Interventions for Infantile Haemangiomas of the Skin

Abridged Cochrane Systematic Review and Grade Assessments

M. Novoa; E. Baselga; S. Beltran; L. Giraldo; A. Shahbaz; H. Pardo-Hernandez ID; I. Arevalo-Rodriguez ID


The British Journal of Dermatology. 2019;180(3):527-533. 

In This Article


Our Cochrane systematic review identified 28 controlled trials with 1728 children enrolled and randomized.[1] In general, we found little evidence for a number of outcomes, especially patient-reported outcomes, such as subjective measure of improvement, proportion of children who consider they still have a problem, proportion of parents who consider their child still has a problem and aesthetic appearance. Furthermore, we included no trials assessing a large number of haemangioma treatments, such as excision, cryotherapy, imiquimod, vincristine or rapamycin, among others.

For this abridged report, we selected information for three important comparisons on the basis of current use. In brief, moderate-quality evidence showed that compared with placebo, propranolol 3 mg kg−1 daily probably improves clinician-assessed clearance at 24 weeks (based on 156 children, from one study) and probably leads to a clinician-assessed change in mean haemangioma volume at 24 weeks, as another measure of resolution (based on 40 children, from one study). We found no evidence of a difference in terms of short- or long-term severe adverse events between the two groups (based on 509 children, from three studies) or in terms of cardiovascular adverse events, bronchospasm or hypoglycaemia events (based on low-quality evidence). Regarding timolol maleate vs. placebo, low-quality evidence indicated that achieving clinician-confirmed reduction of redness at 24 weeks (used as a measure of resolution) may be increased with topical timolol maleate 0·5% gel applied twice daily, as opposed to placebo (based on 41 children, from one study). Regarding short- or long-term serious cardiovascular events, in both groups there were zero events of bradycardia and hypotension (based on low-quality evidence from 41 children in one study). No other safety data were assessed. In addition, when oral propranolol was compared with topical timolol maleate, there was no evidence of a difference between oral propranolol (via a tablet, at a daily dose of 1·0 mg kg−1) and topical timolol maleate (0·5% eye drops applied twice daily) in producing a ≥ 50% reduction in haemangioma size at 24 weeks (based on 26 children from one study; low-quality evidence). Regarding short- or long-term general adverse events, although there were more events in the oral propranolol group, such as severe diarrhoea, lethargy and loss of appetite, this result was based on a low number of events and very low-quality evidence; therefore, we are uncertain about the safety implications (based on 26 children from one study).

As a main strength of our review, we aimed to minimize potential biases during the development of this review. We followed the methodology for systematic reviews outlined in the Cochrane Handbook for Systematic Reviews of Interventions.[17] We feel that this review was comprehensive in identifying clinical trials addressing the issue of efficacy and safety of suggested interventions for the management of IH. However, we found that most of the included interventions were evaluated in single studies, precluding meta-analysis. Data were lacking for a number of outcomes, especially patient-relevant outcomes, such as reports of improvement by parents/children or aesthetic/cosmetic assessment, among others. Results for these outcomes could provide critical information about the patient/carer perspective on the benefits and harms of the proposed interventions for the treatment of this condition.

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 (via a tablet, at a daily dose of 1·0 mg kg−1) and topical timolol maleate (0·5% eye drops applied twice daily) 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. In addition, it is critical to conduct a comprehensive assessment of related harms, due to these interventions having well documented adverse events, including bradycardia, hypotension and hypoglycaemia.

Propranolol and timolol maleate require further assessment in randomized controlled trials 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.