Interventions for infantile haemangiomas of the skin

Monica Novoa; Eulalia Baselga; Sandra Beltran; Lucia Giraldo; Ali Shahbaz; Hector Pardo‐Hernandez; Ingrid Arevalo‐Rodriguez

doi:10.1002/14651858.CD006545.pub3

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Figure 1

Study flow diagram.

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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.

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Figure 3

'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included study.

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Analysis 1.1

Comparison 1 Pulsed dye laser versus wait‐and‐see, Outcome 1 Clearance.

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Analysis 1.2

Comparison 1 Pulsed dye laser versus wait‐and‐see, Outcome 2 Adverse events: skin atrophy.

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Analysis 1.3

Comparison 1 Pulsed dye laser versus wait‐and‐see, Outcome 3 Adverse events: skin hypopigmentation.

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Analysis 1.4

Comparison 1 Pulsed dye laser versus wait‐and‐see, Outcome 4 Adverse events: minimal crusting.

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Analysis 1.5

Comparison 1 Pulsed dye laser versus wait‐and‐see, Outcome 5 Adverse events: pain.

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Analysis 1.6

Comparison 1 Pulsed dye laser versus wait‐and‐see, Outcome 6 Other measures of resolution: no redness.

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Analysis 1.7

Comparison 1 Pulsed dye laser versus wait‐and‐see, Outcome 7 Parents who consider that their child still has a problem.

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Analysis 1.8

Comparison 1 Pulsed dye laser versus wait‐and‐see, Outcome 8 Aesthetic appearance: better cosmetic outcome.

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Analysis 1.9

Comparison 1 Pulsed dye laser versus wait‐and‐see, Outcome 9 Requirement for surgical correction.

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Analysis 2.1

Comparison 2 Oral propranolol versus placebo, Outcome 1 Clearance, as assessed by a clinician.

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Analysis 2.2

Comparison 2 Oral propranolol versus placebo, Outcome 2 Serious adverse events.

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Analysis 2.3

Comparison 2 Oral propranolol versus placebo, Outcome 3 Serious cardiovascular adverse events.

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Analysis 2.4

Comparison 2 Oral propranolol versus placebo, Outcome 4 Other adverse events.

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Analysis 2.5

Comparison 2 Oral propranolol versus placebo, Outcome 5 Other measures of resolution: change in volume.

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Analysis 2.6

Comparison 2 Oral propranolol versus placebo, Outcome 6 Other measures of resolution: no improvement in redness.

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Analysis 3.1

Comparison 3 Topical timolol maleate versus placebo, Outcome 1 Other measures of resolution (6 months).

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Analysis 4.1

Comparison 4 Topical bleomycin versus placebo, Outcome 1 Other measures of resolution: reduction in size at day 7.

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Analysis 5.1

Comparison 5 X‐ray radiation versus sham radiation, Outcome 1 Clearance.

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Analysis 6.1

Comparison 6 Topical timolol maleate versus Nd:YAG laser, Outcome 1 Other measures of resolution (continuous).

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Analysis 6.2

Comparison 6 Topical timolol maleate versus Nd:YAG laser, Outcome 2 Other measures of resolution (dichotomous).

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Analysis 7.1

Comparison 7 Nd:YAG laser versus oral propranolol, Outcome 1 Clearance.

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Analysis 7.2

Comparison 7 Nd:YAG laser versus oral propranolol, Outcome 2 Adverse events: hyperpigmentation.

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Analysis 7.3

Comparison 7 Nd:YAG laser versus oral propranolol, Outcome 3 Adverse event: pigmentation and thinning.

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Analysis 7.4

Comparison 7 Nd:YAG laser versus oral propranolol, Outcome 4 Adverse events: superficial scar.

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Analysis 7.5

Comparison 7 Nd:YAG laser versus oral propranolol, Outcome 5 Other measures of resolution: excellent response.

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Analysis 8.1

Comparison 8 Pulsed dye laser + topical propranolol versus pulsed dye laser, Outcome 1 Clearance, as assessed by a clinician.

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Analysis 9.1

Comparison 9 Pulsed dye laser + topical timolol maleate versus pulsed dye laser, Outcome 1 Clearance.

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Analysis 9.2

Comparison 9 Pulsed dye laser + topical timolol maleate versus pulsed dye laser, Outcome 2 Other measures of resolution: mean size reduction.

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Analysis 10.1

Comparison 10 Nd:YAG laser + oral propranolol versus Nd:YAG laser, Outcome 1 Clearance.

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Analysis 10.2

Comparison 10 Nd:YAG laser + oral propranolol versus Nd:YAG laser, Outcome 2 Adverse events: hyperpigmentation.

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Analysis 10.3

Comparison 10 Nd:YAG laser + oral propranolol versus Nd:YAG laser, Outcome 3 Adverse events: pigmentation and thinning.

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Analysis 10.4

Comparison 10 Nd:YAG laser + oral propranolol versus Nd:YAG laser, Outcome 4 Adverse events: superficial scar.

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Analysis 10.5

Comparison 10 Nd:YAG laser + oral propranolol versus Nd:YAG laser, Outcome 5 Other measures of resolution: excellent response.

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Analysis 11.1

Comparison 11 Nd:YAG laser + oral propranolol versus oral propranolol, Outcome 1 Clearance.

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Analysis 11.2

Comparison 11 Nd:YAG laser + oral propranolol versus oral propranolol, Outcome 2 Adverse events: hyperpigmentation.

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Analysis 11.3

Comparison 11 Nd:YAG laser + oral propranolol versus oral propranolol, Outcome 3 Adverse events: pigmentation and thinning.

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Analysis 11.4

Comparison 11 Nd:YAG laser + oral propranolol versus oral propranolol, Outcome 4 Adverse events: superficial scar.

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Analysis 11.5

Comparison 11 Nd:YAG laser + oral propranolol versus oral propranolol, Outcome 5 Other measures of resolution: excellent response.

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Analysis 12.1

Comparison 12 ⁹⁰SR‐⁹⁰Y radiation + topical timolol maleate versus ⁹⁰SR‐⁹⁰Y radiation, Outcome 1 Clearance.

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Analysis 12.2

Comparison 12 ⁹⁰SR‐⁹⁰Y radiation + topical timolol maleate versus ⁹⁰SR‐⁹⁰Y radiation, Outcome 2 Adverse events.

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Analysis 13.1

Comparison 13 Sequential dual‐wavelength laser + oral propranolol versus concurrent dual‐wavelength laser + oral propranolol, Outcome 1 Other outcomes of resolution: mean efficacy rating.

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Analysis 14.1

Comparison 14 Oral propranolol versus topical propranolol, Outcome 1 Clearance.

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Analysis 14.2

Comparison 14 Oral propranolol versus topical propranolol, Outcome 2 Adverse events: syncopal attack.

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Analysis 15.1

Comparison 15 Oral propranolol versus intralesional propranolol, Outcome 1 Clearance.

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Analysis 15.2

Comparison 15 Oral propranolol versus intralesional propranolol, Outcome 2 Adverse events: syncopal attack.

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Analysis 16.1

Comparison 16 Topical propranolol versus intralesional propranolol, Outcome 1 Clearance.

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Analysis 17.1

Comparison 17 Oral atenolol versus oral propranolol, Outcome 1 Clearance.

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Analysis 18.1

Comparison 18 Oral propranolol versus oral prednisolone, Outcome 1 Severe adverse events.

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Analysis 18.2

Comparison 18 Oral propranolol versus oral prednisolone, Outcome 2 Adverse events: complications in general.

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Analysis 18.3

Comparison 18 Oral propranolol versus oral prednisolone, Outcome 3 Other measures of resolution: colour fading.

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Analysis 18.4

Comparison 18 Oral propranolol versus oral prednisolone, Outcome 4 Other measures of resolution: mean size reduction.

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Analysis 18.5

Comparison 18 Oral propranolol versus oral prednisolone, Outcome 5 Other measures of resolution: proportional change in the total surface area.

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Analysis 19.1

Comparison 19 Oral propranolol versus oral captopril, Outcome 1 Clearance.

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Analysis 19.2

Comparison 19 Oral propranolol versus oral captopril, Outcome 2 Adverse events: cardiac side effects.

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Analysis 20.1

Comparison 20 Oral propranolol versus topical timolol maleate, Outcome 1 Adverse events.

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Analysis 20.2

Comparison 20 Oral propranolol versus topical timolol maleate, Outcome 2 Other measures of resolution: size reduction > 50%.

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Analysis 21.1

Comparison 21 Oral propranolol versus oral propranolol + oral prednisolone, Outcome 1 Adverse events in general.

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Analysis 21.2

Comparison 21 Oral propranolol versus oral propranolol + oral prednisolone, Outcome 2 Other measures of resolution: mean size reduction.

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Analysis 21.3

Comparison 21 Oral propranolol versus oral propranolol + oral prednisolone, Outcome 3 Other measures of resolution: decrease in redness.

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Analysis 22.1

Comparison 22 Oral propranolol versus oral ibuprofen + oral paracetamol, Outcome 1 Clearance.

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Analysis 22.2

Comparison 22 Oral propranolol versus oral ibuprofen + oral paracetamol, Outcome 2 Adverse events.

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Analysis 22.3

Comparison 22 Oral propranolol versus oral ibuprofen + oral paracetamol, Outcome 3 Other measures of resolution: mean size of ulceration.

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Analysis 23.1

Comparison 23 Oral propranolol + topical timolol maleate versus oral propranolol, Outcome 1 Adverse events in general.

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Analysis 23.2

Comparison 23 Oral propranolol + topical timolol maleate versus oral propranolol, Outcome 2 Other measures of resolution: colour fading/visual analogue scale score.

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Analysis 23.3

Comparison 23 Oral propranolol + topical timolol maleate versus oral propranolol, Outcome 3 Other measures of resolution: size reduction/visual analogue scale score.

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Analysis 23.4

Comparison 23 Oral propranolol + topical timolol maleate versus oral propranolol, Outcome 4 Other measures of resolution: size reduction > 50%.

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Analysis 24.1

Comparison 24 Oral propranolol + topical timolol maleate versus topical timolol maleate, Outcome 1 Adverse events.

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Analysis 24.2

Comparison 24 Oral propranolol + topical timolol maleate versus topical timolol maleate, Outcome 2 Other measures of resolution: size reduction > 50%.

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Analysis 25.1

Comparison 25 Oral prednisolone versus oral prednisolone + oral propranolol, Outcome 1 Adverse events: complications.

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Analysis 25.2

Comparison 25 Oral prednisolone versus oral prednisolone + oral propranolol, Outcome 2 Other measures of resolution: colour fading.

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Analysis 25.3

Comparison 25 Oral prednisolone versus oral prednisolone + oral propranolol, Outcome 3 Other measures of resolution: mean size reduction.

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Analysis 26.1

Comparison 26 Intralesional methylene blue versus intralesional triamcinolone, Outcome 1 Clearance.

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Analysis 27.1

Comparison 27 Oral prednisolone versus intravenous methylprednisolone, Outcome 1 Other measures of resolution: haemangioma size.

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Analysis 28.1

Comparison 28 HIFU 3.5 W versus HIFU 4.5 W, Outcome 1 Clearance.

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Analysis 28.2

Comparison 28 HIFU 3.5 W versus HIFU 4.5 W, Outcome 2 Adverse events: ulceration or scars.

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Analysis 29.1

Comparison 29 HIFU 3.5 W versus HIFU 4.0 W, Outcome 1 Clearance.

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Analysis 29.2

Comparison 29 HIFU 3.5 W versus HIFU 4.0 W, Outcome 2 Adverse events: ulceration or scars.

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Analysis 30.1

Comparison 30 HIFU 4.0 W versus HIFU 4.5 W, Outcome 1 Clearance.

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Analysis 30.2

Comparison 30 HIFU 4.0 W versus HIFU 4.5 W, Outcome 2 Adverse events: ulceration or scars.

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Summary of findings for the main comparison. Oral propranolol compared to placebo for infantile haemangiomas of the skin

Oral propranolol compared to placebo for infantile haemangiomas (strawberry birthmarks) of the skin
Patient or population: infantile haemangiomas (strawberry birthmarks) of the skin Setting: all settings (outpatient care) Intervention: oral propranolol Comparison: placebo
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Risk with placebo	Risk with oral propranolol	Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
Clearance, as assessed by a clinician at any follow‐up ‐ 3 mg/kg/day 24 weeks' follow‐up	36 per 1000	604 per 1000 (153 to 1000)	RR 16.61 (4.22 to 65.34)	156 (1 RCT)	⊕⊕⊝⊝ MODERATE¹
A subjective measure of improvement, as assessed by the parent or child, at any follow‐up ‐ not reported	See comment	See comment	Not estimable	‐	See comment	We did not identify any studies reporting this outcome.
Adverse events experienced at short or long term ‐ Serious adverse events 24 weeks' follow‐up	37 per 1000	38 per 1000 (12 to 124)	RR 1.05 (0.33 to 3.39)	509 (3 RCTs)	⊕⊝⊝⊝ LOW²
Other measures of resolution, as assessed by a clinician, at any follow‐up ‐ percentage change in mean haemangioma volume at 24 weeks	Mean: ‐14.1% (SD not reported)	Mean: ‐60% (SD not reported)	MD 45.9% lower (80.2% lower to 11.6% lower)	40 (1 RCT)	⊕⊕⊕⊝ MODERATE³	Mean difference was reported by the study authors, but no SDs were reported for group means.
Proportion of parents who consider their child still has a problem, at any follow‐up ‐ not reported	See comment	See comment	Not estimable	‐	See comment	We did not identify any studies reporting this outcome.
Proportion of children who consider they still have a problem, at any follow‐up ‐ not reported	See comment	See comment	Not estimable	‐	See comment	We did not identify any studies reporting this outcome.
Aesthetic appearance as assessed by physician, child, or parent, at any follow‐up ‐ not reported	See comment	See comment	Not estimable	‐	See comment	We did not identify any studies reporting this outcome.
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group (the event rate in the single study or the mean event rate in the meta‐analysis) and the relative effect of the intervention (and its 95% CI). CI: confidence interval; MD: mean difference; RCT: randomised controlled trial; RR: risk ratio; SD: standard deviation
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low quality: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low quality: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
¹Downgraded by one level for imprecision (wide confidence interval around the estimate of the effect). ²Downgraded by two levels for imprecision (wide confidence interval around the estimate of the effect and low number of events). ³Downgraded by one level for risk of bias.

Summary of findings for the main comparison. Oral propranolol compared to placebo for infantile haemangiomas of the skin

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Summary of findings 2. Topical timolol compared to placebo for infantile haemangiomas of the skin

Topical timolol maleate compared to placebo for infantile haemangiomas (strawberry birthmarks) of the skin
Patient or population: infantile haemangiomas (strawberry birthmarks) of the skin Setting: all settings (outpatient care) Intervention: topical timolol maleate Comparison: placebo
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Risk with placebo	Risk with topical timolol maleate	Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
Clearance, as assessed by a clinician at any follow‐up ‐ not reported	See comment	See comment	Not estimable	‐	See comment	We did not identify any studies reporting this outcome.
A subjective measure of improvement, as assessed by the parent or child, at any follow‐up ‐ not reported	See comment	See comment	Not estimable	‐	See comment	We did not identify any studies reporting this outcome.
Adverse events experienced at short or long term ‐ Serious cardiovascular adverse events ‐ bradycardia 24 weeks' follow‐up	See comment	See comment	Not estimable	41 (1 RCT)	⊕⊕⊝⊝ LOW¹	No events of bradycardia reported in Chan 2013.
Other measures of resolution, as assessed by a clinician, at any follow‐up ‐ no redness	45 per 1000	369 per 1000 (50 to 1000)	RR 8.11 (1.09 to 60.09)	41 (1 RCT)	⊕⊕⊝⊝ LOW²
Proportion of parents who consider their child still has a problem, at any follow‐up ‐ not reported	See comment	See comment	Not estimable	‐	See comment	We did not identify any studies reporting this outcome.
Proportion of children who consider they still have a problem, at any follow‐up ‐ not reported	See comment	See comment	Not estimable	‐	See comment	We did not identify any studies reporting this outcome.
Aesthetic appearance as assessed by physician, child, or parent, at any follow‐up ‐ not reported	See comment	See comment	Not estimable	‐	See comment	We did not identify any studies reporting this outcome.
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group (the event rate in the single study) and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low quality: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low quality: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
¹Downgraded by two levels for imprecision (low number of participants and events). ²Downgraded by two levels for imprecision (wide confidence interval around the estimate of the effect and low number of participants and events).

Summary of findings 2. Topical timolol compared to placebo for infantile haemangiomas of the skin

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Summary of findings 3. Oral propranolol compared to topical timolol for infantile haemangiomas of the skin

Oral propranolol compared to topical timolol maleate for infantile haemangiomas (strawberry birthmarks) of the skin
Patient or population: infantile haemangiomas (strawberry birthmarks) of the skin Setting: all settings (outpatient care) Intervention: oral propranolol Comparison: topical timolol maleate
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Risk with topical timolol maleate	Risk with oral propranolol	Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
Clearance, as assessed by a clinician at any follow‐up ‐ not reported	See comment	See comment	Not estimable	‐	See comment	We did not identify any studies reporting this outcome.
A subjective measure of improvement, as assessed by the parent or child, at any follow‐up ‐ not reported	See comment	See comment	Not estimable	‐	See comment	We did not identify any studies reporting this outcome.
Adverse events experienced at short or long term ‐ general adverse events 24 weeks' follow‐up	See comment	See comment	RR 7.00 (0.40 to 123.35)	26 (1 RCT)	⊕⊝⊝⊝ VERY LOW¹	There were 3 events in the oral propranolol group and no events in the topical timolol maleate group. Due to no events in the control group, absolute events could not be calculated.
Other measures of resolution, as assessed by a clinician, at any follow‐up ‐ size reduction ≥ 50% 24 weeks' follow up	615 per 1000	695 per 1000 (394 to 1000)	RR 1.13 (0.64 to 1.97)	26 (1 RCT)	⊕⊕⊝⊝ LOW²
Proportion of parents who consider their child still has a problem, at any follow‐up ‐ not reported	See comment	See comment	Not estimable	‐	See comment	We did not identify any studies reporting this outcome.
Proportion of children who consider they still have a problem, at any follow‐up ‐ not reported	See comment	See comment	Not estimable	‐	See comment	We did not identify any studies reporting this outcome.
Aesthetic appearance as assessed by physician, child, or parent, at any follow‐up ‐ not reported	See comment	See comment	Not estimable	‐	See comment	We did not identify any studies reporting this outcome.
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group (the event rate in the single study) and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low quality: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low quality: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
¹Downgraded by three levels: one level due to unclear risk of selection and performance bias and two levels for imprecision (wide confidence interval around the estimate of the effect and low number of participants and events). ²Downgraded by two levels: one level due to unclear risk of selection and performance bias and one level for imprecision (small sample size).

Summary of findings 3. Oral propranolol compared to topical timolol for infantile haemangiomas of the skin

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Comparison 1. Pulsed dye laser versus wait‐and‐see

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clearance Show forest plot	1	121	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.62, 1.42]

2 Adverse events: skin atrophy Show forest plot	1	121	Risk Ratio (M‐H, Random, 95% CI)	3.46 [1.36, 8.77]

3 Adverse events: skin hypopigmentation Show forest plot	1	121	Risk Ratio (M‐H, Random, 95% CI)	3.05 [1.57, 5.93]

4 Adverse events: minimal crusting Show forest plot	1	22	Risk Ratio (M‐H, Random, 95% CI)	5.0 [0.27, 93.55]

5 Adverse events: pain Show forest plot	1	22	Risk Ratio (M‐H, Random, 95% CI)	5.0 [0.27, 93.55]

6 Other measures of resolution: no redness Show forest plot	1	121	Risk Ratio (M‐H, Random, 95% CI)	4.83 [1.75, 13.36]

7 Parents who consider that their child still has a problem Show forest plot	1	121	Risk Ratio (M‐H, Random, 95% CI)	1.24 [0.56, 2.78]

8 Aesthetic appearance: better cosmetic outcome Show forest plot	1	22	Risk Ratio (M‐H, Random, 95% CI)	1.75 [0.71, 4.31]

9 Requirement for surgical correction Show forest plot	1	121	Risk Ratio (M‐H, Random, 95% CI)	2.37 [0.64, 8.75]

Comparison 1. Pulsed dye laser versus wait‐and‐see

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Comparison 2. Oral propranolol versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clearance, as assessed by a clinician Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 At 1 mg/kg/day	1	157	Risk Ratio (M‐H, Random, 95% CI)	13.48 [3.41, 53.30]
1.2 At 3 mg/kg/day	1	156	Risk Ratio (M‐H, Random, 95% CI)	16.61 [4.22, 65.34]
2 Serious adverse events Show forest plot	3	509	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.33, 3.39]

3 Serious cardiovascular adverse events Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3.1 Bradycardia	3	509	Risk Ratio (M‐H, Random, 95% CI)	0.70 [0.03, 14.32]
3.2 Hypotension	3	509	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.10, 6.71]
4 Other adverse events Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

4.1 Bronchospasm	1	456	Risk Ratio (M‐H, Random, 95% CI)	0.41 [0.04, 3.89]
4.2 Bronchitis	1	456	Risk Ratio (M‐H, Random, 95% CI)	5.62 [0.79, 40.07]
4.3 Bronchiolitis	1	456	Risk Ratio (M‐H, Random, 95% CI)	1.33 [0.42, 4.21]
4.4 Hypoglycaemia	1	456	Risk Ratio (M‐H, Random, 95% CI)	0.70 [0.03, 14.32]
4.5 Sleep disturbance	2	495	Risk Ratio (M‐H, Random, 95% CI)	1.54 [0.79, 3.00]
5 Other measures of resolution: change in volume Show forest plot	1		Mean Difference (Random, 95% CI)	‐45.9 [‐80.20, ‐11.60]

6 Other measures of resolution: no improvement in redness Show forest plot	1	40	Risk Ratio (M‐H, Random, 95% CI)	9.00 [0.52, 156.91]

Comparison 2. Oral propranolol versus placebo

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Comparison 3. Topical timolol maleate versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Other measures of resolution (6 months) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 No redness	1	41	Risk Ratio (M‐H, Random, 95% CI)	8.11 [1.09, 60.09]
1.2 IH volume reduction of ≥ 5%	1	41	Risk Ratio (M‐H, Random, 95% CI)	5.21 [1.28, 21.21]

Comparison 3. Topical timolol maleate versus placebo

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Comparison 4. Topical bleomycin versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Other measures of resolution: reduction in size at day 7 Show forest plot	1	30	Risk Ratio (M‐H, Random, 95% CI)	21.0 [1.34, 328.86]

Comparison 4. Topical bleomycin versus placebo

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Comparison 5. X‐ray radiation versus sham radiation

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clearance Show forest plot	1	100	Risk Ratio (M‐H, Random, 95% CI)	1.08 [0.63, 1.87]

Comparison 5. X‐ray radiation versus sham radiation

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Comparison 6. Topical timolol maleate versus Nd:YAG laser

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Other measures of resolution (continuous) Show forest plot	1	60	Mean Difference (IV, Random, 95% CI)	‐0.91 [‐1.27, ‐0.55]

1.1 Haemoglobin level (redness)	1	60	Mean Difference (IV, Random, 95% CI)	‐0.91 [‐1.27, ‐0.55]
2 Other measures of resolution (dichotomous) Show forest plot	1	60	Risk Ratio (M‐H, Random, 95% CI)	3.0 [0.90, 10.01]

2.1 Excellent improvement	1	60	Risk Ratio (M‐H, Random, 95% CI)	3.0 [0.90, 10.01]

Comparison 6. Topical timolol maleate versus Nd:YAG laser

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Comparison 7. Nd:YAG laser versus oral propranolol

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clearance Show forest plot	1	65	Risk Ratio (M‐H, Random, 95% CI)	2.57 [0.28, 23.44]

2 Adverse events: hyperpigmentation Show forest plot	1	65	Risk Ratio (M‐H, Random, 95% CI)	2.57 [0.28, 23.44]

3 Adverse event: pigmentation and thinning Show forest plot	1	40	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.11, 1.05]

4 Adverse events: superficial scar Show forest plot	2	105	Risk Ratio (M‐H, Random, 95% CI)	1.52 [0.24, 9.58]

5 Other measures of resolution: excellent response Show forest plot	1	40	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.08, 1.46]

Comparison 7. Nd:YAG laser versus oral propranolol

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Comparison 8. Pulsed dye laser + topical propranolol versus pulsed dye laser

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clearance, as assessed by a clinician Show forest plot	1	19	Risk Ratio (M‐H, Random, 95% CI)	2.25 [0.57, 8.86]

Comparison 8. Pulsed dye laser + topical propranolol versus pulsed dye laser

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Comparison 9. Pulsed dye laser + topical timolol maleate versus pulsed dye laser

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clearance Show forest plot	1	32	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.07, 14.64]

2 Other measures of resolution: mean size reduction Show forest plot	1	32	Mean Difference (IV, Random, 95% CI)	5.62 [1.21, 10.03]

Comparison 9. Pulsed dye laser + topical timolol maleate versus pulsed dye laser

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Comparison 10. Nd:YAG laser + oral propranolol versus Nd:YAG laser

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clearance Show forest plot	1	67	Risk Ratio (M‐H, Random, 95% CI)	3.28 [0.97, 11.06]

2 Adverse events: hyperpigmentation Show forest plot	1	67	Risk Ratio (M‐H, Random, 95% CI)	1.46 [0.35, 6.02]

3 Adverse events: pigmentation and thinning Show forest plot	1	40	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.12, 3.57]

4 Adverse events: superficial scar Show forest plot	2	107	Risk Ratio (M‐H, Random, 95% CI)	0.37 [0.09, 1.48]

5 Other measures of resolution: excellent response Show forest plot	1	40	Risk Ratio (M‐H, Random, 95% CI)	8.5 [2.25, 32.06]

Comparison 10. Nd:YAG laser + oral propranolol versus Nd:YAG laser

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Comparison 11. Nd:YAG laser + oral propranolol versus oral propranolol

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clearance Show forest plot	1	62	Risk Ratio (M‐H, Random, 95% CI)	8.44 [1.14, 62.66]

2 Adverse events: hyperpigmentation Show forest plot	1	62	Risk Ratio (M‐H, Random, 95% CI)	3.75 [0.44, 31.68]

3 Adverse events: pigmentation and thinning Show forest plot	1	40	Risk Ratio (M‐H, Random, 95% CI)	0.22 [0.05, 0.90]

4 Adverse events: superficial scar Show forest plot	2	102	Risk Ratio (M‐H, Random, 95% CI)	0.60 [0.05, 7.63]

5 Other measures of resolution: excellent response Show forest plot	1	40	Risk Ratio (M‐H, Random, 95% CI)	2.83 [1.42, 5.67]

Comparison 11. Nd:YAG laser + oral propranolol versus oral propranolol

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Comparison 12. ⁹⁰SR‐⁹⁰Y radiation + topical timolol maleate versus ⁹⁰SR‐⁹⁰Y radiation

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clearance Show forest plot	1	72	Risk Ratio (M‐H, Random, 95% CI)	1.42 [1.07, 1.87]

2 Adverse events Show forest plot	1	72	Risk Ratio (M‐H, Random, 95% CI)	1.14 [0.56, 2.29]

Comparison 12. ⁹⁰SR‐⁹⁰Y radiation + topical timolol maleate versus ⁹⁰SR‐⁹⁰Y radiation

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Comparison 13. Sequential dual‐wavelength laser + oral propranolol versus concurrent dual‐wavelength laser + oral propranolol

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Other outcomes of resolution: mean efficacy rating Show forest plot	1	61	Mean Difference (IV, Random, 95% CI)	‐0.77 [‐1.16, ‐0.38]

Comparison 13. Sequential dual‐wavelength laser + oral propranolol versus concurrent dual‐wavelength laser + oral propranolol

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Comparison 14. Oral propranolol versus topical propranolol

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clearance Show forest plot	1	30	Risk Ratio (M‐H, Random, 95% CI)	3.0 [1.01, 8.95]

2 Adverse events: syncopal attack Show forest plot	1	30	Risk Ratio (M‐H, Random, 95% CI)	7.0 [0.39, 124.83]

Comparison 14. Oral propranolol versus topical propranolol

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Comparison 15. Oral propranolol versus intralesional propranolol

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clearance Show forest plot	1	30	Risk Ratio (M‐H, Random, 95% CI)	4.5 [1.16, 17.44]

2 Adverse events: syncopal attack Show forest plot	1	30	Risk Ratio (M‐H, Random, 95% CI)	7.0 [0.39, 124.83]

Comparison 15. Oral propranolol versus intralesional propranolol

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Comparison 16. Topical propranolol versus intralesional propranolol

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clearance Show forest plot	1	30	Risk Ratio (M‐H, Random, 95% CI)	1.5 [0.29, 7.73]

Comparison 16. Topical propranolol versus intralesional propranolol

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Comparison 17. Oral atenolol versus oral propranolol

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clearance Show forest plot	1	23	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.55, 2.27]

Comparison 17. Oral atenolol versus oral propranolol

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Comparison 18. Oral propranolol versus oral prednisolone

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Severe adverse events Show forest plot	1	19	Risk Ratio (M‐H, Random, 95% CI)	0.15 [0.02, 1.02]

2 Adverse events: complications in general Show forest plot	1	20	Risk Ratio (M‐H, Random, 95% CI)	0.22 [0.06, 0.78]

3 Other measures of resolution: colour fading Show forest plot	1	20	Mean Difference (IV, Random, 95% CI)	‐1.0 [‐3.08, 1.08]

4 Other measures of resolution: mean size reduction Show forest plot	1	20	Mean Difference (IV, Random, 95% CI)	23.20 [‐3.36, 49.76]

5 Other measures of resolution: proportional change in the total surface area Show forest plot	1	19	Mean Difference (IV, Random, 95% CI)	0.23 [‐0.08, 0.54]

Comparison 18. Oral propranolol versus oral prednisolone

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Comparison 19. Oral propranolol versus oral captopril

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clearance Show forest plot	1	30	Risk Ratio (M‐H, Random, 95% CI)	15.0 [0.93, 241.20]

2 Adverse events: cardiac side effects Show forest plot	1	30	Risk Ratio (M‐H, Random, 95% CI)	0.11 [0.01, 1.90]

Comparison 19. Oral propranolol versus oral captopril

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Comparison 20. Oral propranolol versus topical timolol maleate

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Adverse events Show forest plot	1	26	Risk Ratio (M‐H, Random, 95% CI)	7.0 [0.40, 123.35]

2 Other measures of resolution: size reduction > 50% Show forest plot	1	26	Risk Ratio (M‐H, Random, 95% CI)	1.13 [0.64, 1.97]

Comparison 20. Oral propranolol versus topical timolol maleate

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Comparison 21. Oral propranolol versus oral propranolol + oral prednisolone

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Adverse events in general Show forest plot	2	60	Risk Ratio (M‐H, Random, 95% CI)	0.30 [0.10, 0.91]

2 Other measures of resolution: mean size reduction Show forest plot	1	20	Mean Difference (IV, Random, 95% CI)	7.20 [‐1.87, 16.27]

3 Other measures of resolution: decrease in redness Show forest plot	1	40	Risk Ratio (M‐H, Random, 95% CI)	0.77 [0.45, 1.32]

Comparison 21. Oral propranolol versus oral propranolol + oral prednisolone

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Comparison 22. Oral propranolol versus oral ibuprofen + oral paracetamol

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clearance Show forest plot	1	64	Risk Ratio (M‐H, Random, 95% CI)	2.67 [0.78, 9.15]

2 Adverse events Show forest plot	1	64	Risk Ratio (M‐H, Random, 95% CI)	7.0 [0.38, 130.26]

3 Other measures of resolution: mean size of ulceration Show forest plot	1	64	Mean Difference (IV, Random, 95% CI)	0.31 [0.01, 0.61]

Comparison 22. Oral propranolol versus oral ibuprofen + oral paracetamol

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Comparison 23. Oral propranolol + topical timolol maleate versus oral propranolol

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Adverse events in general Show forest plot	1	26	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.04, 2.80]

2 Other measures of resolution: colour fading/visual analogue scale score Show forest plot	1	31	Mean Difference (IV, Random, 95% CI)	1.18 [0.09, 2.27]

3 Other measures of resolution: size reduction/visual analogue scale score Show forest plot	1	31	Mean Difference (IV, Random, 95% CI)	0.41 [‐0.84, 1.66]

4 Other measures of resolution: size reduction > 50% Show forest plot	1	26	Risk Ratio (M‐H, Random, 95% CI)	1.22 [0.79, 1.88]

Comparison 23. Oral propranolol + topical timolol maleate versus oral propranolol

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Comparison 24. Oral propranolol + topical timolol maleate versus topical timolol maleate

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Adverse events Show forest plot	1	26	Risk Ratio (M‐H, Random, 95% CI)	3.0 [0.13, 67.51]

2 Other measures of resolution: size reduction > 50% Show forest plot	1	26	Risk Ratio (M‐H, Random, 95% CI)	1.38 [0.84, 2.24]

Comparison 24. Oral propranolol + topical timolol maleate versus topical timolol maleate

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Comparison 25. Oral prednisolone versus oral prednisolone + oral propranolol

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Adverse events: complications Show forest plot	1	20	Risk Ratio (M‐H, Random, 95% CI)	1.29 [0.82, 2.03]

2 Other measures of resolution: colour fading Show forest plot	1	20	Mean Difference (IV, Random, 95% CI)	1.0 [‐1.02, 3.02]

3 Other measures of resolution: mean size reduction Show forest plot	1	20	Mean Difference (IV, Random, 95% CI)	‐16.0 [‐42.58, 10.58]

Comparison 25. Oral prednisolone versus oral prednisolone + oral propranolol

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Comparison 26. Intralesional methylene blue versus intralesional triamcinolone

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clearance Show forest plot	1	268	Risk Ratio (M‐H, Random, 95% CI)	2.36 [1.84, 3.02]

Comparison 26. Intralesional methylene blue versus intralesional triamcinolone

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Comparison 27. Oral prednisolone versus intravenous methylprednisolone

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Other measures of resolution: haemangioma size Show forest plot	1	20	Mean Difference (IV, Random, 95% CI)	51.5 [21.49, 81.51]

Comparison 27. Oral prednisolone versus intravenous methylprednisolone

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Comparison 28. HIFU 3.5 W versus HIFU 4.5 W

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clearance Show forest plot	1	40	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.39, 1.95]

2 Adverse events: ulceration or scars Show forest plot	1	40	Risk Ratio (M‐H, Random, 95% CI)	0.07 [0.00, 1.09]

Comparison 28. HIFU 3.5 W versus HIFU 4.5 W

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Comparison 29. HIFU 3.5 W versus HIFU 4.0 W

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clearance Show forest plot	1	40	Risk Ratio (M‐H, Random, 95% CI)	0.78 [0.36, 1.68]

2 Adverse events: ulceration or scars Show forest plot	1	40	Risk Ratio (M‐H, Random, 95% CI)	0.11 [0.01, 1.94]

Comparison 29. HIFU 3.5 W versus HIFU 4.0 W

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Comparison 30. HIFU 4.0 W versus HIFU 4.5 W

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clearance Show forest plot	1	40	Risk Ratio (M‐H, Random, 95% CI)	1.13 [0.55, 2.32]

2 Adverse events: ulceration or scars Show forest plot	1	40	Risk Ratio (M‐H, Random, 95% CI)	0.57 [0.20, 1.65]

Comparison 30. HIFU 4.0 W versus HIFU 4.5 W

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