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Meta-Analysis
. 2018 Apr 18;4(4):CD006545.
doi: 10.1002/14651858.CD006545.pub3.

Interventions for infantile haemangiomas of the skin

Monica Novoa  1 , Eulalia Baselga, Sandra Beltran, Lucia Giraldo, Ali Shahbaz, Hector Pardo-Hernandez, Ingrid Arevalo-Rodriguez
Affiliations
Meta-Analysis

Interventions for infantile haemangiomas of the skin

Monica Novoa et al. Cochrane Database Syst Rev. .

Abstract

Background: Infantile haemangiomas (previously known as strawberry birthmarks) are soft, raised swellings of the skin that occur in 3% to 10% of infants. These benign vascular tumours are usually uncomplicated and tend to regress spontaneously. However, when haemangiomas occur in high-risk areas, such as near the eyes, throat, or nose, impairing their function, or when complications develop, intervention may be necessary. This is an update of a Cochrane Review first published in 2011.

Objectives: To assess the effects of interventions for the management of infantile haemangiomas in children.

Search methods: We updated our searches of the following databases to February 2017: the Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, AMED, LILACS, and CINAHL. We also searched five trials registries and checked the reference lists of included studies for further references to relevant trials.

Selection criteria: Randomised controlled trials (RCTs) of all types of interventions, versus placebo, active monitoring, or other interventions, in any child with single or multiple infantile haemangiomas (IHs) located on the skin.

Data collection and analysis: We used standard methodological procedures expected by Cochrane. The primary outcome measures were clearance, a subjective measure of improvement, and adverse events. Secondary outcomes were other measures of resolution; proportion of parents or children who consider there is still a problem; aesthetic appearance; and requirement for surgical correction. We used GRADE to assess the quality of the evidence for each outcome; this is indicated in italics.

Main results: We included 28 RCTs, with a total of 1728 participants, assessing 12 different interventions, including lasers, beta blockers (e.g. propranolol, timolol maleate), radiation therapy, and steroids. Comparators included placebo, an active monitoring approach, sham radiation, and interventions given alone or in combination.Studies were conducted in a number of countries, including China, Egypt, France, and Australia. Participant age ranged from 12 weeks to 13.4 years. Most studies (23/28) included a majority of females and different types of IHs. Duration of follow-up ranged from 7 days to 72 months.We considered most of the trials as at low risk of random sequence generation, attrition bias, and selective reporting bias. Domains such as allocation concealment and blinding were not clearly reported in general. We downgraded evidence for issues related to risk of bias and imprecision.We report results for the three most important comparisons, which we chose on the basis of current use. Outcome measurement of these comparisons was at 24 weeks' follow-up.Oral propranolol versus placeboCompared with placebo, oral propranolol 3 mg/kg/day probably improves clinician-assessed clearance (risk ratio (RR) 16.61, 95% confidence interval (CI) 4.22 to 65.34; 1 study; 156 children; moderate-quality evidence) and probably leads to a clinician-assessed reduction in mean haemangioma volume of 45.9% (95% CI 11.60 to 80.20; 1 study; 40 children; moderate-quality evidence). We found no evidence of a difference in terms of short- or long-term serious adverse events (RR 1.05, 95% CI 0.33 to 3.39; 3 studies; 509 children; low-quality evidence), nor in terms of bronchospasm, hypoglycaemia, or serious cardiovascular adverse events. The results relating to clearance and resolution for this comparison were based on one industry-sponsored study.Topical timolol maleate versus placeboThe chance of reduction of redness, as a measure of clinician-assessed resolution, may be improved with topical timolol maleate 0.5% gel applied twice daily when compared with placebo (RR 8.11, 95% CI 1.09 to 60.09; 1 study; 41 children;low-quality evidence). Regarding short- or long-term serious cardiovascular events, we found no instances of bradycardia (slower than normal heart rate) or hypotension in either group (1 study; 41 children; low-quality evidence). No other safety data were assessed, and clearance was not measured.Oral propranolol versus topical timolol maleateWhen topical timolol maleate (0.5% eye drops applied twice daily) was compared with oral propranolol (via a tablet taken once per day, at a 1.0 mg/kg dose), there was no evidence of a difference in haemangioma size (as a measure of resolution) when measured by the proportion of patients with a clinician-assessed reduction of 50% or greater (RR 1.13, 95% CI 0.64 to 1.97; 1 study; 26 participants; low-quality evidence). Although there were more short- or long-term general adverse effects (such as severe diarrhoea, lethargy, and loss of appetite) in the oral propranolol group, there was no evidence of a difference between groups (RR 7.00, 95% CI 0.40 to 123.35; 1 study; 26 participants; very low-quality evidence). This comparison did not measure clearance.None of our key comparisons evaluated, at any follow-up, a subjective measure of improvement assessed by the parent or child; proportion of parents or children who consider there is still a problem; or physician-, child-, or parent-assessed aesthetic appearance.

Authors' conclusions: We found there to be a limited evidence base for the treatment of infantile haemangiomas: a large number of interventions and outcomes have not been assessed in RCTs.Our key results indicate that in the management of IH in children, oral propranolol and topical timolol maleate are more beneficial than placebo in terms of clearance or other measures of resolution, or both, without an increase in harms. We found no evidence of a difference between oral propranolol and topical timolol maleate with regard to reducing haemangioma size, but we are uncertain if there is a difference in safety. Oral propranolol is currently the standard treatment for this condition, and our review has not found evidence to challenge this. However, these results are based on moderate- to very low-quality evidence.The included studies were limited by small sample sizes and risk of bias in some domains. Future trials should blind personnel and participants; describe trials thoroughly in publications; and recruit a sufficient number of children to deduce meaningful results. Future trials should assess patient-reported outcomes, as well as objective outcomes of benefit, and should report adverse events comprehensively. Propranolol and timolol maleate require further assessment in RCTs of all types of IH, including those considered problematic, as do other lesser-used interventions and new interventions. All treatments should be compared against propranolol and timolol maleate, as beta blockers are approved as standard care.

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Conflict of interest statement

Monica Novoa: nothing to declare. Eulalia Baselga: I have been the principal investigator for propranolol trials in infantile haemangioma, which included reviewing the final data, and for this I received honorarium/a consulting fee from Pierre Fabre Dermatology. I have received financial support for travel to meetings from Pierre Fabre Dermatology. I have received consultancy fees from the following: Pierre Fabre Dermatology and Sanofi‐Regeneron. I have received payment for lectures from the following: Ordesa, Meda, Cantabria, and Almirall. I have given paid educational presentations for the following companies: Pierre Fabre Dermatology, Almirall, ISDIN, Novartis, Ferrer, Leo, IFC (Cantabria), and Ordesa. I have received travel/accommodation funding to attend the European Academy of Dermatology & Venereology and Spanish Academy of Dermatology meeting from the following: Novartis, Almirall, Ferrer, ISDIN, Cantabria, and Lao. Sandra Beltrán: nothing to declare. Lucia Giraldo: nothing to declare. Ali Shahbaz: nothing to declare. Hector Pardo‐Hernandez: nothing to declare. Ingrid Arevalo‐Rodriguez: nothing to declare.

Dr Baselga was involved in the development of Leaute‐Labreze 2015. She did not participate in the 'Risk of bias' assessment and data extraction for this study.

Figures

1
1
Study flow diagram.
2
2
'Risk of bias' graph: review authors' judgements about each 'Risk of bias' item presented as percentages across all included studies.
3
3
'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included study.
See this image and copyright information in PMC

Update of

Comment in

References

References to studies included in this review

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Malik 2013 {published data only}
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Ambika 2013 {published data only}
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Liu 2009 {published data only}
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Midena 2008 {published data only}
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Miranda 2005 {published data only}
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NCT01074437 {published data only}
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Pancar 2011 {published data only}
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Poetke 2000 {published data only}
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Rouvas 2009 {published data only}
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Zhao 1997 {published data only}
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Zhong 2014 {published data only}
    1. Zhong SX, Tao YC, Zhou JF, Yao L, Li SS. Evaluation on efficacy of different doses of propranolol in treatment of infantile hemangioma. Journal of Jilin University Medicine Edition 2014;40(4):880‐3. [CENTRAL: CN‐01041728]
Zhou 2000 {published data only}
    1. Zhou JY, Fang GJ, Wang XM. Clinical study of microwave operation in treating nasal hemangioma. International and 6th National Head and Neck Cancer Conference. Shanghai, china, 9‐13 June, 2000. 2000:195. [CENTRAL: CN‐00343206]
Zhou 2002 {published data only}
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Zhou 2015 {published data only}
    1. Zhou W, He S, Yang Y, Jian D, Chen X, Ding J. Formulation, characterization and clinical evaluation of propranolol hydrochloride gel for transdermal treatment of superficial infantile hemangioma. Drug Development & Industrial Pharmacy 2015;41(7):1109‐19. [CENTRAL: CN‐01254273] - PubMed

References to studies awaiting assessment

Kuang 2014 {published data only}
    1. Kuang X, Lu J. Concurrent versus sequential combination therapy of propranolol and dual‐wavelength laser (585nm and 1064nm) to treat refractory infantile hemangiomas. Journal of Dermatology 2014;41:100. [CENTRAL: CN‐01055093]
Maier 2012 {published data only}
    1. Maier H, Wanka A, Schmalwieser AW, Maier B, Dani T, Neumann R, et al. Prospective, randomized, investigator‐blind, controlled therapy study on treatment of haemangioma of infancy: Pulsed dye laser versus cryotherapy versus observation. Experimental Dermatology 2012;21(3):e15. [EMBASE: 70792062]
NCT00004436 {published data only}
    1. NCT00004436. Randomized study of hormonal regulation of infantile hemangioma. clinicaltrials.gov/ct2/show/NCT00004436 (accessed 23 April 2010).
NCT00555464 {published data only}
    1. NCT00555464. Clinical Trial of Vincristine vs. Prednisolone for Treatment of Complicated Hemangiomas. clinicaltrials.gov/ct2/show/NCT00555464 (accessed 23 April 2010).
NCT00744185 {published data only}
    1. NCT00744185. Propranolol on capillary hemangiomas. clinicaltrials.gov/ct2/show/NCT00744185 (accessed 23 April 2010).
NCT01072045 {published data only}
    1. NCT01072045. Comparative Study of the Use of Beta Blocker and Oral Corticosteroid in the Treatment of Infantile Hemangioma. clinicaltrials.gov/ct2/show/NCT01072045 (accessed 23 April 2010).
Pandey 2010 {published data only}
    1. Pandey A, Gangopadhyay AN, Sharma SP, Kumar V, Gupta DK, Gopal SC. Evaluation of topical steroids in the treatment of superficial hemangioma. SKINmed 2010;8(1):9‐11. [CENTRAL: CN‐00760496] - PubMed

References to ongoing studies

NCT01147601 {published data only}
    1. NCT01147601. Topical Timolol 0.5% solution for proliferating infantile haemangiomas. clinicaltrials.gov/ct2/show/NCT01147601?term=NCT01147601 (accessed 25 March 2011).
NCT02913612 {published data only}
    1. NCT02913612. Efficacy, Safety and Pharmacokinetics of Topical Timolol in Infants With Infantile Hemangioma (IH) (TIM01). clinicaltrials.gov/ct2/show/NCT02913612 Date first received: 12 August 2016.

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