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doi:10.1111/jpc.12464

ORIGINAL ARTICLE

Treatment of periorbital infantile haemangiomas: A systematic

literature review on propranolol or steroids
Shiqiong Xu,* Renbing Jia,* Shengfang Ge, Ming Lin and Xianqun Fan
Department of Ophthalmology, Ninth Peoples Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

Aim: The aim of this study was to compare the efcacy and safety of propranolol versus corticosteroids for the treatment of periorbital infantile
haemangiomas (IHs).
Methods: A literature review using PubMed, Ovid Medline, EBSCO, Springer, Web of Knowledge, Cochrane Library, CNKI and associated
references before 2 March 2013 was conducted. The main outcomes were distribution of locations, response rate, rebound growth rate,
spherical and cylinder power before and after treatment, amblyopia rate and adverse events.
Results: Thirty-one studies including 425 patients met the inclusion criteria. A total of 70.6% of patients were female, 89.6% of the periorbital
IHs were located in the upper or lower eyelid area. The most common administration routes involved oral propranolol and intralesional injection
of corticosteroids. The mean response rate was 94.0% for propranolol and 82.3% for corticosteroid (P = 0.001). The rebound growth rate was
13.9% for propranolol and 12.0% for steroids (P = 0.71). Astigmatism was reduced in both propranolol and steroid studies (P < 0.0001, P < 0.0001),
but a signicant reduction in spherical power was only demonstrated in propranolol studies (P = 0.005). A total of 31.1% of patients treated with
corticosteroids developed post-operative amblyopia compared with 16.7% of patients treated with propranolol (P = 0.04). Oral propranolol
seemed to induce more temporary adverse events than intralesional corticosteroids administration (24.0% vs. 9.6%, P = 0.006).
Conclusion: Propranolol may represent an effective therapy for periorbital IHs compared with the use of corticosteroids; however, further
randomised control studies are needed to compare adverse events.
Key words: corticosteroid; infantile haemangioma; periorbital; propranolol.

What is already known on this topic What this paper adds

1 Oral propranolol and intralesional injection of corticosteroids
are both methods of treatment for IHs in a series of cases.
2 Intralesional injection of corticosteroids has been a long time
the rst-line treatment for infantile haemangioma (IH).
3 Oral propranolol has been successfully using for IH since 2008.
1 This systematic review compared efcacy and safety of pro-
pranolol with corticosteroid especially in the IHs located in the
periocular area including volume changes, refraction errors,
astigmatism and adverse events.
2 Oral propranolol may play a better role in treating periorbital IH
with regard to its efcacy.
3 Further studies are needed to compare adverse events of beta-
blockers in treating periorbital IH.

An infantile haemangioma (IH) is benign vascular endothelial
neoplasm characterised by a bright red surface that occurs in up
to 4% of children by the age of 1 year,1 and are more likely to
occur in low birthweight, premature infants following maternal
infertility treatment.2 Despite their self-limiting course,3 a
periorbital IH can cause visual impairment or disfigurement,
Correspondence: Prof Xianqun Fan, Department of Ophthalmology, Ninth
Peoples Hospital, Shanghai Jiao Tong University School of Medicine,
NO.639 Zhi Zao Ju Road, Shanghai, 200011, China. Fax: +86 21 23271699;
email: fanxq@sh163.net
Conict of interest: The authors indicate no nancial conict of interest.
*The rst two authors contributed equally to the work presented here and
should therefore be regarded as equivalent authors.
Accepted for publication 19 September 2013.
such as amblyopia due to astigmatism or occlusion of the visual
axis, displacement of the globe, proptosis and optic nerve
compression.47 Early treatment is therefore indicated to prevent
vision loss due to amblyopia.
The modalities for IH treatment include surgery and admin-
istration of corticosteroids, propranolol and -interferon.
Corticosteroids have been the mainstay of IH treatment for
many years.6,814 However, the efficacy of propranolol for the
treatment of IH has recently been demonstrated,15,16 and
numerous reports have suggested that oral propranolol holds
high promise for IH treatment.1723
This systematic review considered studies published before
March 2013 and aimed to provide an overall comparison of the
efficacy and adverse events of propranolol versus corticosteroids
for the treatment of periorbital IH.

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Journal of Paediatrics and Child Health 2013 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
Propranolol or steroids for infantile haemangioma
Methods and Materials
Search strategies
The electronic databases PubMed, Ovid Medline, EBSCO,
Springer, ISI Web of Knowledge, Cochrane Library (clinical
trial) and CNKI were searched by two independent reviewers on
2 March 2013 using the following keywords: orbital OR orbit
OR periorbital OR periocular OR eyelid; beta blocker OR pro-
pranolol OR corticosteroids OR steroids; and capillary heman-
giomas OR capillary hemangioma OR capillary haemangioma
OR capillary haemangiomas OR infantile hemangioma OR
infantile haemangioma OR infantile hemangiomas OR infantile
haemangiomas. Additional studies from reference lists in eli-
gible articles were searched manually.
Selection of studies
The titles, abstracts and full texts of publications were assessed by
two reviewers. Areas of conflict were discussed, and discrepan-
cies were resolved by consultation with a third blinded investi-
gator. The inclusion criteria were (i) IH located in the periorbital
or periocular area; and (ii) patients treated with either
corticosteroids or propranolol. The exclusion criteria were (i)
patients with simultaneous use of two or more different medi-
cations or therapies other than propranolol or corticosteroids;
(ii) patients with any other skin lesions not located in the
periocular or periorbital area; (iii) if the same institution
reported two or more studies for the same population, the study
with the fewer patients was excluded; (vi) animal studies,
unpublished studies and conference proceedings; and (v) review
articles and letters to the editor were excluded.
Data extraction and statistical analysis
Two independent reviewers extracted data from studies that
met the eligibility criteria and differences were resolved
through discussion. The main outcomes were distribution of
locations, efficacy including spherical power (dioptres) and
cylinder power before and after treatment, response rate,
rebound growth rate, amblyopia rate and adverse events. Few
valid instruments are available to determine the methodologi-
cal quality of observational studies. As a result, the methodo-
logical index for non-randomised studies (MINORS)24 was
applied to assess the quality of each included study in which
the maximum score for non-comparative studies is 16; items
are scored as 0 for not reported, 1 for inadequate report and 2
for adequate report.
The study parameter values obtained from the extracted data
were entered into RevMan software (version 5.1; The Cochrane
Collaboration) for statistical analysis. A probability (P) value
<0.05 was considered statistically significant. For continuous
data, the weighted mean difference and 95% confidence inter-
vals were calculated. An I2 range of 0% and 50% represented
no heterogeneity. We evaluated the pooled summary effects
using a fixed-effect model to reduce the effects of heterogeneity
between trials. Otherwise, data were combined using a
random-effect model. Where meta-analysis was inappropriate,
data were summarised for each trial.
272
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S Xu et al.
Results
Study selection and description of included studies
A total of 618 studies of potential interest were retrieved from the
literature search: 183 studies were eliminated because of dupli-
cations after reviewing the titles and 363 studies were excluded
based on the exclusion criteria. The remaining 72 studies were
checked in detail and a further 41 were excluded for the follow-
ing reasons: 8 used multiple medications, 18 lacked exact data, 8
focused on the clinical characteristics of periorbital IH before
treatment rather than on post-treatment outcomes, 5 focused on
intralesional injection techniques and 2 were review articles with
no data analysis. Thirty-one studies were finally included. There
were no randomised controlled studies. All included studies were
case series, among which 15 involved propranolol therapy and
16 used corticosteroids. Twenty-six studies examined response
rates,2550 12 reported rebound growth rates,2528,32,34,37,41,43,48,49,51
13 analysed spherical power,2932,3943,5154 14 studies surveyed
cylinder power,2832,3943,5154 16 looked at amblyopia rates
after treatment27,28,31,32,36,3943,48,5155 and 21 reported adverse
events.2534,36,3841,43,45,51,52,54,55 Because all of the included studies
were observational studies, the MINORS score was applied to
define the quality of evidence. In this systematic review, the
MINORS score ranged from 5 to 15 with an average of 9.3 2.7,
demonstrating a medium degree of quality among the studies
included. A flow chart of the study selection process and details of
the studies are listed in Figure 1 and Table 1.
Clinical characteristics of patients
A total of 425 patients were included, among which 187
received propranolol therapy and 238 received corticosteroids.
The average age at initial treatment was 6.4 months. The
mean duration of follow-up was 16.1 months. A total of
70.6% of patients were female. Twenty-four studies reported
the location of the IH: 89.6% of periorbital IHs were located in
the upper or lower eyelid area, 4.9% had orbital extension,
3.8% were located in the medial or lateral canthus and 1.7%
were located in the glabellar area. The clinical characteristics
and locations of the periorbital IH before treatment are listed
in Table 2.
Dosage and administration
In most studies, propranolol was administered orally at an initial
dosage of 0.11 mg/kg/day and increased incrementally to
23 mg/kg/day.25,27,3134,36,38,52 Some studies administered oral
propranolol 2 mg/kg/day directly;28,30,32,35,37 only one study used
1 mg/mL intralesional propranolol with 0.2 mL/cm and a
maximum volume of 1 mL for a 5-cm lesion.26
In the steroid groups, the most common treatment was
intralesional injection of a combination of triamcinolone
(40 mg) and betamethasone/dexamethasone (46 mg).3950,5355
A second or third injection was necessary when the size of the
lesion was insufficiently reduced. Two studies used topical
clobetasol propionate cream once daily and 1% prednisolone
eye drops four times daily;50,51 and one study used oral steroids
starting with prednisolone (2 mg/kg/day).50
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S Xu et al.
Fig. 1 Flow chart of selection process for
included studies.
Efcacy
Twenty-six studies, including 14 on propranolol and 12 on
corticosteroids, analysed the response rate. In most studies, the
authors mentioned the response rate,25,26,30,31,3346,4850 while in
some studies, response was defined as a volume reduction of
more than 25% of the initial size.2729,32,47 In the systematic
review, response was defined as volume shrinkage of more
than 25% or the response rate already given by the author in
the included studies. The mean response rate was 94.0% (range
75.0100%) in the propranolol studies and 82.3% in cortico-
steroid studies (range 5092.59%; P = 0.001). Thirteen of the
propranolol studies25,27,2938,52 mentioned previous medications,
including 24.0% (36/150) of patients who had failed to respond
favourably to previous corticosteroids and had changed to pro-
pranolol therapy, with considerable improvement. Twelve
studies reported rebound growth rates, including seven pro-
pranolol and five corticosteroid studies. In the propranolol
studies, 13.9% (12/86) of patients showed evidence of rebound
compared with 12.0% (8/48) in the steroid studies (P = 0.71)
(Table 3).
Thirteen studies analysed spherical power and the data were
pooled in a forest plot. Patients who received propranolol had a
significant reduction in spherical power (reduction in hypero-
Journal of Paediatrics and Child Health 50 (2014) 271279
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Journal of Paediatrics and Child Health 2013 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
Propranolol or steroids for infantile haemangioma
pia) after treatment (I2 = 0%, P = 0.005, Z = 2.79), but there was
no significant change in spherical power before and after
corticosteroid treatment (I2 = 0%, P = 0.51, Z = 0.56). Fourteen
studies examined cylinder power, and both groups showed sig-
nificant reductions in cylinder power after treatment. The
studies using oral propranolol had low heterogeneity (I2 = 76%,
P < 0.0001, Z = 11.88 for corticosteroid studies; I2 = 30%, P <
0.0001, Z = 8.42 for oral propranolol studies) (Figs 2,3).
Sixteen studies looked at the amblyopia rate after treatment,
including 6 propranolol and 10 steroid studies. By the end of the
last follow-up, 16.7% (11/66) of propranolol patients and
31.1% (41/132) of corticosteroid patients suffered from amblyo-
pia (P = 0.04) (Table 3).
Adverse events
Twenty-one studies, including 9 on corticosteroid and 12 on
propranolol, reported adverse events. A total of 36 out of 150
propranolol patients and 10 out of 104 steroid patients had side
effects; however, there was no significant difference between
the two groups (24.0% vs. 9.6%, P = 0.006). In the propranolol
studies, the most common adverse events were sleep disorders
(31.3%), bronchospasm or respiratory symptoms (18.8%),
mild hypotension and cold extremities (18.8%), gastrointestinal
273
Propranolol or steroids for infantile haemangioma S Xu et al.

Table 1 Details of studies included in the systematic review

Included study Year Cases Age (months) of Therapies MINORS

initial treatment score

El-Essawy R25 2011 15 8.1 Oral propranolol 11

Awadein A26 2011 22 5.9 Intralesional propranolol injection for 12 points 6
Intralesional steroids injection for 10 points
Missoi TG27 2011 17 4.5 Oral propranolol 9
Vassallo P28 2013 14 20.8 Oral propranolol 8
Al Dhaybi R52 2011 18 2.7 Oral propranolol 13
Li YC29 2010 4 5.2 Oral propranolol 8
Snir M30 2011 30 1.6 Oral propranolol 6
Fabian ID31 2011 3 6.3 Oral propranolol 14
Cheng JF32 2010 10 32.8 Oral propranolol 12
Haider KM33 2010 17 312 weeks Oral propranolol 7
Claerhout I34 2011 10 6.8 Oral propranolol 10
Arneja JS35 2010 2 2.5 Oral propranolol 12
Fridman G36 2011 5 3.2 Oral propranolol 11
Thoumazet H37 2012 8 4.9 Oral propranolol 8
Zhao HF38 2011 12 3.3 Oral propranolol 5
Gawley SD39 2011 14 3 Intralesional steroids mixture injection 12
Motwani MV53 1995 5 3.9 Intralesional steroids mixture injection 8
Weiss AH54 2008 14 4.7 Intralesional steroids mixture injection 15
Langmann A40 1994 4 2.5 Intralesional steroids mixture injection 10
Morrell AJ41 1991 27 10.6 Intralesional steroids mixture injection 8
Friling R42 2009 7 4.2 Intralesional steroids mixture injection 8
Kushner BJ43 1982 10 8.1 Intralesional steroids mixture injection 6
Elsas FJ51 1994 5 3 Topical steroids 9
Boyd MJ44 1991 25 NM Intralesional steroids mixture injection 7
Coats DK45 2003 7 NM Intralesional steroids mixture injection 9
Iwanaka BT46 1994 5 5.4 Intralesional steroids mixture injection 14
Verity DH47 2008 9 NM Intralesional steroids mixture injection 12
Kushner BJ48 1985 25 6.7 Intralesional steroids mixture injection 10
Nelson LB49 1984 2 13 Intralesional steroids mixture injection 7
Schwartz SR50 2007 54 3.3 Topical steroids (clobetasol propionate 0.05% TID) 9
Intralesional steroids mixture injection
Oral steroids (prednisolone 2 mg/kg/day)
OKeefe m55 2003 24 6 Intralesional steroids mixture injection 6

Oral propranolol started at initial dose from 0.11 mg/kg/day and increased to 2 mg/kg/day. Oral propranolol started at 2 mg/kg/day directly. Intralesional
injection of a 1 : 1 combination of triamcinolone 40 mg/mL and dexamethasone/betamethasone 46 mg/mL at one or multiple sites into the lesion. Topical
clobetasol propionate cream qd and prednisolone 1% eye drops QID. NM, not mentioned; QID, four times a day; TID, three times a day.

symptoms (12.4%), fever (6.2%), hyperglycaemia (3.1%), skin
rash (3.1%), abnormal behaviour (3.1%) and mild bradycardia
(3.1%). The most common adverse event in the corticosteroids
groups was damage to local appearance after intralesional injec-
tion (60%), including slight bruising, superficial necrosis, fat
atrophy, subcutaneous deposits and ulceration. Other adverse
effects were reduced linear growth (10%) and local infection
(10%) (Table 4).
Discussion
It is necessary to treat periorbital IH because of the high risk of
amblyopia and the associated poor cosmetic outcomes.56 Pro-
pranolol is an emerging therapy and has been considered as a
possible substitute for corticosteroids for treating periorbital IH
since the excellent response reported in 2008.15 Many studies
have subsequently demonstrated the efficacy and safety of oral
propranolol for periorbital IH.
Propranolol is a non-selective beta-blocker that can shrink
a lesion through vasoconstriction, inhibition of angiogenesis
and induction of apoptosis mediated by Src, mitogen-activated
protein kinase and the caspase cascade pathway.17
Obtaining a sufficient number of patients to generate mean-
ingful results to compare the superiorities of propranolol and
corticosteroids for periorbital IH treatment remains challenging.
Because there have been no randomised controlled studies,
case series that differed in some respects were included in the
current review. Despite heterogeneity in 31 of the included

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S Xu et al. Propranolol or steroids for infantile haemangioma

studies, the final total of 425 patients included in this literature

Table 2 Clinical characteristics of infantile haemangiomas review allowed us to draw some meaningful conclusions con-
Propranolol Corticosteroids cerning the clinical characteristics of periorbital IH, and the
relative efficacies and safeties of propranolol and corticosteroids
Male (%) 28.7 (37/129) 29.9 (49/164) therapies.
Female (%) 71.3 (92/129) 70.1 (115/164) Infants who developed periorbital IH were more likely to be
Age of initial treatment (months) 7.4 5.4 female as 70.6% of the children in this study were female,
Duration of follow-up (months) 8.7 24.6 which is consistent with the results of risk-factor studies.57
Location No. of patients Periorbital IH is often located in the upper or lower eyelid,58 and
89.6% of children in the current analysis suffered from an upper
Eyelid 310 (89.6%) or lower eyelid IH, in which tumour growth can potentially
Orbital extension 17 (4.9%) occlude the visual axis and induce mechanical deformation of
Canthus 13 (3.8%) the structurally immature cornea, resulting in anisometropic
Glabella 6 (1.7%) astigmatism and deprivation amblyopia. This type of amblyopia
was shown to develop more often after the age of 3 years.31,59
In cases with orbital extension, proptosis appeared to be the
major complaint.
In most propranolol studies, patients underwent physical
Table 3 Outcomes of treatment with propranolol or corticosteroids examination, and vital signs, blood glucose level and electrocar-
diograms results were assessed. Patients with contraindications,
Propranolol Corticosteroids P-value especially respiratory or cardiac disorders, were excluded. Pro-
Response rate 94% (141/150) 82.3% (140/170) 0.001
pranolol can be an effective adjunct to corticosteroid therapy.60
Rebound growth rate 13.9% (12/86) 12.0% (9/75) 0.71 However, 24.0% patients had failed to respond favourably to
Amblyopia rate 16.7% (11/66) 31.1% (41/132) 0.04 previous corticosteroid therapy and were changed to proprano-
Side effects rate 24.0% (36/150) 9.6% (10/104) 0.006 lol therapy, resulting in considerable improvement. The inci-
dence of lesion resolution was significantly higher in the

Fig. 2 Forest plots of spherical errors before and after treatment with propranolol or corticosteroids. CI, condence interval; SD, standard deviation.

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Propranolol or steroids for infantile haemangioma S Xu et al.

Fig. 3 Forest plots of cylinder power before and after treatment with propranolol or corticosteroids. CD, cylinder power; CI, condence interval.

Some reduction of astigmatism has been reported with both

Table 4 Constituent ratio of adverse events in patients treated with intralesional steroid injection and oral propranolol.61 In our
propranolol or steroids study, although astigmatism was reduced in both the proprano-
Propranolol N Rate (%) lol and steroid studies, only propranolol therapy resulted in a
significant reduction in spherical power because the anatomic
Mild hyperglycaemia 1 3.1 results paralleled the functional results.52 The amblyopia rate
Cold extremities/hypotension 6 18.8 was thus significantly lower in the propranolol studies.
Mild bradycardia 1 3.1 In this systematic review, there was no evidence of significant
Skin rash 1 3.1
difference in the risk of adverse events in oral propranolol
Gastrointestinal symptoms 4 12.4
administration compared with intralesional corticosteroids
Sleep disorders 10 31.3
injections, although local skin damage accounted for 60% of the
Fever 2 6.2
complications associated with intralesional steroids administra-
Abnormal behaviour 1 3.1
tion. Although intralesional corticosteroids were associated with
Bronchospasm or respiratory symptoms 6 18.8
Total events (n) 32 100.0
fewer systematic adverse events than oral propranolol, serious
Corticosteroids complications involving central retinal artery occlusion are
Reductions of linear growth 3 30.0 inevitable unless the procedure is performed by experienced
Abscess at the site of injection 1 10.0 operators.6264 Propranolol was associated with more adverse
Local appearances damage 6 60.0 effects, the most common of which were sleep disorders. This
Total 10 100.0 was in accord with other studies that showed a high incidence of
adverse effects (18 of 28 infants, 64%).65 However, the majority
of published studies found that the adverse effects of proprano-
lol administration were minimal and benign,6668 and the risks of
propranolol studies (94% of patients) compared with the the most concerning events of low blood pressure and brady-
corticosteroid studies (82.3%). As seen in other studies, early cardia were not as high as previously thought. A solution to
lesion regression started within the first 3 days after the initial many of the side effects of propranolol therapy may be the use
dose of propranolol.4 of more selective beta-1 antagonists such as metoprolol, which,

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S Xu et al.
at low dosage, have little beta-2 activity.69 Furthermore, it is not
certain that the systematic adverse events such as gastrointesti-
nal symptoms, fever and abnormal behaviour were associated
with oral propranolol therapy although most propranolol-
associated adverse events subsided following dose reduction and
discontinuation of oral propranolol.
Limitations
This systematic review revealed that the dominate studies con-
cerning periorbital IHs were retrospective case series studies
with no control groups and a lack of randomised controlled
trials. We expected to find randomised or case control studies,
but to our disappointment, none of the databases contained
such studies. There were some registrations of randomised
control studies concerning cutaneous IHs; however, most of
them were in process without clear outcomes and few of them
were IHs located in the periorbital area. Also, the current litera-
ture was particularly weakened by inclusion of heterogeneous
patient groups
Conclusion
In conclusion, available peer-reviewed literature indicated
that propranolol therapy might be effective for periorbital IH,
especially when regarding the improvements in spherical
errors. However, further randomised control studies are
needed to compare the routes of administration, different
types and long-term adverse events of beta-blockers in treating
periorbital IH.
Acknowledgements
Funding/Support
This work was supported by the National Key Program for Basic
Research of China grant (2010CB529902), the National Natural
Science Foundation of China grant (81100683, 81372909)
and the Science and Technology Commission of Shanghai
(13ZR1423600, 12ZR1417300).
Contributions of Authors
Design of the study (SX, RJ); Conduct of the study (XF, RJ, ML);
Literature search and selection on Medline, Pubmed, CNKI,
Cochrane Library (SX, SG); Detail review of the selected studies
(SX, RJ); Data Collection, extraction and analysis (SX); Prepa-
ration and review of the manuscript (SX, XF, ML, SG).
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Untitled, by Lux Daskalakis (8) from Operation Art 2011.

Journal of Paediatrics and Child Health 50 (2014) 271279 279

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