a complication of segmental, rather than multifocal, infantile hemangiomas . J Pediatr . 2012 ; 160 : 1021 - 6 . e3 .
27. Tomlinson D , Hinds PS , Bartels U , Hendershot E , Sung L . Parent reports of quality of life for pediatric patients with cancer with no realistic chance of cure . J Clin Oncol . 2011 ; 29 : 639 - 45 .
28. Bauland CG , Luning TH , Smit JM , Zeebregts CJ , Spauwen PH . Untreated hemangiomas: growth pattern and residual lesions . Plast Reconstr Surg . 2011 ; 127 : 1643 - 8 .
29. Haggstrom AN , Drolet BA , Baselga E , Chamlin SL , Garzon MC , Horii KA , et al. Prospective study of infantile hemangiomas: clinical characteristics predicting complications and treatment . Pediatrics . 2006 ; 118 : 882 - 7 .
30. Ji Y , Wang Q , Chen S , Xiang B , Xu Z , Li Y , et al. Oral atenolol therapy for proliferating infantile hemangioma: a prospective study . Medicine (Baltimore) . 2016 ; 95 : e3908 .
31. Chan H , McKay C , Adams S , Wargon O. RCT of timolol maleate gel for superficial infantile hemangiomas in 5- to 24-week-olds . Pediatrics . 2013 ; 131 : e1739 - 47 .
32. Puttgen K , Lucky A , Adams D , Pope E , McCuaig C , Powell J , et al. Topical timolol maleate treatment of infantile hemangiomas . Pediatrics . 2016 ; 138 : e20160355 .
33. Xu G , Lv R , Zhao Z , Huo R . Topical propranolol for treatment of superficial infantile hemangiomas . J Am Acad Dermatol . 2012 ; 67 : 1210 - 3 .
34. Ji Y , Chen S , Xu C , Li L , Xiang B. The use of propranolol in the treatment of infantile haemangiomas: an update on potential mechanisms of action . Br J Dermatol . 2015 ; 172 : 24 - 32 .