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

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

Interventions for infantile haemangiomas of the skin

Monica Novoa ¹, Eulalia Baselga ², Sandra Beltran ¹, Lucia Giraldo ¹, Ali Shahbaz ³, Hector Pardo‐Hernandez ⁴, Ingrid Arevalo‐Rodriguez ^5,^6,^✉

Editor: Cochrane Skin Group

PMCID: PMC6513200 PMID: 29667726

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 placebo

Compared 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 placebo

The 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 maleate

When 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.

Plain language summary

Treatments for haemangiomas (a cluster of small blood vessels that form a lump) of the skin in children

What is the aim of this review?

This Cochrane Review aimed to assess the benefits and harms of treatments for haemangiomas of the skin in infants and children (known as 'infantile haemangiomas'). We collected and analysed 28 relevant clinical trials to answer this question.

Key messages

Only one of our key comparisons (propranolol versus placebo) measured clearance of the haemangioma, with moderate‐quality evidence supporting this result. We found low‐ or moderate‐quality evidence for the following specific measures of resolution: reduction in volume, redness, and size. We found very low‐ and low‐quality evidence for results concerning side effects, meaning we were unable to draw definitive conclusions about safety.

Oral propranolol is currently the standard treatment for this condition, and we did not find evidence to contest this treatment in terms of efficacy and safety. However, potential biases in the design of many of the included trials affect our confidence in the results of the review. High‐quality future research should assess the effects of propranolol and timolol maleate, as well as other new and older medications, on outcomes that are important to patients.

What was studied in the review?

Infantile haemangiomas are soft, raised swellings on the skin, often with a bright‐red surface caused by a non‐cancerous overgrowth of blood vessels in the skin. The majority of lesions are uncomplicated and will shrink on their own by age seven; however, some require treatment if they occur in high‐risk areas (e.g. near the eyes) or cause psychological distress.

We included all types of treatment for infantile haemangiomas, which could have been given alone or in combination, or compared to each other, to a 'placebo' (i.e. a treatment with no active agent), or against children whose haemangiomas were untreated but observed.

What are the main results of the review?

We included 28 studies, with a total of 1728 participants, which assessed lasers, beta blockers (e.g. propranolol), steroids, radiation therapy, and other treatments. Treatments were compared against an active monitoring approach (observation), placebo, sham radiation, or other interventions (given alone or in combination with another treatment). Studies were conducted in multiple countries; participant age ranged from 12 weeks to 13.4 years; and most studies included more girls than boys (23/28). Children had different types of haemangioma. Duration of follow‐up ranged from 7 days to 72 months.

The following results were measured 24 weeks after the beginning of treatment. All non‐safety outcomes presented here were clinician assessed (i.e. assessed by the physician in charge of a patient).

When compared with placebo treatment, propranolol taken by mouth at a dose of 3 mg/kg/day is probably more beneficial in terms of complete or almost‐complete clearance of swelling and reduction in volume of the haemangioma (moderate‐quality evidence). We found no evidence of a difference between the two treatments in terms of short‐ or long‐term serious or other side effects (low‐quality evidence). Most of the evidence for this comparison was based on an industry‐sponsored study.

Timolol maleate 0.5% gel applied topically twice daily may reduce redness as a measure of resolution when assessed against placebo (low‐quality evidence). Short‐ or long‐term serious cardiovascular events were not reported in either group. There were no other safety data for timolol maleate compared with placebo (low‐quality evidence). This comparison did not assess clearance of the swelling.

There was no evidence of a difference between propranolol taken by mouth (via a tablet once per day, at a 1.0 mg/kg dose) and topical timolol maleate (0.5% eye drops applied twice daily) in terms of their effect on reducing haemangioma size by 50% or more (low‐quality evidence). There were more general short‐ or long‐term side effects (such as severe diarrhoea, tiredness, and decreased appetite) with propranolol, but due to very low‐quality evidence, these results are uncertain. This comparison did not assess clearance of the swelling.

Most of the comparisons assessed, including those described above, did not report on the following outcomes: parent or child's opinion of improvement; the proportion of parents or children who consider there is still a problem; and cosmetic appearance.

How up‐to‐date is this review?

We searched for studies up to February 2017.

Summary of findings

Background

Please refer to the following website for definitions of technical terms: www.ncbi.nlm.nih.gov/mesh.

Description of the condition

Infantile haemangiomas (IH) are the most common vascular tumours among children, occurring in 3% to 10% of infants (Léauté‐Labrèze 2015). They were previously known as 'strawberry birthmarks' or 'strawberry naevi', or 'capillary haemangiomas', terms currently withdrawn by current classifications about vascular tumours (www.issva.org/classification). They are benign and of endothelial cellular origin, characterised by a rapid pattern of propagation in the first months of life, then followed by a period of involution that can take several years (Bruckner 2006). Sometimes the IH is characterised by a precursor lesion at birth. Infantile haemangiomas undergo a phase of rapid growth within the first few months of the first year (Baselga 2016; Wang 2017). Regression is completed in 60% of patients by their fourth birthday, 76% by their seventh birthday, and approximately 90% by their ninth birthday (Zimmermann 2010). However, it has been observed in some retrospective studies that the complete regression has been achieved at 3.5 years (Baselga 2016), and also at four years of follow‐up (Darrow 2015). While most lesions develop in a straightforward way, about 12% of cases result in clinically significant complications requiring referral (Leaute‐Labreze 2015). In addition, IH can result in lifelong sequelae, which can cause psychological distress (Léauté‐Labrèze 2015). More than 50% of untreated IH leave permanent sequelae that may cause disfigurement (Baselga 2016). Bauland and colleagues found residual lesions in 69% of 137 IH studied (Bauland 2011), and Baselga and colleagues in 54.9% out of 184 IH studied (Baselga 2016).

Infantile haemangiomas appear more commonly among Caucasians (understood to be white individuals), being evident in up to 12% of all children (Zimmermann 2010). Infantile haemangiomas affect females in a ratio of 3:1 (Zimmermann 2010). Sixty per cent of IH are located in the head and neck area, whereas 25% occur on the trunk and 15% on the extremities (Zimmermann 2010). Infantile haemangiomas can be divided by their morphology into superficial haemangiomas, subcutaneous (deep) haemangiomas, and mixed haemangiomas (www.issva.org/classification) (Sethuraman 2014). Superficial haemangiomas appear as a bright‐red vascular plaque with an irregular surface. Subcutaneous or deep haemangiomas present as protruding vascular swelling under normal or bluish skin. Mixed or combined haemangiomas show a combination of both superficial and deep characteristics. Infantile haemangiomas usually present as single lesions, although 20% of affected infants develop multiple tumours (van de Kerkhof 1998; Zimmermann 2010). The skin covering haemangiomas may become ulcerated, exposing the underlying blood vessels and making them more liable to bleed from minor trauma and become infected,

Infantile haemangiomas are not normally present at birth, or they are present only as a precursive mark, in the form of a pink macule, telangiectatic patches, or areas that appear bruised (Vega 2017). Infantile haemangiomas generally proliferate during the first year of life, with most growth being completed by age six to nine months. Eighty per cent of haemangioma growth is completed by age three months, and 80% of haemangiomas have completed growth by age five months (Tollefson 2012). Despite the self limiting nature of most IH, several complications have been observed, including bleeding, ulceration and infection, deformation and disfigurement, impairment of vision, and airway obstruction (Achauer 1997; Syed 1999). Children under the age of three are seldom aware of their haemangiomas. Most IH resolve spontaneously; however, when they cause complications, they can be dangerous or present a risk to a person's life.

The diagnosis of an IH is typically made clinically, based on its appearance and characteristic behaviour. When there is doubt in the diagnosis, additional studies such as Doppler ultrasound or skin biopsy may be performed (Holland 2013).

Studies have shown that blood vessel cells (positive for glucose transporter 1 (GLUT1)) in IH are similar to those found in the placenta (Ma 2017); this has raised the possibility that placental cells may become dislodged during pregnancy, travel into the foetus, and grow postnatally to form a haemangioma (Ma 2017). Some mechanisms have been studied in the pathogenesis of infantile haemangiomas such as tissue hypoxia and pathologic vasculogenesis leading to endothelial cell proliferation (Ma 2017). Predisposing factors have also been described in some studies, including low birth weight, advanced maternal age, multiple gestations, pre‐eclampsia, and gestational diabetes mellitus (Castren 2016). Infantile haemangiomas have also been more frequently noted in children whose mothers had chorionic villus sampling (CVS) compared with the general population (Kaplan 1990).

Management of IH can be challenging. Each option involves significant drawbacks or side effects, or both. Although most haemangiomas are self limited and do not need treatment, some indications for treatment include the following: high‐output cardiac failure, bleeding, ulceration, risk of permanent disfigurement, or airway or visual obstruction. Location, age of the patient, risk of complications, and growth rate are all factors that physicians must consider in managing patients with IH (Holland 2013).

Recently, Léauté‐Labrèze 2015 described their chance observation of an antiproliferative effect of propranolol (PR) on IH. Since the introduction of propranolol in 2008, this drug has showed a highly effective profile with tolerable adverse events, in comparison with previous recommended interventions used for IH (e.g. steroids, interferon, chemotherapy) (Zou 2013). Minimal or no side effects have been reported with propranolol, and the response rate has approached 100% (Léauté‐Labrèze 2015). Propranolol is now the first‐line treatment for IH and has been approved for this indication (Baselga 2016; Chinnadurai 2016a).

Description of the intervention

The diagnosis of an IH is typically made clinically, based on appearance and characteristic behaviour. When the diagnosis is uncertain, additional tests such as a Doppler ultrasound or skin biopsy may be performed (Holland 2013). The vast majority of infantile haemangiomas will regress on their own and require no further treatment; therefore, an active monitoring approach is usually implemented (Darrow 2015). However, IH can occur in high‐risk areas, such as near the eyes, throat, and nose, impairing their function. If vision is obscured at a critical stage in brain development, complications such as failure to develop binocular vision can result (Darrow 2015). A large variety of treatments have been used historically, and many are still in use.

Beta blockers, for example oral propranolol, are the current standard care, approved both by the US Food and Drug Administration and the European Medicines Agency, with complete regression without sequelae after six months of treatment in 60% of cases (Darrow 2015). Propranolol has also been assessed for intralesional and topical administration (Zaher 2013). The recommended dose of propranolol in oral administration is 3 mg/kg/day divided into two doses, for at least six months (Leaute‐Labreze 2015). Reported adverse effects include hypoglycaemia, bradycardia, hypotension, bronchospasm, sleep disturbance, and gastrointestinal disorders (Ji 2015). Propranolol interacts with other medications such as insulin, non‐steroidal anti‐inflammatories, antiarrhythmics, and calcium channel blockers (Holland 2013). In practice, when medication is warranted for infantile haemangioma, propranolol is the first‐choice drug. Parents and healthcare professionals must monitor infants closely for adverse effects (Leaute‐Labreze 2015).

In addition, topical timolol maleate, a non‐selective beta blocker, is available in a 0.25% and 0.5% solution, as well as an extended release 0.5% (5 mg/mL) gel‐forming solution. Frequency and method of application have varied from once daily under occlusion to twice daily without occlusion; 1 to 2 drops have typically been used and are usually given for 2 to 6 months (Zheng 2018). Adverse effects of timolol maleate in the paediatric population, especially in high‐risk premature infants, include bradycardia and bronchospasm (Holland 2013).

The following other treatments besides oral propranolol and topical timolol maleate have been assessed and might still be in use (Glassberg 1989).

Atenolol is a cardioselective beta blocker; it is a large, lipophobic molecule and has limited ability to cross the blood–brain barrier (Bayart 2017). Its use may sometimes be preferred if patients experience side effects with propranolol. Treatment with atenolol is recommended in an oral dose of 1 mg/kg/day for three to six months, depending on the positive response or the presence of adverse events such as bradycardia, hypotension, dizziness, and lethargy (Abarzua‐Araya 2014; Raphael 2011). Some interactions with other medicaments have been suggested, including verapamil, clonidine, and ibuprofen (Doshan 1986; Hansson 1975).
Bleomycin, a well‐known anticancer and sclerosing agent, has been used to treat haemangiomas (Luo 2011). Recommended dosage and duration of treatment depends on the age of the patient and the size of the lesion. Some clinicians have used a standard injection of bleomycin of 0.3 to 0.6 mg/kg per injection, and others have used a mixture of 5 mL 2% lidocaine, 5 mg dexamethasone, and 8 mg bleomycin A5 (Pienaar 2006). Some documented adverse events for this agent include oedema and ulceration (Luo 2011). No interactions with other drugs have been reported.
Captopril, an angiotensin‐converting enzyme inhibitor, has been suggested for potential use in the treatment of IH, due to its effects in inhibition of angiogenesis and vasculogenesis (Christou 2012). Dosage and duration of administration have not yet been standardised; Zaher and colleagues used oral captopril at 0.5 to 1 mg/kg/day, in a titrating dose, while Tan and colleagues used a dose of 0.1 to 0.5 mg/kg under response (Tan 2012; Zaher 2016). Cardiac side effects requiring dose reduction or suspension have been documented for its use in IH (Zaher 2016). Treatments known to have interactions with captopril include aliskiren, everolimus, sirolimus, and lithium (Medicines.ie 2018).
High‐intensity focused ultrasound (HIFU) is a non‐invasive surgical option with rapid evolvement in recent years that is mainly used in the management of solid tumours (Fu 2012). Documented side effects include damage in the focal point, endothelial cell loss, necrosis, and vascular discontinuity (Fu 2012). Different levels of energy have been used for different purposes, ranging from 2.6 to 4.5 W (Fu 2012). Lesions in the Fu 2012 studies were small‐ to medium‐sized (from 0.8 cm x 0.6 cm to 6.0 cm x 5.0 cm). No interactions have been reported.
Interferon, an inhibitor of angiogenesis, developed as an antiviral agent, has been suggested as a potential intervention for IH (Ezekowitz 1992; Greinwald 1999), especially for infants with life‐threatening haemangiomas unresponsive to corticosteroids. Some studies have suggested a dosage of interferon alpha‐2b of 3 million units/m² subcutaneously, from daily to 5 times per week for 6 to 24 months (Ezekowitz 1992; Greinwald 1999). Reported side effects include fever, malaise, transient neutropenia, and liver disease (Holland 2013). Known interactions of interferon alpha‐2 include use of theophylline, acalabrutinib, and lamivudine, among others (EMC 2018).
Methylene blue is an inhibitor of nitric oxide synthase and guanylate cyclase and is used in the management of vasoplegia syndrome, septic shock, hepato‐pulmonary syndrome, and malaria, among others (Ginimuge 2010). This intervention has not been widely evaluated in the management of IH. The mechanism of action of methylene blue in photodynamic therapy has shown effects in the elimination of bacterial agents in superficial and deep excisional wounds, as well as the treatment of resistant plaque psoriasis. Reported adverse effects in high doses include cardiac arrhythmias, coronary vasoconstriction, decreased cardiac output, renal blood flow, and mesenteric blood flow (Ginimuge 2010). As methylene is a monoamine oxidase (MAO) inhibitor, it could interplay with MAO inhibitors as well as selective serotonin reuptake inhibitor (SSRI) to produce serious serotonin toxicity (Ginimuge 2010).
Imiquimod is an immune‐response modifier (a substance that changes the way the immune system works), which has been used in the management of condyloma, actinic keratoses, and basal cell carcinoma (McCuaig 2009). It has been suggested that imiquimod 5% cream, applied once daily for up to 16 weeks, can induce involution of superficial IH (McCuaig 2009). Reported side effects of imiquimod include local erythema, crusting, and contact dermatitis (McCuaig 2009).
Laser treatments (including pulsed dye, argon, carbon dioxide, neodymium‐doped yttrium aluminum garnet (Nd:YAG), sequential/concurrent dual‐wavelength laser and erbium) should be considered if there is a contraindication for systemic treatment, such as a history of sensitivity to beta blockers, asthma, renal disease, heart disease, or hypoglycaemia (Chinnadurai 2016a; Chinnadurai 2016b). Some reported side effects of laser treatment include purpura, swelling, blisters, hypopigmentation, bleeding, infection, and atrophic or hypertrophic scarring (Chinnadurai 2016a; Chinnadurai 2016b). Protocols of administrations are multiple and depend on the laser pulse width, age of the patient, IH anatomical location, cooling materials, and size of the tumour (Chinnadurai 2016a; Chinnadurai 2016b). A study recently assessed the concurrent or sequential administration of laser with other potential interventions (Lu 2016). Infants require a general anaesthetic for treatment because laser treatment can be painful. Early childhood anaesthesia carries the usual risks of complications associated with anaesthesia and as well as with neurocognitive impairment.
Oral ibuprofen plus oral paracetamol, as a combination of non‐steroidal anti‐inflammatory and analgesic drugs (NSAIDs), has a role in the management of ulcerated IH located in the head and neck region (Tiwari 2016). Recently, Tawfik 2015 assessed a combination of oral ibuprofen and paracetamol in doses of 10 and 16.2 mg/kg 8‐hourly versus oral propranolol for up to 6 months.
Radiation therapy has been conventionally used for treating life‐ or function‐threatening haemangiomas that have been unresponsive to treatment with corticosteroids. Side effects of using ionising radiation include blisters, infection, and ulcers, while possible lasting complications include pigmentation restricted to certain areas or hypopigmentation, the creation of scars, soft tissue dysplasia, and the retardation of bone growth (Fragu 1991; Probert 1975). Radiation therapy for haemangiomas includes ⁹⁰SR‐⁹⁰Y radiation and soft X‐ray radiation. Adverse effects include radionecrosis (acute) and scarring and skin cancer (long term).
Rapamycin is a macrolide compound with immunosuppression and antiangiogenic activity (Li 2017). Oral and local administration have been assessed. Reported side effects include hyperlipidaemia, impaired glucose tolerance, anaemia, and acute renal toxicity (Li 2017).
Steroids (administered topically, intralesionally, or systemically). Intralesional corticosteroids may be used for the treatment of small haemangiomas, usually involving the facial area. However, many dermatologists prefer systemic corticosteroids for periocular lesions, since intralesional administration has resulted in serious side effects including retinal artery occlusion and eyelid necrosis (Shorr 1986). Prednisolone is the most frequent steroid assessed for management of IH (Aly 2015), at a dosage of 2 mg/kg/day for six months. There is an interaction of steroids with concomitant administration of phenytoin, phenobarbital, ephedrine, estrogens, and diuretics (Bauman 2014). Steroid side effects include growth retardation, increased susceptibility to infectious disease, and hypertension (George 2004). Other minor, reversible complications associated with the administration of steroids include haematomas, periocular calcification, and eyelid pigmentation.
Surgery is indicated for lesions that interfere with function if pharmacologic therapy fails or is contraindicated, as well as where ulceration or bleeding has occurred (Liang 2014). Surgical excision might also be used to improve the final cosmetic appearance if loose skin is left after IH regression (Smolinski 2005). In addition, cryotherapy can be used for small and flat haemangiomas, in order to accelerate haemangioma involution (shrinkage) (Grantzow 2001). Surgical intervention is commonly used for the correction of scarring as well as removal of residual tissue, but it can be used also for excision of life‐threatening haemangiomas (Holland 2013).
Vincristine is a vinca alkaloid that has been assessed in the treatment of IH, especially those IH unaffected by corticosteroids or in patients who cannot bear corticosteroids (Glade 2010). Single weekly doses of 1 to 1.5 mg/m² have been assessed (median of three cycles). Potential serious adverse events included constipation, neuromyopathy,(Glade 2010), and risk associated with placement of the central line (Holland 2013).
Active monitoring. This approach has been shown to produce the best cosmetic outcomes for uncomplicated infantile haemangiomas (Dinehart 2001). In general, most haemangiomas resolve spontaneously without significant sequelae and follow‐up can be the clinician's choice (Liang 2014).

How the intervention might work

Propranolol

Propranolol has been to shown to restrict the haemangioma's capillaries, causing a subsequent decrease in blood flow within the tumour. In addition, it has been suggested that propranolol can hinder angiogenesis and encourage apoptosis in IH cells (Wnek 2017). Potential mechanisms of action of propranolol include the stimulation of apoptosis in haemangioma endothelial cells through GLUT1 receptor antagonism; the prevention of catecholamine‐induced angiogenesis; the constraint of the renin‐angiotensin axis; and the interruption of signalling pathways that regulate progenitor cells (Wnek 2017). In contrast with corticosteroids, propranolol is effective during the proliferative phase of growth. Studies have recently suggested that propranolol administration in IH therapy generates a biological response involving changes in the expression of chosen apoptosis‐regulating factors (Wnek 2017).

Timolol maleate

Topical timolol hinders IH growth and encourages the regression of superficial IH, although some studies have raised concerns about the effect of systemic absorption, as well side effects such as sleep disturbance (Danarti 2016).

Atenolol

The main effects of atenolol involve the beta‐1 receptors with minor beta‐2 effects (Abarzua‐Araya 2014). Because atenolol does not act on pulmonary beta‐2 receptors, it can be used in infants with pulmonary conditions, including reactive airway disease. Likewise, atenolol does not act on pancreatic beta‐2 receptors and thus does not interfere with regulation of gluconeogenesis, glycogenolysis, and lipolysis (Bayart 2017).

Bleomycin

The action of bleomycin involves a decrease in the production of vascular endothelial cells, as well as the tempering of angiogenesis of the infantile haemangiomas (Luo 2011; Qiu 2015). In addition, its administration has an effect in the G2 and S phases of endothelial cells by inducing DNA deterioration and preventing its reconstruction, resulting in collapse, shrinkage, and fibrosis (Luo 2011; Qiu 2015).

Captopril

Because some components of the renin‐angiotensin system (RAS) are expressed in proliferating IH, modulation of downstream products of RAS, including angiotensin‐converting enzymes, could have a role in the treatment of IH (Zaher 2016). Similar to propranolol, captopril leads to a decrease in vascular endothelial growth factor production via downregulation of angiotensin II (Itinteang 2011). In addition, captopril can inhibit the effect of kininase II and increase the plasma bradykinin levels (Waeber 1980).

High‐intensity focused ultrasound (HIFU)

It has been suggested that the effectiveness of HIFU in the treatment of IH, as well as superficial skin lesions, could be similar to that shown in treating body parts and tumour (Fu 2012; Orsi 2010). High‐intensity focused ultrasound produces coagulative necrosis in a focal point without effects in adjacent structures by means of ultrasonic tissue penetration. Biological effects of HIFU include coagulative necrosis, nuclei damage, membrane disruption, and apoptosis (Kennedy 2005).

Interferon

Interferon therapy works by inhibiting locomotion of capillary endothelium in vitro (Ezekowitz 1992). Although research from case series reports indicate similar results for interferon alpha‐2a and interferon alpha‐2b (Chang 1997), other research has indicated that the body may produce neutralising antibodies that reduce the efficacy of interferon alpha‐2a as compared to interferon alpha‐2b (Antonelli 1991). Earlier research on interferon showed it to have an effect on vascular tumours such as Kaposi's sarcoma (Ezekowitz 1992).

Intralesional methylene blue

Feng and colleagues have suggested that methylene has a role in the management of IH due to its endothelial effects by induced thrombosis of the lesion, blocking the vascular supply and accelerating the necrosis of the haemangioma (Feng 2000).

Imiquimod

Imiquimod has a pro‐apoptotic and antiangiogenic activity. It activates the immune response system via the Toll‐like receptor‐7 on dendritic cells (Hu 2015; McCuaig 2009), resulting in induction of cytokines and interferon‐gamma, as well as matrix metalloproteinase (McCuaig 2009).

Laser

Lasers generally work by destroying blood vessels in the IH, with the equivalent wavelength of light absorbed by IH haemoglobin (Anderson 1981). The light from the laser is transformed into heat, and it is transmitted to the vessel wall, producing coagulation and vessel closure (Tawfik 2015). Oxyhaemoglobin has been the classic target chromophore for vascular lesions, due to its absorption peaks at 418, 542, and 577 nm. Oxyhaemoglobin contained within vascular lumina absorb the light energy emitted from pulsed dye laser (PDL) devices, minimising collateral damage (Rothfleisch 2002).

In order to increase the tissue penetration of PDL, the original wavelength of 577 nm, which corresponds to the third absorption peak of oxyhaemoglobin, has been increased over the past decade to 585 nm, and the pulse duration has also been increased from 450 microseconds to 1.5 milliseconds. Cryogen‐cooling devices have been added in order to reduce pain and related adverse events (Rothfleisch 2002).

Argon laser devices radiate blue‐green light, with emissions between 488 to 514 nanometers on the electromagnetic spectrum (Rothfleisch 2002). Argon laser energy is emitted by a continuous beam, which penetrates tissue at a depth of 1 mm to 2 mm. Emissions are absorbed mainly by oxyhaemoglobin, although epidermal and dermal melanin also have a degree of absorption (Rothfleisch 2002). The popularity of the argon laser has markedly declined over the past decade because of its associated limitations and the development of the pulse dye laser (Rothfleisch 2002).

Carbon dioxide laser emits light in the infrared spectrum (10,600 nm), which is primarily absorbed by water molecules. Its action involves the excision or debulking of vascular tissue or actinically damaged facial skin (Al 2003; Krupa 2009).

Neodymium‐doped yttrium aluminum garnet (Nd:YAG) laser has been reported to have a weaker melanin absorption and a deeper effect on lesions (Rothfleisch 2002). In addition, Nd:YAG has a high absorption coefficient of methaemoglobin and deoxyhaemoglobin, both of which are major parts of blue veins. Due to the long pulsed duration feature, Nd:YAG has a slower and more uniformed heat effect in the IH vessels, which generates coagulation without rupturing the vessel or causing purpura or hyperpigmentation (Rothfleisch 2002).

Dual‐wavelength laser combines PDL laser with YAG laser, allowing oxygenated haemoglobin to be transformed into methaemoglobin, and significantly increasing the Nd:YAG laser absorption rate. Local heat is reduced by a cooling system of ‐4 °C at the lesion site (Lu 2016).

The erbium laser (Er:YAG laser) produces a smaller zone of thermal injury, removing the epidermis in two or three passes, compared with the conventional CO₂ resurfacing lasers (McDaniel 1997). The 2940‐nanometre wavelength of erbium produces a collagen absorption peak at 3030 nm (McDaniel 1997).

Oral ibuprofen plus oral paracetamol

In general, the mechanism of action of NSAIDs involves the inhibition of prostanoid biosynthesis (Abramson 1989). NSAIDs in combination with analgesics can have a role in the management of ulcerated IH, especially for pain relief (Tiwari 2016).

Radiation

Ionising radiation could be preferred due to its low chance of causing local scarring (Zhu 2015). In general, the pathophysiology of radiation‐induced changes in the skin involves: 1) a transient early erythema, which remits after 24 to 48 hours; 2) a main erythematous reaction related to the severe loss of epidermal basal cells; 3) a subsequent phase of erythema combined with dermal ischaemia and possible necrosis; and 4) the appearance of dermal atrophy, telangiectasia, and necrosis (Hopewell 1990).

Rapamycin

Rapamycin has been reported to have a superior antihaemangioma activity due to its inhibition of the proliferation of haemangioma endothelial cells and vascular endothelial growth factor production (Li 2017).

Steroids

High‐dose intralesional (injected directly into the lesion) or systemic (whole body) steroid therapies work by stopping the growth of the haemangioma through the promotion of stabilisation or regression, and possibly by softening the lesion (Bennett 2001).

Surgery

Surgical management involves removing the haemangioma in order to restore normal facial features (Liang 2014). Several techniques have been proposed including circular excision with purse‐string closure (Mulliken 2002), as well as single‐stage resection (Daramola 2012).

Vincristine

Vincristine is thought to act as an antiangiogenic through its effect on vascular endothelial growth factor (Azzopardi 2012). In addition, vincristine works by reducing the creation of microtubules, triggering mitotic arrest during metaphase, which produces apoptosis of tumour cells in vitro (Glade 2010).

Active monitoring

Despite the fact that it is hypothesised that several growth factors (e.g. hormonal, mechanical) are involved in the abnormal proliferation of endothelial cells in IH, the mechanism of action behind haemangiogenesis remains unknown (Marchuk 2001). In addition, most infantile haemangiomas are reported to involute completely by four years of age (Couto 2012).

Why it is important to do this review

A significant minority of babies (up to 1 in 10) develop infantile haemangiomas (Léauté‐Labrèze 2015). While the majority of IH are non‐problematic and will regress and disappear in five to seven years, a few will become problematic or cause mental distress to children and their parents (Csoma 2017). Some IH may also result in complications, including congestive heart failure, lifelong disfigurement, bleeding, ulceration, and visual and airway‐related obstruction (Csoma 2017). In such cases, medical intervention with a variety of medical treatments may be necessary. Propranolol therapy has been recommended as the most effective way of treating IH, as it inhibits proliferation and incites regression of IH during the proliferative phase (Zhang 2017). However, other methods may still be in use. It was therefore necessary to review the efficacy and potential adverse events of these interventions for the management of IH.

A first assessment of these interventions was published by Leonardi‐Bee in 2011 (Leonardi‐Bee 2011), reporting information from four trials with limited evidence.

Objectives

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

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials.

Types of participants

Any child (usually under 24 months) with single or multiple infantile haemangiomas located on the skin. We excluded participants above the age of 18 years. We excluded studies with a mixture of populations (including children and adults) that did not provide separate information for children. In addition, we excluded children with cases of very rare types of haemangiomas (including congenital haemangioma, haemangiomas associated with Kasabach‐Merritt syndrome, and eruptive neonatal haemangiomatosis) and internal haemangiomas.

Types of interventions

We considered all types of interventions used in the treatment of infantile haemangiomas. Interventions could be given alone or in combination. The most commonly used interventions include the following.

Beta blockers: propranolol, timolol maleate, and atenolol
Lasers: pulsed dye, argon, carbon dioxide, Nd:YAG, and erbium
Steroids: administered topically, intralesionally, or systemically
Surgery: excision or cryotherapy
Other treatments: imiquimod, interferon alpha‐2a, bleomycin, vincristine, and rapamycin (administered topically, intralesionally, orally, or systemically)

Comparators included placebo, active monitoring (i.e. wait‐and‐see), or other interventions (e.g. systemic steroids versus laser therapy). Comparator interventions could be given alone or in combination.

Types of outcome measures

Primary outcomes

Clearance, as assessed by a clinician at any follow‐up: proportion of children with lesions completely cleared or with minimal residual signs (defined as faint macular erythema with no palpable component).
A subjective measure of improvement, as assessed by the parent or child, at any follow‐up.
Adverse events experienced at short (immediately after treatment until 48 hours after) or long term (more than 48 hours after treatment) related to each intervention. These included skin atrophy (scarring where the skin is thinned, with or without depression at the skin surface), skin hypopigmentation (loss of skin pigmentation), and complications (including bleeding, ulceration, infection, deformation, disfigurement, vision impairment, airway obstruction, pain associated with treatment or ulceration, and/or side effects of treatments). We also considered reports of number of adverse events in general, as well as serious/severe adverse events (as defined by trial authors).

Secondary outcomes

Other measures of resolution, as assessed by a clinician, at any follow‐up. These included surface area, height or volume of lesion, and redness of lesion, preferably using an objective measure of assessment, such as photographs.
Proportion of parents who consider their child still has a problem, at any follow‐up.
Proportion of children who consider they still have a problem, at any follow‐up.
Aesthetic appearance as assessed by physician, child, or parent, at any follow‐up.
Requirement for surgical correction, as assessed by a physician, at any follow‐up.

Timing

We considered data recorded for six months or less from baseline to reflect short‐term benefit, and we analysed these data separately from data recorded after six months' follow‐up, apart from adverse events data, where we considered up to 48 hours from baseline short term.

Search methods for identification of studies

We aimed to identify all relevant randomised controlled trials regardless of language or publication status (published, unpublished, in press, or ongoing).

Electronic searches

For this update, we revised our search strategies in line with current Cochrane Skin Group practices. Details of the previous search strategies are available in Leonardi‐Bee 2011.

We searched the following databases up to 22 February 2017:

the Cochrane Skin Group Specialised Register using the search strategy in Appendix 1;
the Cochrane Central Register of Controlled Trials (CENTRAL) 2017, Issue 1 in the Cochrane Library using the strategy in Appendix 2;
MEDLINE via Ovid (from 1946) using the strategy in Appendix 3;
Embase via Ovid (from 1974) using the strategy in Appendix 4;
AMED via Ovid (Allied and Complementary Medicine, from 1985) using the strategy in Appendix 5;
PsycINFO via Ovid (from 1806) using the strategy in Appendix 6;
LILACS (Latin American and Caribbean Health Science Information database, from 1982) using the strategy in Appendix 7; and
CINAHL via EBSCO (Cumulative Index of Nursing and Allied Health Literature, from 1981) using the strategy in Appendix 8.

Searching other resources

Trials registers

On 22 February 2017 we searched the following ongoing trials databases using the terms 'haemangioma', 'hemangioma', 'strawberry', 'naevi', or 'naevus':

ISRCTN register (www.isrctn.com);
ClinicalTrials.gov (www.clinicaltrials.gov);
Australian New Zealand Clinical Trials Registry (www.anzctr.org.au);
World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) (apps.who.int/trialsearch/); and
EU Clinical Trials Register (www.clinicaltrialsregister.eu).

Searching reference lists

We checked the bibliographies of included studies for additional references to relevant trials.

Adverse effects

We did not perform a separate search for adverse effects of interventions used for the treatment of infantile haemangiomas. We considered adverse and side effects described in included studies only.

Data collection and analysis

Selection of studies

Two review authors (LG and SB) independently selected eligible studies. Authors reviewed titles and abstracts of all articles identified by the search to assess whether they met the inclusion criteria. The full texts of selected studies were further assessed to confirm their relevance for inclusion in the review. An additional third review author was consulted when disagreements arose (IAR). At any stage of the review, review authors were not blinded to the authors’ names and institutions, journal of publication, or study results. All excluded studies and reasons for their exclusion are listed in the Characteristics of excluded studies tables.

Data extraction and management

Two review authors (LG and SB) independently performed data extraction using predesigned data collection spreadsheets. We extracted participant characteristics, methods of randomisation, blinding, comparisons of interest, number of children originally randomised by arm, and follow‐up losses and outcomes. A third review author was consulted when disagreements arose (MN or IAR). We entered extracted data into Review Manager 5 for further analysis (Review Manager 5.3).

Assessment of risk of bias in included studies

As outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), two review authors (LG and SB) independently assessed risk of bias in included trials. We took six domains into consideration: random sequence generation, blinding of participants and personnel, blinding of outcome assessment, allocation concealment, selective reporting, and other biases. We assessed blinding of participants and blinding of personnel separately, as in most cases this information was partially reported (i.e. study authors reported blinding for participants or for personnel, but not both). We judged each domain to be at low, high, or unclear risk of bias. Disagreements were solved in consultation with a third review author (IAR). We assessed the direction and magnitude of bias, as well as its correlational impact on any findings (Higgins 2011). We summarised information in 'Risk of bias' tables in the Characteristics of included studies.

Measures of treatment effect

We expressed results as risk ratios (RR) with 95% confidence intervals (CI) for dichotomous outcomes, and difference in means (MD) with 95% CI for continuous outcomes. Transformation of data was not required.

Unit of analysis issues

Where there were multiple intervention groups within a trial, we made pair‐wise comparisons of similar active interventions versus no treatment, placebo, or other active intervention. Although we did not find any randomised controlled trials that used cross‐over or internally controlled designs, we would have analysed the former using data only from the first phase pooled, where possible, with parallel‐design studies. For the latter, we would have used appropriate techniques for paired designs without pooling with studies of other designs.

Dealing with missing data

In cases where participant dropout led to missing data, we conducted an intention‐to‐treat analysis. For dichotomous outcomes, we regarded children with missing outcome data as treatment failures and included them in the analysis. For continuous outcomes, we would have considered using the last recorded value carried forward for children with missing outcome data; however, these circumstances did not occur. If high levels of missing data were seen within the analyses, we planned to conduct sensitivity analyses to assess the robustness of the results from the approaches described above, by comparing the results with those excluding the missing data from the analyses. However, these circumstances did not occur.

Assessment of heterogeneity

We investigated heterogeneity with close visual examination of the forest plots. Additionally, we assessed statistical heterogeneity of effect sizes by means of the I² statistic. The I² statistic is employed to describe the per cent of total variation across all contributing trials due to heterogeneity rather than sampling error (Higgins 2011). If we identified signs of heterogeneity (I² > 30%), we performed further exploration by prespecified subgroup analysis; furthermore, if we identified considerable per cent of heterogeneity (I² > 80%), we did not present pooled results.

Assessment of reporting biases

We planned to use funnel plots, with respect to primary outcomes, to illustrate whether treatment estimates were related to study size or to determine variability among trials in an attempt to detect publication bias. If 10 or more trials are available, extrapolation based on asymmetry is plausible. However, due to scarcity of data in all comparisons, we were unable to perform a full analysis of reporting bias.

Data synthesis

For studies with a similar type of active intervention, we performed a meta‐analysis to calculate a weighted treatment effect across trials using a random‐effects (DerSimonian and Laird) model. We planned and carried out statistical analyses using Review Manager 5 (Review Manager 5.3). When it was not possible to perform a meta‐analysis, we presented data narratively.

Subgroup analysis and investigation of heterogeneity

We planned to perform a subgroup analysis and to determine interaction tests to check for subgroup differences where meaningful. For the primary outcomes, we considered subgroup analyses for the following factors:

dosage;
duration of treatment;
types of infantile haemangioma (superficial, deep, mixed, others);
location of birthmark (low‐risk or high‐risk areas).

Due to scarcity of data in all comparisons, we were unable to perform a full investigation of heterogeneity.

Sensitivity analysis

We planned to conduct sensitivity analyses using trials classified as having low risk of bias in three core domains: allocation concealment, incomplete outcome data, and blinding of outcome assessment, as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). However, due to scarcity of data in all comparisons, we were unable to perform a full sensitivity analysis.

'Summary of findings' tables

We assessed quality of the body of evidence (also known as certainty in the evidence) pertaining to primary and secondary outcomes using the principles of the GRADE system (Guyatt 2008). We also constructed 'Summary of findings' tables. Factors taken into consideration in the evaluation of quality of the evidence are study risk of bias, heterogeneity of data, directness of the evidence, precision of effect estimates, and potential publication bias (Guyatt 2008; Guyatt 2011a; Guyatt 2011b; Guyatt 2011c; Guyatt 2011d; Guyatt 2011e; Guyatt 2011f; Guyatt 2011g; Guyatt 2011h). We developed the 'Summary of findings' table using a web‐based version of the GRADEpro software (GRADEpro GDT), according to the methods and recommendations described in Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We selected information about currently used treatments for these 'Summary of findings' tables.

We developed 'Summary of findings' tables for the following comparisons:

oral propranolol versus placebo;
topical timolol maleate versus placebo;
oral propranolol versus topical timolol maleate.

We assessed the quality of the evidence for the following outcomes in these comparisons:

clearance (as assessed by a clinician);
subjective measurements of improvement;
adverse events;
other measures of resolution;
proportion of parents who consider their child still has a problem;
proportion of children who consider they still have a problem; and
aesthetic appearance.

For the outcome 'adverse events', we presented in the corresponding table the most frequent or the most important adverse event, or both, related to each intervention. When information about adverse events in general (including serious/severe adverse events) was available, we presented these results instead of individual findings.

Results

Description of studies

See Characteristics of included studies and Characteristics of excluded studies.

Results of the search

Our updated searches identified 932 new records in addition to the 128 identified in the first version of this review. From the combined total of 1060 records, we screened out 969 records based on titles and abstracts. We examined the remaining 91 records in full text. From these, we excluded 45 studies (16 identified in the previous version of this review and 29 from this update, see Characteristics of excluded studies). We included 28 studies reported in 37 references (see Characteristics of included studies). We classified seven studies as awaiting assessment (see Characteristics of studies awaiting classification) and two further studies as ongoing (see Characteristics of ongoing studies). For a further description of the screening process, see the study flow diagram (Figure 1),

Included studies

Twenty‐eight studies (reported in 37 references) were eligible for inclusion in this updated review. All studies were published. The 28 studies enrolled and randomised a total of 1728 participants. Details of the included studies are provided in the Characteristics of included studies tables. Four of the 28 studies were included in the previous version of this review, with 24 new studies included in this update.

Design

A total of 21 studies used a two‐arm design; six used a three‐arm design; and one used a four‐arm, parallel‐group design.

Sample sizes

Numbers of children in the studies ranged from 12 in Zhang 2013 to 460 in Leaute‐Labreze 2015. Only five studies reported a calculation of sample sizes prior to the beginning of the trial (Bauman 2014; Hogeling 2011; Kessels 2013; Leaute‐Labreze 2015; Pope 2007).

Setting

Studies were conducted in Canada (Pope 2007), China (Feng 2000; Fu 2012; Gong 2015; Li 2016; Lu 2016; Tan 2012; Xu 2006; Zhang 2013; Zhong 2015; Zhu 2015), Germany (Jung 1977), Chile (Abarzua‐Araya 2014), the UK (Batta 2002), the USA (Bauman 2014), Australia (Chan 2013; Hogeling 2011), Iran (Asilian 2015; Ehsani 2014), the Netherlands (Kessels 2013), France (Leaute‐Labreze 2013; Leaute‐Labreze 2015), India (Malik 2013; Tiwari 2016), and Egypt (Aly 2015; Tawfik 2015; Zaher 2013; Zaher 2016).

Participants

Baseline data were reported in 17 trials (Abarzua‐Araya 2014; Asilian 2015; Batta 2002; Bauman 2014; Chan 2013; Ehsani 2014; Gong 2015; Hogeling 2011; Jung 1977; Kessels 2013; Leaute‐Labreze 2013; Leaute‐Labreze 2015; Li 2016; Lu 2016; Pope 2007; Zaher 2013; Zaher 2016). Four trials did not report the number of males and females included (Aly 2015; Malik 2013; Tiwari 2016; Xu 2006). One trial had equal numbers of males and females (Zhang 2013). The remaining 23 trials had a greater number of females than males, ranging from 58% in Li 2016 to 86% in Zaher 2013. The maximum age of enrolment at the beginning of the trial, as an inclusion criterion, ranged from 14 weeks in Batta 2002 to five years in Hogeling 2011; four studies did not clearly state this information (Lu 2016; Tawfik 2015; Zaher 2013; Zaher 2016). Age was heterogeneously reported in the included studies (mean, medians, ranges for total, or subgroups were reported). In 19 studies reporting mean age, this ranged from 12 weeks in Pope 2007 to 13.4 years in Tawfik 2015.

Subtypes of haemangiomas

Different subtypes of infantile haemangiomas were assessed, including children with mixed or deep IH (Li 2016; Lu 2016; Pope 2007; Zhong 2015), ulcerated or problematic IH (Hogeling 2011; Malik 2013; Tiwari 2016; Zaher 2013; Zaher 2016), or high‐risk haemangiomas (Abarzua‐Araya 2014; Aly 2015; Asilian 2015; Hogeling 2011; Lu 2016; Zaher 2013; Zaher 2016; Zhu 2015). One study assessed facial haemangiomas (defined as "periorbital/orbital tumours with visual impairment and/or large size/disfiguring haemangiomas") (Pope 2007). Six studies exclusively assessed superficial haemangiomas (Asilian 2015; Batta 2002; Chan 2013; Gong 2015; Kessels 2013; Zhu 2015), while one trial evaluated mixed haemangiomas only (Li 2016). Jung 1977 assessed planotuberous or tuberocavernous haemangiomas. The remaining trials did not provide additional information about the type of IH included or included a mixture of subtypes (Bauman 2014; Ehsani 2014; Feng 2000; Fu 2012; Leaute‐Labreze 2013; Leaute‐Labreze 2015; Tan 2012; Tawfik 2015; Xu 2006; Zhang 2013).

Interventions

The included trials assessed the following interventions for treating infantile haemangiomas.

Lasers: pulsed dye laser (PDL), Nd:YAG laser, sequential/concurrent dual‐wavelength laser.
Beta blockers: oral/topical propranolol, topical timolol maleate.
Steroids: oral prednisolone.
Other treatments: topical bleomycin, intralesional methylene blue.
High‐intensity focused ultrasound (HIFU).
Radiation therapy: soft X‐ray radiation, ⁹⁰SR‐⁹⁰Y radiation.

Some treatments were used in combination.

Comparators included active monitoring (observation), placebo, sham radiation, and the following interventions (single or in combination with another intervention).

Beta blockers: intralesional/oral/topical propranolol, topical timolol maleate, oral atenolol.
Oral ibuprofen plus oral paracetamol, oral captopril.
Lasers: concurrent dual‐wavelength laser, PDL alone, Nd:YAG laser.
Steroids: oral prednisolone, intralesional triamcinolone, methylprednisolone (infusion).
HIFU.
Radiation therapy: ⁹⁰SR‐⁹⁰Y radiation.

We identified no evidence for argon laser, carbon dioxide laser, erbium laser, excision, cryotherapy, imiquimod, interferon alpha, vincristine, or rapamycin. We found the following treatment comparisons.

PDL versus wait‐and‐see (i.e active monitoring) (Batta 2002; Kessels 2013).
Oral propranolol versus placebo (Hogeling 2011; Leaute‐Labreze 2013; Leaute‐Labreze 2015).
Topical timolol maleate versus placebo (Chan 2013).
Topical bleomycin versus placebo (Xu 2006).
X‐ray radiation versus sham radiation (Jung 1977).
Nd:YAG laser versus topical timolol maleate (Tawfik 2015).
Nd:YAG laser versus oral propranolol (Tan 2012; Zhong 2015).
PDL + topical propranolol versus PDL alone (Ehsani 2014).
PDL + topical timolol maleate versus PDL alone (Asilian 2015).
Nd:YAG laser + oral propranolol versus Nd:YAG laser (Tan 2012; Zhong 2015).
Nd:YAG laser + oral propranolol versus oral propranolol (Tan 2012; Zhong 2015).
⁹⁰SR‐⁹⁰Y radiation + topical timolol maleate versus ⁹⁰SR‐⁹⁰Y radiation (Zhu 2015).
Sequential dual‐wavelength laser + oral propranolol versus concurrent dual‐wavelength laser + oral propranolol (Lu 2016).
Oral propranolol versus topical propranolol (Zaher 2013).
Oral propranolol versus intralesional propranolol (Zaher 2013).
Topical propranolol versus intralesional propranolol (Zaher 2013).
Oral propranolol versus oral atenolol (Abarzua‐Araya 2014).
Oral propranolol versus oral prednisolone (Bauman 2014; Malik 2013).
Oral propranolol versus oral captopril (Zaher 2016).
Oral propranolol versus topical timolol maleate (Gong 2015).
Oral propranolol versus oral propranolol + oral prednisolone (Aly 2015; Malik 2013).
Oral propranolol versus oral ibuprofen + oral paracetamol (Tiwari 2016).
Oral propranolol + topical timolol maleate versus oral propranolol (Gong 2015; Li 2016).
Oral propranolol + topical timolol maleate versus topical timolol maleate (Gong 2015).
Oral propranolol + oral prednisolone versus oral prednisolone (Malik 2013).
Intralesional methylene blue versus intralesional triamcinolone (Feng 2000).
Oral prednisolone versus oral methylprednisolone (Pope 2007).
HIFU at 3.5 W versus HIFU at 4.5 W (Fu 2012).
HIFU at 3.5 W versus HIFU at 4.0 W (Fu 2012).
HIFU at 4.0 W versus HIFU at 4.5 W (Fu 2012).

Duration of treatment and follow‐up

The most common duration of treatment was 24 weeks, found in five trials (Abarzua‐Araya 2014; Aly 2015; Chan 2013; Hogeling 2011; Tan 2012). In six trials, there was no fixed length of intervention for all children; the intervention was stopped for the following reasons: when the lesion was cleared; there was no clear improvement; in the presence of important side effects; or for parent's/clinician request, among other reasons (Batta 2002; Bauman 2014; Gong 2015; Kessels 2013; Zaher 2013; Zaher 2016). In 11 trials, this information was unclear or poorly reported (Asilian 2015; Ehsani 2014; Feng 2000; Fu 2012; Li 2016; Lu 2016; Malik 2013; Pope 2007; Tawfik 2015; Tiwari 2016; Zhang 2013).

Duration of follow‐up ranged from 7 days in Xu 2006 to 72 months in Jung 1977. The most frequent duration of follow‐up was six months, found in nine trials (Abarzua‐Araya 2014; Asilian 2015; Chan 2013; Fu 2012; Hogeling 2011; Tan 2012; Zaher 2013; Zhong 2015; Zhu 2015). In three trials this information was unclear (Feng 2000; Lu 2016; Zhang 2013).

Outcomes

Fourteen trials assessed our primary outcome measure of clearance (Abarzua‐Araya 2014; Asilian 2015; Batta 2002; Ehsani 2014; Feng 2000; Fu 2012; Jung 1977; Leaute‐Labreze 2015; Tan 2012; Tawfik 2015; Tiwari 2016; Zaher 2013; Zaher 2016; Zhu 2015). One trial reported a subjective measure of improvement (Pope 2007). Adverse events were fully reported in 20 trials (Abarzua‐Araya 2014; Aly 2015; Asilian 2015; Batta 2002; Bauman 2014; Chan 2013; Ehsani 2014; Fu 2012; Gong 2015; Hogeling 2011; Kessels 2013; Leaute‐Labreze 2015; Li 2016; Malik 2013; Tan 2012; Tiwari 2016; Zaher 2013; Zaher 2016; Zhong 2015; Zhu 2015). Other measures of resolution such as redness, reduction of volume, colour fading, haemoglobin levels, or mean size reduction were assessed in 16 trials (Aly 2015; Asilian 2015; Batta 2002; Bauman 2014; Chan 2013; Gong 2015; Hogeling 2011; Kessels 2013; Li 2016; Lu 2016; Malik 2013; Pope 2007; Tawfik 2015; Tiwari 2016; Xu 2006; Zhong 2015). One trial reported the proportion of parents who consider their child still has a problem (Batta 2002); the same trial also reported on requirement for surgical correction. No trials reported the proportion of children who consider they still have a problem. In addition, one trial reported findings related to aesthetic appearance (Kessels 2013).

Excluded studies

Among the 45 studies excluded after full‐text assessment, six were excluded due to ineligible population or other diseases (Liu 2009; Midena 2008; Pancar 2011; Rouvas 2009; Tierney 2009; Zhou 2002), and one for being developed in animals (Zhou 2015). The remaining 38 excluded studies were not randomised trials. Details of these studies and reasons for exclusion are listed in the Characteristics of excluded studies tables.

Studies awaiting classification

We assessed seven studies as awaiting classification because only partial information was available for these references (from abstracts, conference proceedings, or registration entries in trial platforms, among other reasons) (Kuang 2014; Maier 2012; NCT00004436; NCT00555464; NCT00744185; NCT01072045; Pandey 2010). Preliminary details are reported in the Characteristics of studies awaiting classification tables.

Ongoing studies

We identified two ongoing trials from the updated searches (NCT01147601; NCT02913612). The designs of the trials are listed below.

NCT01147601: topical 0.5% timolol maleate versus placebo, 2 to 3 drops to cover the haemangioma, twice daily.
NCT02913612: timolol maleate gel forming solution drug versus wait‐and‐see (i.e. active monitoring).

Risk of bias in included studies

We summarised the risk of bias of all the studies in the Characteristics of included studies section. The 'Risk of bias' graph (review authors' judgements about each 'Risk of bias' item presented as percentages across all included studies) is presented in Figure 2. The 'Risk of bias' summary (review authors' judgements about each 'Risk of bias' item for each included study) is presented in Figure 3.

'Risk of bias' graph: review authors' judgements about each 'Risk of bias' item presented as percentages across all included studies.

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

Allocation

Seventeen trials used an adequate method of randomisation and were hence rated as at low risk of bias (Batta 2002; Bauman 2014; Chan 2013; Ehsani 2014; Gong 2015; Hogeling 2011; Jung 1977; Kessels 2013; Leaute‐Labreze 2013; Leaute‐Labreze 2015; Li 2016; Malik 2013; Pope 2007; Tan 2012; Tawfik 2015; Tiwari 2016; Zhong 2015), while the other 11 did not provide sufficient information about the sequence generation process to permit judgement (unclear risk of bias) (Abarzua‐Araya 2014; Aly 2015; Asilian 2015; Feng 2000; Fu 2012; Lu 2016; Xu 2006; Zaher 2013; Zaher 2016; Zhang 2013; Zhu 2015).

Nine studies specified adequate methods of allocation concealment and were hence rated as at low risk of bias (Abarzua‐Araya 2014; Aly 2015; Batta 2002; Bauman 2014; Chan 2013; Hogeling 2011; Leaute‐Labreze 2015; Pope 2007; Zaher 2016). The remaining trials (n = 19) did not specify allocation concealment methods and so were assessed as at unclear risk of bias.

Blinding

Eight trials reported blinding of participants (Abarzua‐Araya 2014; Asilian 2015; Chan 2013; Hogeling 2011; Jung 1977; Leaute‐Labreze 2013; Leaute‐Labreze 2015; Zhu 2015), and we judged these trials to be at a low risk of performance bias. The remaining studies (n = 20) did not report this information clearly and so were judged to be at unclear risk of performance bias in relation to participants.

Five trials reported blinding of study personnel and so were rated as at low risk of performance bias (Abarzua‐Araya 2014; Bauman 2014; Chan 2013; Hogeling 2011; Leaute‐Labreze 2013). We rated the remaining 23 trials as at unclear risk of performance bias in relation to personnel.

Fifteen trials reported blinding of outcome assessment and so were rated as at low risk of bias (Aly 2015; Chan 2013; Ehsani 2014; Gong 2015; Hogeling 2011; Kessels 2013; Leaute‐Labreze 2013; Leaute‐Labreze 2015; Li 2016; Malik 2013; Pope 2007; Tan 2012; Tawfik 2015; Zaher 2016; Zhong 2015). The remaining trials (n = 13) did not report this information explicitly and so were rated as at unclear risk of bias.

We rated only three trials as at low risk of bias for all three of the blinding items assessed (Chan 2013; Hogeling 2011; Leaute‐Labreze 2013).

Incomplete outcome data

Risk of attrition bias was high in Jung 1977 because of a high dropout rate (47% in the intervention group and 44% in the control group) with no reasons given. We assessed two trials as at unclear risk of bias (Tan 2012; Tiwari 2016). The risk of attrition bias was low in the remaining 25 trials due to a low or null dropout rate.

Selective reporting

There was evidence of selective omissions of outcomes or critical information from the publications of seven trials (Feng 2000; Hogeling 2011; Jung 1977; Malik 2013; Pope 2007; Xu 2006; Zhang 2013). In the Pope 2007 trial, the scores for a subjective measure of improvement as rated by the parents were not presented; the authors instead presented the correlation between the scores of the parents and the scores of the outcome assessors (intraclass correlation coefficient: 0.92). The choice of selective omission of the outcome did not appear to be based on outcome result, since highly significant findings were seen for the reported outcomes. We judged Ehsani 2014 to be at unclear risk of selective reporting because an outcome in their protocol was not included in their study report. We judged the remaining trials (n = 20) as at low risk of reporting bias.

Other potential sources of bias

There may be other sources of bias in one study related to the role of the sponsors in the development of the research (Leaute‐Labreze 2015); hence we rated this trial as at unclear risk of bias for this domain. We found Bauman 2014 to be at unclear risk of other potential sources of bias due to the termination of the trial, which might generate biases in the results. We identified no additional sources of bias in the remaining studies (n = 26).

Effects of interventions

See: Table 1; Table 2; Table 3

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.

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.

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.

Date	Event	Description
4 April 2018	New citation required and conclusions have changed	This update included studies of many more interventions, including beta blockers, which are currently the standard treatment for infantile haemangiomas.
4 April 2018	New search has been performed	A new search led to the addition of 24 new included studies, and we updated the review in line with MECIR standards.

Date	Event	Description
15 March 2012	Amended	Corrected a 'What's new' event on a previous version of the review
1 August 2008	Amended	Converted to new review format

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clearance	1	121	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.62, 1.42]
2 Adverse events: skin atrophy	1	121	Risk Ratio (M‐H, Random, 95% CI)	3.46 [1.36, 8.77]
3 Adverse events: skin hypopigmentation	1	121	Risk Ratio (M‐H, Random, 95% CI)	3.05 [1.57, 5.93]
4 Adverse events: minimal crusting	1	22	Risk Ratio (M‐H, Random, 95% CI)	5.0 [0.27, 93.55]
5 Adverse events: pain	1	22	Risk Ratio (M‐H, Random, 95% CI)	5.0 [0.27, 93.55]
6 Other measures of resolution: no redness	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	1	121	Risk Ratio (M‐H, Random, 95% CI)	1.24 [0.56, 2.78]
8 Aesthetic appearance: better cosmetic outcome	1	22	Risk Ratio (M‐H, Random, 95% CI)	1.75 [0.71, 4.31]
9 Requirement for surgical correction	1	121	Risk Ratio (M‐H, Random, 95% CI)	2.37 [0.64, 8.75]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clearance, as assessed by a clinician	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	3	509	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.33, 3.39]
3 Serious cardiovascular adverse events	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	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	1		Mean Difference (Random, 95% CI)	‐45.9 [‐80.20, ‐11.60]
6 Other measures of resolution: no improvement in redness	1	40	Risk Ratio (M‐H, Random, 95% CI)	9.00 [0.52, 156.91]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Other measures of resolution (6 months)	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]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Other measures of resolution (continuous)	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)	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]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clearance	1	65	Risk Ratio (M‐H, Random, 95% CI)	2.57 [0.28, 23.44]
2 Adverse events: hyperpigmentation	1	65	Risk Ratio (M‐H, Random, 95% CI)	2.57 [0.28, 23.44]
3 Adverse event: pigmentation and thinning	1	40	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.11, 1.05]
4 Adverse events: superficial scar	2	105	Risk Ratio (M‐H, Random, 95% CI)	1.52 [0.24, 9.58]
5 Other measures of resolution: excellent response	1	40	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.08, 1.46]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clearance	1	32	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.07, 14.64]
2 Other measures of resolution: mean size reduction	1	32	Mean Difference (IV, Random, 95% CI)	5.62 [1.21, 10.03]

Methods	Design: parallel, 2 arms Country: USA Method of randomisation: pre‐generated encrypted schedule (Page 324) Blinding: single‐blind/investigator Location: Children's National Medical Center Length of follow‐up: until 4 months
Participants	Diagnosis: actively proliferating and symptomatic IH Sex: females: 14; males: 5 Age: 2 weeks to 6 months Inclusion criteria: infants with symptomatic haemangiomas Exclusion criteria: inadequate social support, non‐proliferating IH, other treatment for IH, liver disease, abnormal blood glucose level (BG), hypertension, hypotension, reactive airway disease, cardiac anomalies, and PHACE Number of randomised children: 19
Interventions	Intervention A (number of children: 11): propranolol 2.0 mg/kg/d orally 3 times daily Intervention B (number of children: 8): prednisolone 2.0 mg/kg/d orally twice daily
Outcomes	Primary outcome: reduction in size of haemangioma, measured by the proportional change in the total surface area based on the lesion's outer margin dimensions at 4 months Secondary outcome: adverse events, graded by severity (1 to 5)
Notes	Trial registration: NCT00967226 Funder: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Center for Research Resources of the National Institutes of Health (Page 330) Role of funder: only financial support A priori sample size estimation: yes (planned sample size: 55 children) Conducted: between 1 September 2010 and 1 August 2012 Declared conflicts of interest: yes (page 330)
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: " ...were randomised ... using a CNMC institutional tamper‐proof, pregenerated encrypted schedule..." Page 324 Comment: Authors reported information about adequate random sequence generation.
Allocation concealment (selection bias)	Low risk	Quotes: " ...were randomised ... using a CNMC institutional tamper‐proof, pregenerated encrypted schedule..." Page 324. "The CNMC research pharmacy dispensed study drugs." Page 324 Comment: Authors reported information about adequate allocation concealment.
Blinding of participants (Performance bias)	Unclear risk	Quote: "Unblinded caretakers received counselling and written instructions to administer the medication 15 minutes before meals. (...) Caretakers were trained to recognize signs of hypoglycaemia, hypotension, and bradycardia that would warrant withholding of medication." Page 324 Comment: Unclear information was reported regarding the impact of lack of blinding for caretakers in the development of this trial.
Blinding of personnel (performance bias)	Low risk	Quote: "At enrolment, the blinded investigators assigned a number (...). The same blinded investigator repeated the measurements of size and skin involvement monthly." Page 324 Comment: Authors reported information about adequate blinding of personnel.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Quote: "Unblinded caretakers received counselling and written instructions to administer the medication 15 minutes before meals. (...) Caretakers were trained to recognize signs of hypoglycaemia, hypotension, and bradycardia that would warrant withholding of medication." Page 324 Comment: Unclear information was reported regarding the impact of lack of blinding for caretakers in the development of this trial.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Authors performed intention‐to‐treat analysis; all children were analysed for the primary outcome.
Selective reporting (reporting bias)	Low risk	All outcomes mentioned in the methods were reported on in the results.
Other bias	Unclear risk	Quote: "The study was terminated prior to targeted enrolment at the DSMB's recommendation owing to severe AEs described herein that prompted early withdrawal of 6 of the 8 prednisolone participants." Page 325 Comment: Reason for termination of trial could be a potential source of bias.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clearance	1	67	Risk Ratio (M‐H, Random, 95% CI)	3.28 [0.97, 11.06]
2 Adverse events: hyperpigmentation	1	67	Risk Ratio (M‐H, Random, 95% CI)	1.46 [0.35, 6.02]
3 Adverse events: pigmentation and thinning	1	40	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.12, 3.57]
4 Adverse events: superficial scar	2	107	Risk Ratio (M‐H, Random, 95% CI)	0.37 [0.09, 1.48]
5 Other measures of resolution: excellent response	1	40	Risk Ratio (M‐H, Random, 95% CI)	8.5 [2.25, 32.06]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clearance	1	62	Risk Ratio (M‐H, Random, 95% CI)	8.44 [1.14, 62.66]
2 Adverse events: hyperpigmentation	1	62	Risk Ratio (M‐H, Random, 95% CI)	3.75 [0.44, 31.68]
3 Adverse events: pigmentation and thinning	1	40	Risk Ratio (M‐H, Random, 95% CI)	0.22 [0.05, 0.90]
4 Adverse events: superficial scar	2	102	Risk Ratio (M‐H, Random, 95% CI)	0.60 [0.05, 7.63]
5 Other measures of resolution: excellent response	1	40	Risk Ratio (M‐H, Random, 95% CI)	2.83 [1.42, 5.67]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clearance	1	72	Risk Ratio (M‐H, Random, 95% CI)	1.42 [1.07, 1.87]
2 Adverse events	1	72	Risk Ratio (M‐H, Random, 95% CI)	1.14 [0.56, 2.29]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clearance	1	30	Risk Ratio (M‐H, Random, 95% CI)	3.0 [1.01, 8.95]
2 Adverse events: syncopal attack	1	30	Risk Ratio (M‐H, Random, 95% CI)	7.0 [0.39, 124.83]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clearance	1	30	Risk Ratio (M‐H, Random, 95% CI)	4.5 [1.16, 17.44]
2 Adverse events: syncopal attack	1	30	Risk Ratio (M‐H, Random, 95% CI)	7.0 [0.39, 124.83]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Severe adverse events	1	19	Risk Ratio (M‐H, Random, 95% CI)	0.15 [0.02, 1.02]
2 Adverse events: complications in general	1	20	Risk Ratio (M‐H, Random, 95% CI)	0.22 [0.06, 0.78]
3 Other measures of resolution: colour fading	1	20	Mean Difference (IV, Random, 95% CI)	‐1.0 [‐3.08, 1.08]
4 Other measures of resolution: mean size reduction	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	1	19	Mean Difference (IV, Random, 95% CI)	0.23 [‐0.08, 0.54]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clearance	1	30	Risk Ratio (M‐H, Random, 95% CI)	15.0 [0.93, 241.20]
2 Adverse events: cardiac side effects	1	30	Risk Ratio (M‐H, Random, 95% CI)	0.11 [0.01, 1.90]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Adverse events	1	26	Risk Ratio (M‐H, Random, 95% CI)	7.0 [0.40, 123.35]
2 Other measures of resolution: size reduction > 50%	1	26	Risk Ratio (M‐H, Random, 95% CI)	1.13 [0.64, 1.97]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Adverse events in general	2	60	Risk Ratio (M‐H, Random, 95% CI)	0.30 [0.10, 0.91]
2 Other measures of resolution: mean size reduction	1	20	Mean Difference (IV, Random, 95% CI)	7.20 [‐1.87, 16.27]
3 Other measures of resolution: decrease in redness	1	40	Risk Ratio (M‐H, Random, 95% CI)	0.77 [0.45, 1.32]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clearance	1	64	Risk Ratio (M‐H, Random, 95% CI)	2.67 [0.78, 9.15]
2 Adverse events	1	64	Risk Ratio (M‐H, Random, 95% CI)	7.0 [0.38, 130.26]
3 Other measures of resolution: mean size of ulceration	1	64	Mean Difference (IV, Random, 95% CI)	0.31 [0.01, 0.61]

PERMALINK

Interventions for infantile haemangiomas of the skin

Monica Novoa

Eulalia Baselga

Sandra Beltran

Lucia Giraldo

Ali Shahbaz

Hector Pardo‐Hernandez

Ingrid Arevalo‐Rodriguez

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

Propranolol

Timolol maleate

Atenolol

Bleomycin

Captopril

High‐intensity focused ultrasound (HIFU)

Interferon

Intralesional methylene blue

Imiquimod

Laser

Oral ibuprofen plus oral paracetamol

Radiation

Rapamycin

Steroids

Surgery

Vincristine

Active monitoring

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Timing

Search methods for identification of studies

Electronic searches

Searching other resources

Trials registers

Searching reference lists

Adverse effects

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

'Summary of findings' tables

Results

Description of studies

Results of the search

1.

Included studies

Design

Sample sizes

Setting

Participants

Subtypes of haemangiomas

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Adverse events in general	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	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	1	31	Mean Difference (IV, Random, 95% CI)	0.41 [‐0.84, 1.66]
4 Other measures of resolution: size reduction > 50%	1	26	Risk Ratio (M‐H, Random, 95% CI)	1.22 [0.79, 1.88]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Adverse events	1	26	Risk Ratio (M‐H, Random, 95% CI)	3.0 [0.13, 67.51]
2 Other measures of resolution: size reduction > 50%	1	26	Risk Ratio (M‐H, Random, 95% CI)	1.38 [0.84, 2.24]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Adverse events: complications	1	20	Risk Ratio (M‐H, Random, 95% CI)	1.29 [0.82, 2.03]
2 Other measures of resolution: colour fading	1	20	Mean Difference (IV, Random, 95% CI)	1.0 [‐1.02, 3.02]
3 Other measures of resolution: mean size reduction	1	20	Mean Difference (IV, Random, 95% CI)	‐16.0 [‐42.58, 10.58]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clearance	1	40	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.39, 1.95]
2 Adverse events: ulceration or scars	1	40	Risk Ratio (M‐H, Random, 95% CI)	0.07 [0.00, 1.09]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clearance	1	40	Risk Ratio (M‐H, Random, 95% CI)	0.78 [0.36, 1.68]
2 Adverse events: ulceration or scars	1	40	Risk Ratio (M‐H, Random, 95% CI)	0.11 [0.01, 1.94]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clearance	1	40	Risk Ratio (M‐H, Random, 95% CI)	1.13 [0.55, 2.32]
2 Adverse events: ulceration or scars	1	40	Risk Ratio (M‐H, Random, 95% CI)	0.57 [0.20, 1.65]

Methods	Design: parallel ‐ 2 arms Country: Chile Method of randomisation: simple randomisation Blinding: double‐blind/children – investigators Location: Department of Dermatology, Universidad Católica de Chile Length of follow‐up: 6 months
Participants	Diagnosis: IH needing treatment defined as functional impairment and aesthetic disfigurement Sex. 65.2% were female and 34.7% were male. Age: between 1 and 15 months Inclusion criteria: infants and children from 1 to 15 months old with IH needing treatment, defined as functional impairment, aesthetic disfigurement, and if they were ulcerated or located on folds Exclusion criteria: history of allergy or hypersensitivity to beta blockers, second‐ or third‐degree atrioventricular block, heart failure, severe bradycardia, asthma or bronchial obstruction, and previous use of systemic corticosteroids or other beta blocker Number of randomised children: 23
Interventions	Intervention A (number of children: 13): atenolol 1 mg/kg/day for 6 months in a single daily dose Intervention B (number of children: 10): propranolol in a dose of 2 mg/kg/day in 3 daily doses for 6 months
Outcomes	Primary outcome: response classified as complete response, partial response, no response Secondary outcomes: adverse events, heart rate, blood pressure, heart failure symptoms, and symptoms of bronchial obstruction
Notes	Trial registration: not stated Funder: none Role of funder: none A priori sample size estimation: not stated Conducted: June 2012 to January 2013 Declared conflicts of interest: no conflicts reported (page 1045)
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "Patients who met inclusion criteria were randomised by simple randomisation (...)." Page 1046 Comment: There was insufficient information to rate this item as low or high risk of bias.
Allocation concealment (selection bias)	Low risk	Quote: "Allocation concealment was respected." Page 1046 Comment: Authors reported information about allocation concealment.
Blinding of participants (Performance bias)	Low risk	Quote: "The drugs were similar in aspect and the patients and main investigators were blind." Page 1046 Comment: Authors reported information about adequate blinding of participants and personnel.
Blinding of personnel (performance bias)	Low risk	Quote: "The drugs were similar in aspect and the patients and main investigators were blind." Page 1046 Comment: Authors reported information about adequate blinding of participants and personnel.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	There was insufficient information to rate this item as low or high risk of bias.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No children were lost at follow‐up.
Selective reporting (reporting bias)	Low risk	Selective reporting of information was not detected.
Other bias	Low risk	No other biases were detected.

Methods	Design: parallel ‐ 2 arms Country: Egypt Method of randomisation: children were randomly assigned into 2 groups: Group A were given oral propranolol for 6 months combined with oral prednisolone for the initial 2 weeks, while Group B were given oral propranolol alone for 6 months. Blinding: single‐blind/assessors Location: Pediatric Surgery Department, Ain Shams University, Egypt Length of follow‐up: 8 months
Participants	Diagnosis: cutaneous haemangioma causing complications such as deformity, ulceration, bleeding, infection, or damage of orifices Sex: not stated Age: between 4 weeks and 8 months Inclusion criteria: the included participants had an age less than 9 months, with cutaneous haemangioma causing complications such as deformity, ulceration, bleeding, infection, or damage of orifices. Exclusion criteria: congenital haemangioma, main/extensive deep subcutaneous component, those receiving previous treatment for IH or with hypersensitivity to propranolol, known cardiac disease (heart failure or AV block), pulmonary disease (asthma or bronchiolitis), diabetes mellitus, visceral haemangiomas, or PHACE syndrome Number of randomised children: 40
Interventions	Intervention A (Number of children: 20): children were given oral propranolol dosed as 2 mg/kg/day in 3 divided doses for 6 months combined with oral prednisolone dosed as 2 mg/kg/day in 2 divided doses for the initial 2 weeks, then stopped after gradual tapering over 1 week. Propranolol was gradually tapered over 2 weeks before stopping. Intervention B (Number of children: 20): children were given oral propranolol monotherapy in the same previous dose for 6 months.
Outcomes	Primary: decrease in the dimensions of the haemangiomas Secondary: lightening of colour and flattening of their surfaces
Notes	Trial registration: not stated Funder: not stated Role of funder: not stated A priori sample size estimation: not stated Conducted: December 2011 to March 2014 Declared conflicts of interest: not declared
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "All patients were randomly assigned into one of the two groups at equal probability using sealed envelope method." Page 1504 Comment: Insufficient information to rate this item as low or high risk of bias.
Allocation concealment (selection bias)	Low risk	Quote: "All patients were randomly assigned into one of the two groups at equal probability using sealed envelope method." Page 1504 Comment: Authors reported information about adequate allocation concealment.
Blinding of participants (Performance bias)	Unclear risk	It is highly probable that participants were aware of intervention group assigned, but it is unclear whether this had an impact or not in trial results.
Blinding of personnel (performance bias)	Unclear risk	It is highly probable that researchers were aware of intervention group assigned, but it is unclear whether this had an impact or not in trial results.
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Quote: "Response to therapy was measured by blinded volume estimations at weeks (...)." Page 1504 Comment: Authors reported information about adequate blinding of outcome assessment.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No children were lost at follow‐up.
Selective reporting (reporting bias)	Low risk	Selective reporting of information was not detected.
Other bias	Low risk	No other biases were detected.

Methods	Design: parallel ‐ 2 arms Country: Iran Method of randomisation: children were divided into 2 groups in double‐blind manner. Each group had 16 haemangiomas. Group A was treated with 585 PDL and timolol maleate and Group B with 585 PDL plus lubricant gel as a placebo. Blinding: double‐blind Location: Alzahra hospital (Referral Center for Treatment of Skin Diseases) Length of follow‐up: 6 months
Participants	Diagnosis: cutaneous haemangioma causing complications such as deformity, ulceration, bleeding, infection, or damage of orifices Sex: 24 female, 8 male Age: between 1 and 12 months Inclusion criteria: healthy infants between 1 month and 12 months old with superficial haemangioma ≤ 3 cm and with a history of sensitivity to beta blockers or asthma, renal disease, heart disease, hypoglycaemia, use of drugs that interact with beta blockers Exclusion criteria: haemangiomas > 3 cm, infants older than 1 year, no sensitivity to beta blockers Number of randomised children: 30 (2 children with 2 haemangiomas)
Interventions	Intervention A (Number of children: 15): children were treated with 4 sessions of PDL and timolol maleate gel 0.05%. Intervention B (Number of children: 15): PDL plus lubricant gel as placebo
Outcomes	Primary: improvement in appearance, colour, and size. 2 forms of assessment were used: (1) clinical score for the overall change and (2) visual analogue scale similar to that employed in other objective studies. Secondary: not stated
Notes	Trial registration: not stated Funder: not stated Role of funder: not stated A priori sample size estimation: not stated Conducted: January 2011 to January 2012 Declared conflicts of interest: not declared
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "Then, patients were divided into two groups in [a] double blind manner." Comment: There was insufficient information to rate this item as low or high risk of bias.
Allocation concealment (selection bias)	Unclear risk	There was insufficient information to rate this item as low or high risk of bias.
Blinding of participants (Performance bias)	Low risk	Quote: " (...) Group B with 585 PDL plus lubricant gel as placebo." Page 2 Comment: Placebo intervention was used.
Blinding of personnel (performance bias)	Unclear risk	There was insufficient information to rate this item as low or high risk of bias.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	There was insufficient information to rate this item as low or high risk of bias.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No children were lost at follow‐up.
Selective reporting (reporting bias)	Low risk	Selective reporting of information was not detected.
Other bias	Low risk	No other biases were detected.

Methods	Design: prospective, 2‐arm, randomised controlled trial Country: UK Method of randomisation: block telephone randomisation Blinding: only observer for secondary outcomes Location: The Birmingham Children’s Hospital NHS Trust Length of follow‐up: unclear: researchers followed children up at age 3, 6, 9, and 12 months.
Participants	Diagnosis: children with superficial early haemangiomas, in the proliferative or early proliferative growth phase Sex: male: 43; female: 78 Age: between 1 and 14 weeks at start of trial Inclusion criteria: children with superficial early haemangiomas, in the preproliferative or early proliferative growth phase Exclusion criteria: children with mixed or deep haemangiomas, eyelid haemangiomas, large facial haemangioma at risk of causing great cosmetic deformity, and haemangiomas obstructing vital structures Number of randomised children: 121
Interventions	Intervention group (N = 60 children): PDL with 585 nm venous flash lamp pulsed dye laser at a pulse duration of 0.45 ms, spot diameter of 3 to 5 nm, and energy fluence of 6.0 to 7.5 J/cm² to produce purpura of the entire lesion, repeated every 2 to 4 weeks Control group (N = 61 children): 'wait and see' approach
Outcomes	Primary outcomes: proportion of children with lesions completely healed/minimal residual signs; proportion of parents who consider the child has a problem; adverse events Secondary outcomes: objective measure of resolution by clinician using photographs (surface area and vertical height); average haemangioma problem grading of 5 independent parents
Notes	Trial registration: not stated Funder: Haemangioma and Laser Trust (HALT) and Sunday Mercury Newspaper Role of funder: no role in study design, data collection, data analysis, data interpretation, or writing of report A priori sample size estimation: not stated Conducted: recruitment between May 1999 and May 2000 Declared conflicts of interest: no conflicts reported (page 527)
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quotation: "A block telephone randomisation was provided by the Birmingham Clinical trial unit. We stratified randomisation by completely flat and raised lesions (...)." Page 522 Comment: Authors reported information about adequate random sequence generation.
Allocation concealment (selection bias)	Low risk	Quotation: "A block telephone randomisation was provided by the Birmingham Clinical trial unit. We stratified randomisation by completely flat and raised lesions (...)." Page 522 Comment: Authors reported information about adequate allocation concealment.
Blinding of participants (Performance bias)	Unclear risk	It is highly probable that participants were aware of the intervention group assigned, but it is unclear whether this had an impact or not on the trial results.
Blinding of personnel (performance bias)	Unclear risk	It is highly probable that researchers were aware of the intervention group assigned, but it is unclear whether this had an impact or not on the trial results.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Despite the fact that standardised methods were used, the lead author treated children with PDL and also assessed the primary outcome at 1 year.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Authors performed intention‐to‐treat analysis; all children were analysed for primary outcome.
Selective reporting (reporting bias)	Low risk	All outcomes mentioned in the methods were reported on in the results.
Other bias	Low risk	No other biases were identified.