INTRODUCTION — Infantile hemangiomas are benign tumors of vascular endothelium [1-3]. They are the most common tumors of childhood. They are characterized by a growth phase and involution phase. Despite their benign and self-limited nature, some hemangiomas can cause complications such as ulceration or life-altering disfigurement. In addition, they may compromise vital organ function or herald underlying developmental anomalies of the central nervous system or spine. Infants with cutaneous hemangiomas, most often in the setting of multiple hemangiomas or a solitary segmental hemangioma, occasionally have additional hemangiomas of the liver, brain, respiratory tract, or gastrointestinal tract. Rarely, visceral hemangiomas can be symptomatic and associated with life-threatening complications.

The management of infantile hemangiomas will be discussed below. The epidemiology, pathogenesis, clinical features, complications, and evaluation are discussed separately. Other vascular tumors of childhood are also discussed separately.

●(See "Infantile hemangiomas: Epidemiology, pathogenesis, clinical features, and complications".)

●(See "Infantile hemangiomas: Evaluation and diagnosis".)

●(See "Congenital hemangiomas: Rapidly involuting congenital hemangioma (RICH), noninvoluting congenital hemangioma (NICH), and partially involuting congenital hemangioma (PICH)".)

●(See "Tufted angioma, kaposiform hemangioendothelioma, and the Kasabach-Merritt phenomenon".)

GENERAL APPROACH — The approach to treatment of hemangiomas should be individualized, based upon the size of the lesion(s), morphology, location, presence or possibility of complications, potential for scarring or disfigurement, the age of the patient, and the rate of growth or involution at the time of evaluation [4,5]. The potential risk(s) of treatment must be carefully weighed against the potential benefits.

Consultation with and/or referral to a pediatric dermatologist, vascular anomalies team, or other knowledgeable specialist is warranted for children with hemangiomas with actual or potential risk for complications and/or when therapy is being considered [6]. Such children should be referred as early as possible during the early proliferation phase, ideally by one month of age [7]. (See 'Risk stratification and indications for referral/intervention' below.)

Hemangiomas are managed with clinical examination(s) and education of the family regarding the natural course; potential complications; treatment indications; and risks, benefits, and expectations of available treatment options. Depending upon the type of lesion and the parents' level of concern, the patient may need to be re-evaluated frequently during the proliferative phase and again before school entry. Serial photographs of the lesion can help to monitor the clinical course.

Education of the family should include information about the natural course; potential complications; treatment indications; and risks, benefits, and expectations of available treatment options for hemangiomas. The family should be provided with realistic expectations about the duration of involution and the possibility of residual changes. The involution phase may continue up to the age of 10 years, although in some studies complete involution has been noted at a median age of four years [8,9]. However, this timeline is highly variable and dependent on hemangioma size, morphology, and location. It must also be emphasized that, in many cases, involution does not result in normal-appearing skin. More than one-half of children with untreated hemangiomas experience residual changes such as scarring, atrophy, redundant skin, discoloration, and telangiectasias [10].

Finally, the family should be provided with anticipatory guidance regarding ways to respond to comments and queries from family members and strangers. Parents are commonly subject to inappropriate comments from strangers, including accusations of child abuse [11]. Often children, who are usually extremely curious about the hemangioma, are satisfied to know simply that, "It is a birthmark, it doesn't hurt, and it will get better" [11]. Addressing the psychosocial aspects of care and providing the parents anticipatory guidance, emotional support, and reassurance are essential for the effective management of hemangiomas [4,11-13].

When treatment is indicated, the choice of treatment modality depends upon the above factors, as well as the availability of certain modalities and the experience of the treating clinician.

RISK STRATIFICATION AND INDICATIONS FOR REFERRAL/INTERVENTION — Clinicians should classify an infantile hemangioma as high risk if there is evidence of or potential for the following [7]:

●Life-threatening complications (eg, lesions in the airway, liver, or gastrointestinal tract)

●Functional impairment or ulceration (eg, lesions in the periorbital region)

●Associated structural anomalies (eg, PHACE [posterior fossa anomalies, hemangioma, arterial anomalies, cardiac anomalies, and eye anomalies] syndrome or LUMBAR [lower-body hemangioma and other cutaneous defects, urogenital anomalies, ulceration, myelopathy, bony deformities, anorectal malformations, arterial anomalies, and renal anomalies] syndrome) (see "PHACE syndrome")

●Risk of permanent disfigurement

●Very large (≥5 cm), rapidly growing cutaneous hemangiomas

Examples of high-risk lesions that may require early intervention include [1,7,14]:

●Large, plaque-like (segmental) or combined superficial and deep hemangiomas, especially in trauma-prone locations, have a tendency toward ulceration, which invariably leads to scarring.

●Any lesion of the face, especially when larger or segmental; hemangiomas of the lip (picture 1), nose ("Cyrano nose"), and auricle are particularly prone to disfigurement.

●Large, nodular, superficial hemangiomas, especially those that exhibit a sharp, "cliff-like" border (picture 2), have a "pebbly" surface, or pedunculated lesions (hemangiomas extending from a small base), have the greatest risk of leaving permanent skin change, including residual fibrofatty tissue, that may require surgical revision.

GOALS OF TREATMENT — The goals of hemangioma treatment include [4]:

●Prevention or reversal of life-threatening or function-threatening complications

●Prevention or minimization of disfigurement from residual skin changes

●Minimization of psychosocial distress for the patient and family

●Adequate treatment of ulceration to minimize scarring, bleeding, infection, and pain

UNCOMPLICATED HEMANGIOMAS

Active nonintervention — Active nonintervention (serial observation) is a reasonable approach for many uncomplicated, localized hemangiomas, especially in noncosmetically sensitive locations, because hemangiomas involute spontaneously after the first year of life. However, the decision not to pursue medical and surgical therapy is not necessarily a passive intervention, since the growth and involution of the hemangioma may need to be monitored and the psychosocial implications, particularly of facial hemangiomas, anticipated and addressed [11]. Serial photographs of the lesion may be helpful to monitor the involution process and outcome.

Local therapies — Local pharmacotherapy is primarily used in the treatment of small or superficial infantile hemangiomas and is not indicated for the treatment of complicated lesions. Data on the efficacy of topical therapies, including topical beta blockers, corticosteroids, and imiquimod, are limited.  

Topical beta blockers

Overview of indications — Reports of successful treatment of hemangiomas with systemic propranolol led to the investigation of topical beta blocker therapy for the treatment of infantile hemangiomas [15,16]. Topical beta blockers may be used for the treatment of thin, superficial hemangiomas (eg, hemangiomas of minor cosmetic concern located on the face) as an alternative to observation, particularly if parents desire treatment. Topical beta blockers may also have a role in the treatment of small, ulcerated hemangiomas and in preventing rebound growth in children who are being tapered off oral propranolol [17-19]. (See 'Rebound growth' below and 'Ulcerated hemangiomas' below.)

If a decision is made to use topical beta blockers, we use topical (ophthalmic) timolol gel-forming solution 0.5%. One drop is applied two to three times per day for 6 to 12 months or until stable improvement is achieved.

Efficacy — The efficacy of topical propranolol 1% (not available in the United States) or topical timolol 0.5% has been confirmed by a systemic review and meta-analysis and a large retrospective cohort study [20,21]:

●In a 2015 systemic review and meta-analysis of 14 cohort studies and three randomized trials, the pooled response rate was approximately 80 percent for both topical propranolol and topical timolol [20].

●In a subsequent large multicenter retrospective cohort study, 731 children with predominantly superficial hemangiomas were treated with topical timolol 0.5% twice daily [21]. The primary outcome measure was efficacy assessed by using visual analog scales for color and for size, extent, and volume from review of digital photographs. After six to nine months of therapy, 92 percent of patients showed significant improvement in color and 77 percent in size, extent, and volume.

Safety — Topical timolol is generally well tolerated. However, data on its safety are limited:

●In a retrospective study, 22 high-risk infants (young or preterm infants, infants receiving more than two drops/day, or infants receiving application to a site with potential increased systemic absorption) with hemangiomas predominantly located in the periocular area were treated with topical timolol and received continuous cardiac monitoring (Holter) for at least 24 hours [22]. Two infants developed symptomatic bradycardia associated with apnea or hypothermia requiring discontinuation of timolol; both were preterm (weighing <2500 grams) and had a history of symptomatic bradycardia prior to the initiation of timolol treatment.

●In another study including 40 children of 2 to 35 weeks of age with superficial or mixed-type hemangiomas (nine ulcerated), no bradycardia or changes in pulse rate were detected during treatment with topical timolol gel 0.5% twice daily [23]. Systemic absorption of timolol was examined in a subgroup of 24 children. Timolol was detected in the urine of 20 children and in the serum of all tested children, although serum levels were too low to cause systemic symptoms.

●In a large multicenter retrospective study, 731 children with hemangiomas predominantly superficial and located in the head/neck area were treated with topical timolol 0.5%, one drop twice daily, for an average of 9.5 months [21]. Adverse effects occurred in 25 (3.4 percent) patients, including local irritation (n = 12), ulceration (n = 4), and bronchospasm (n = 3). None of the children experienced cardiovascular adverse effects or required drug discontinuation.

Topical and intralesional corticosteroids — High-potency topical corticosteroids (eg, clobetasol propionate cream) have been used in the past for small, superficial hemangiomas at risk for ulceration or small periocular lesions [24]. They are now infrequently used since the introduction of topical timolol. In the author’s experience, topical corticosteroids may be helpful for the treatment of minor but recurrent ulcerations. Adverse effects of long-term use of topical corticosteroids include skin atrophy, hypopigmentation, and hypertrichosis.

The use of intralesional corticosteroids such as triamcinolone acetonide 10 to 40 mg/mL is limited to small, well-localized, deep hemangiomas [25]. Individual doses should not exceed 3 mg/kg. A response usually is noted within two weeks, with continued response over the ensuing six to eight weeks [26]. Serial injections administered at four-week intervals are sometimes needed. Adverse effects of intralesional corticosteroids most commonly include local skin atrophy from leaks or inadvertent application to normal surrounding skin. Adrenal suppression from systemic absorption is also a possibility, even with localized use [27-29].

Imiquimod — Imiquimod is a topical immune response modifier with antiangiogenic and proapoptotic properties [30]. There are no randomized trials evaluating the efficacy of imiquimod for the treatment of infantile hemangiomas, and results from observational studies and case reports are conflicting [31-36]. Until further studies are available, the decision to prescribe imiquimod should be carefully weighed against active nonintervention and other treatment options for individual patients [37].

HIGH-RISK AND COMPLICATED HEMANGIOMAS — High-risk/complicated hemangiomas that require treatment include large hemangiomas at increased risk of scarring or disfigurement (eg, large or segmental hemangiomas, facial hemangiomas), life-threatening hemangiomas (eg, airway hemangiomas), hemangiomas carrying functional risks (eg, periocular hemangiomas), and hemangioma ulceration that does not respond to standard wound care. (See 'Special situations' below.)

Approach to management during the COVID-19 pandemic — The Hemangioma Investigator Group (HIG) has published recommendations regarding the appropriate use of telemedicine for initial evaluation, treatment initiation, dosing, and follow-up evaluation for patients with infantile hemangiomas requiring treatment with oral propranolol during the coronavirus disease 2019 (COVID-19) pandemic [38]:

●Telemedicine initiation – The HIG suggests that telemedicine initiation of oral propranolol may be considered for infants at standard risk who meet the following criteria [38]:

•Adjusted gestational age >5 weeks

•Normal birth weight

•Normal cardiovascular examination within previous four weeks (including >1 documented heart rate after nursery discharge)

•Normal respiratory examination within previous four weeks

•Healthy in the 24 to 48 hours prior to scheduled telemedicine visit (especially, no respiratory and gastrointestinal signs and symptoms)

•Infantile hemangioma pattern and distribution does not confer risk of PHACE (posterior fossa anomalies, hemangioma, arterial anomalies, cardiac anomalies, and eye anomalies) or LUMBAR (lower-body hemangioma and other cutaneous defects, urogenital anomalies, ulceration, myelopathy, bony deformities, anorectal malformations, arterial anomalies, and renal anomalies) syndrome

•Lack of ulceration or minimal/superficial ulceration

•Caregiver is able to understand instructions and demonstrate comprehension (eg, by repeating instructions provided during visit)

•Multiple infantile hemangiomas with normal liver ultrasound and without cutaneous infantile hemangioma conferring higher risk

●In-person evaluation – The HIG recommends in-person evaluation for infants at high risk:

•Corrected gestational age <5 weeks

•Abnormal cardiovascular examinations or investigations or those who lack documentation of this in the postnatal period

•Medium to high risk of PHACE (ie, large, segmental, facial or scalp infantile hemangioma in segments S1, S3, S4)

•Medium to high risk of LUMBAR syndrome (ie, segmental, perineal, and/or lumbosacral body infantile hemangioma with or without visible associated anatomic abnormalities)

•Significant infantile hemangioma ulceration

•Ongoing poor oral feeding or poor weight gain

•Infantile hemangioma with symptoms of airway compromise (eg, stridor) or beard area infantile hemangioma at high risk for airway infantile hemangioma

•Known pulmonary disease, including ongoing respiratory compromise (eg, dyspnea, frequent wheezing or history of bronchospasm)

•Persistent or ongoing hypoglycemia

•Known or suspected congenital heart disease or suggestive symptoms

•Extensive hepatic hemangiomas

•Known brain malformations

•History of congenital heart disease or sudden death in first-degree relative

•Maternal history of connective tissue disorder

●Initiation via telemedicine and dosing – For patients who are candidates for telemedicine initiation, the HIG suggests a starting dose of 0.5 mg/kg per day divided twice daily and increasing every three to four days by 0.5 mg/kg per day to the target dose of 2 to 3 mg/kg per day divided twice daily.

When to start treatment — We agree with the recommendation of the American Academy of Pediatrics' Clinical Practice Guideline for the Management of Infantile Hemangiomas that infants with high-risk hemangiomas should start treatment or be referred to a specialist at an early age, ideally by four weeks of age [7]. The rationale for early intervention (eg, before the completion of the hemangioma's rapid growth phase) is based on the observation that the most rapid growth of superficial hemangiomas typically occurs between 5.5 and 7.5 weeks of age and that hemangioma precursors are present at birth in nearly two-thirds of the patients [39]. Treatment before the completion of the proliferative phase, which in most cases occurs by five months of age, may prevent poor outcomes. (See "Infantile hemangiomas: Epidemiology, pathogenesis, clinical features, and complications" and "Infantile hemangiomas: Epidemiology, pathogenesis, clinical features, and complications", section on 'Natural history'.)

First-line therapy

Propranolol — Propranolol, a nonselective beta blocker, is the first-line agent for hemangiomas with the potential to impair function or cause permanent disfigurement, if there are no cardiac or neurovascular concerns (algorithm 1) [1,40]. In 2014, propranolol hydrochloride oral solution was approved by the US Food and Drug Administration for the treatment of proliferating infantile hemangioma requiring systemic therapy [41].

Propranolol inhibits the growth and induces the regression of infantile hemangiomas [42]. Potential mechanisms of action for propranolol may include vasoconstriction, decreased expression of vascular endothelial growth factor and basic fibroblast growth factor, and/or triggering of apoptosis [43,44].

Efficacy — In 2008, the serendipitous observation that the use of propranolol to treat heart failure in two young children with infantile hemangiomas was associated with a change in color, softening, and decrease in size of the hemangiomas led to the initiation of larger observational studies and randomized trials. All studies demonstrated improvement with propranolol [42,45-51]:

●In a large, industry-sponsored, randomized trial, 456 infants aged five weeks to five months with a proliferating hemangioma of at least 1.5 cm received placebo or propranolol (1 mg/kg per day or 3 mg/kg per day) for three or six months [51]. Children with high-risk hemangiomas were not included for ethical reasons. The primary outcome was complete or nearly complete resolution of the hemangioma at week 24, assessed by centralized blinded evaluation of digital photographs. Complete or nearly complete resolution of the target hemangioma was observed in 60 percent of patients treated with propranolol 3 mg/kg per day for six months and 4 percent of those treated with placebo. Ten percent of patients in whom treatment was successful required systemic retreatment during follow-up. Mild adverse effects, including diarrhea, sleep disorders, bronchial hyperreactivity, cold extremities, upper respiratory tract infection, and fever, occurred in over 90 percent of patients receiving propranolol and 76 percent of those receiving placebo. Serious adverse events suspected to be related to propranolol were rare (occurred in single patients only) and included second-degree atrioventricular block, bronchiolitis, hemangioma worsening/ulceration, and bradycardia.

●A network meta-analysis of 18 randomized trials and cohort studies including 1265 children aged two weeks to nine years evaluated the relative expected rates of clearance associated with beta blockers and corticosteroids [52]. Oral propranolol in doses ranging from 1 to 4 mg/kg per day had the largest mean estimate of expected clearance (95 percent, 95% Bayesian credible interval [BCI] 88-99), relative to oral corticosteroids (43 percent, 95% BCI 21-66) and placebo or observation (6 percent, 95% BCI 1-11).

●A 2018 systematic review concluded that, compared with placebo, oral propranolol is effective in inducing complete or almost complete hemangioma clearance without a significant increase in the risk of adverse events [53]. However, the included studies were generally of moderate to low quality.

Oral propranolol has also been used to treat infantile hemangiomas beyond the proliferative phase [54,55]. In a multicentric, retrospective study, 42 children aged 7 months to 10 years with documented cessation of hemangioma growth were treated with propranolol 1.5 to 3 mg/kg per day for one to eight months [54]. In all children, the rate of involution increased with propranolol compared with the rate of involution during active nonintervention before treatment.  

Pretreatment evaluation — Treatment with propranolol should be undertaken in consultation with a pediatric dermatologist or other specialist with expertise in the diagnosis and treatment of pediatric vascular tumors and use of propranolol in children (algorithm 1). The pretreatment evaluation (inpatient or outpatient) should include:

●History, with focus on cardiovascular and respiratory abnormalities (eg, poor feeding, dyspnea, tachypnea, diaphoresis, wheezing, heart murmur) and family history of heart block or arrhythmia.

●Physical examination including cardiac and pulmonary assessment and measurement of heart rate and blood pressure. However, since obtaining accurate blood pressure readings in infants is difficult, blood pressure measurement should be attempted only if there is suspicion of underlying cardiovascular disease. (See "The pediatric physical examination: General principles and standard measurements", section on 'Vital signs'.)

●Electrocardiogram in children with:

•Heart rate lower than normal for age

•History of arrhythmia or arrhythmia detected during examination

•Family history of congenital heart disease or maternal history of connective tissue disease

●Imaging studies, including cardiac ultrasound or cardiac magnetic resonance imaging (MRI), should be obtained in children with large facial hemangiomas at risk for PHACE to rule out the possibility of severe aortic coarctation, which is a contraindication to propranolol use. In these patients, baseline head/neck MRI with angiography is also preferred prior to propranolol initiation, unless the clinical situation requires urgent treatment (eg, severe visual obstruction due to an orbital hemangioma). In such cases, propranolol can be initiated at a lower dose and slowly titrated up to a maximum dose of 1 mg/kg/day until imaging can be obtained.

Contraindications — Propranolol treatment is contraindicated in infants and children with:

●Cardiogenic shock

●Documented chronic and significant sinus bradycardia

●Documented chronic and significant hypotension

●Greater than first-degree heart block

●Heart failure

●History of bronchospasm or wheezing

●Hypersensitivity to propranolol

●Preterm infants with corrected age <5 weeks (postnatal age in weeks minus number of weeks preterm)

Initiation of treatment and dosing — In most cases, treatment can be initiated in an outpatient clinical setting by a clinician with experience in the diagnosis and management of infantile hemangiomas (algorithm 1). Every dose increase should also be administered by an experienced clinician in an outpatient setting. However, in accord with an expert consensus panel, we suggest that hospitalization for initiation of oral propranolol be considered in the following circumstances [40]:

●Infants ≤5 weeks of age

●Preterm infants with corrected age ≥5 weeks (postnatal age in weeks minus number of weeks preterm)

●Infants of any age with inadequate social support

●Infants of any age with comorbid conditions affecting the cardiovascular or respiratory system, including symptomatic airway hemangiomas

●Infants of any age with conditions affecting blood glucose maintenance

We generally start treatment with oral propranolol at 1 mg/kg per day in two divided doses, increasing to 2 mg/kg per day, given in two divided doses, after one week. To reduce the risk of hypoglycemia, propranolol is administered immediately after feeding. Administering propranolol after feeds is safer than with feeds, in case the feed is inadequate, and should therefore be preferred.

In case of intercurrent illness associated with vomiting, diarrhea, and/or poor feeding, treatment should be temporarily held and then resumed at the last given dose. If children present with severe respiratory symptoms, including wheezing, propranolol should also be temporarily held and then resumed at a lower dose and titrated up more gradually to a lower target dose (less than 2 mg/kg/day). (See 'Adverse effects' below.)  

Monitoring — Since the effect of oral propranolol peaks at one to three hours after administration, an expert consensus panel has recommended that patients be monitored with measurement of heart rate and blood pressure at one and two hours after the initial dose and after every dose increase of 0.5 mg/kg/day [40]. This is in accord with the US Food and Drug Administration and European Medicines Agency recommendations. However, in clinical practice, many experts (including the author) and other guidelines do not monitor heart rate and blood pressure in clinic after the first dose and after dose increases (algorithm 1) [56-59].

Parents should be educated about recognizing signs of serious adverse effects, which include hypotension, bradycardia, wheezing, and hypoglycemia [60]. Early clinical signs of hypoglycemia include:

●Sweating

●Jitteriness

●Irritability

●Cyanosis

●Poor feeding

●Hypothermia

●Lethargy

All of these clinical signs may be masked by beta blockers except sweating. Thus, sweating may be the most reliable early sign of hypoglycemia to watch for.

Routine screening of serum glucose is not indicated because the timing of hypoglycemic events is variable and unpredictable. In addition, asymptomatic hypoglycemia was not detected in studies that included a random serum glucose as part of routine monitoring [40].

●(See "The pediatric physical examination: General principles and standard measurements", section on 'Heart rate'.)

●(See "Evaluation and diagnosis of hypertension in infants between one month and one year of age", section on 'Blood pressure measurement'.)

●(See "Approach to hypoglycemia in infants and children", section on 'Clinical features'.)

Assessment of response and treatment duration — Children with infantile hemangiomas treated with propranolol should be followed up at one- to three-month intervals for response assessment and dose adjustment for weight gain. The duration of treatment typically ranges between 6 to 12 months (or until the child is a 12- to 18-months-old), but may be longer, depending upon the size and location of the hemangioma and response to treatment.

Although a significant response (reduction in size or nearly complete resolution) is generally seen after three to four months of propranolol treatment, some experts continue therapy until the child reaches the age in which the spontaneous involution phase would normally begin [1]. This typically occurs around one year of age, but may occur earlier or later depending on the hemangioma size.

An open-label, phase 3 multicenter study evaluated the rate of hemangioma resolution in children with high-risk hemangiomas treated with oral propranolol up to the age of 12 months [61]. In this study, 43 children aged 35 to 150 days with hemangiomas that were life-threatening, with periorbital, nasal, labial, laryngotracheal, or limb joint location; disfiguring; or ulcerated and nonresponsive to wound care received oral propranolol 3 mg/kg per day in two divided doses for at least six months or up to the age of 12 months if complete success (defined as hemangioma disappearance or persistence of only minimal degree of telangiectasias, erythema, skin thickening, soft tissue swelling, and absence of functional impact) was not achieved. Complete success was achieved by 34 patients (76 percent, 95% CI 61.7-86.3 percent) treated for a minimum of 6 months and up to a maximum of 12 months of age. After the first six months of treatment, success was achieved by only 21 patients (47 percent, 95% CI 32.7-61.1 percent).

Lack of response to treatment with propranolol is rare. In a French retrospective, multicenter study including 1130 children treated with propranolol, 10 (0.9 percent) had propranolol-resistant hemangiomas [62]. Resistance was defined as continued growth during the proliferative phase or no involution during the postproliferative stage after >4 weeks of oral propranolol at greater than 2 mg/kg per day. Five of the 10 children who did not respond to propranolol had hemangiomas in the postproliferative stage and were older than eight months at the start of treatment. Three children with hemangiomas in the proliferative stage showed a rapid response to adjuvant systemic corticosteroids.

Rebound growth — Rebound growth after propranolol discontinuation has been noted in approximately 14 to 25 percent of children [63-65]. The factors associated with the risk of relapse are not completely understood. Of note, rebound growth has been noted in one patient after administration of the beta-adrenergic receptor agonist salbutamol 10 months after stopping propranolol treatment [66]

Some children with rebound growth may need a second course of propranolol. Topical beta blockers may be used to treat mild to moderate relapses. However, in most cases mild relapses do not require treatment and parents can be reassured about the eventual involution of the lesion.  

In a single-institution study including 158 children with hemangiomas located predominantly in the head and neck region who were treated with propranolol for 3 to 12 months, a relapse occurred in 40 (25 percent) 0.5 to 5 months after treatment cessation [65]. In half of them, the relapse was mild and did not require retreatment. Factors associated with an increased risk of relapse included segmental distribution and depth of the hemangioma.

Adverse effects — Children treated with propranolol should be closely monitored. Serious adverse effects of propranolol therapy for hemangiomas, which include hypotension, bradycardia, hyperkalemia, bronchospasm, and hypoglycemia, are infrequent [51,67,68]. Restless sleep, constipation or diarrhea, and cold extremities or acrocyanosis are more commonly reported [68].

Of the potential serious adverse effects, hypoglycemia is the most worrisome. To reduce this risk, propranolol should be administered during the daytime hours with a feeding shortly before administration. Propranolol should be discontinued during periods of illness or poor oral intake [40,60,69]. Patients who may be at increased risk for propranolol-induced hypoglycemia include children under the age of one year (especially low birth weight infants), patients who were previously treated with prolonged courses of systemic glucocorticoids, and patients with high-output cardiac failure secondary to a large liver hemangioma [69,70]. However, symptomatic hypoglycemia during propranolol use has also been reported in older children [69]:

●In a review of 906 French children (median age 114 days) treated with propranolol for complicated hemangiomas, one or more adverse reactions occurred in 81 (9 percent) [71]. Serious adverse effects (cardiac, respiratory, and hypoglycemia) occurred in 24 patients (2.6 percent).

●Another study using data from the French national medical administrative database covering nearly 100 percent of the French population confirmed an overall good safety profile of oral propranolol for children <3 years without underlying cardiovascular disease [72]. Among 1484 healthy children who received at least two deliveries of oral propranolol, only 2 (0.13 percent) had a cardiovascular adverse effect, compared with 11 of 133 (8.3 percent) children with an underlying congenital cardiovascular disease (standardized morbidity ratio [SMR] 2.8, 95% CI 0-6.7; and SMR 6.0, 95% CI 2.5-9.6, respectively). A moderately increased risk of respiratory adverse events was observed among healthy children exposed to propranolol (SMR for bronchiolitis 1.6, 95% CI 1.1-2.1) but not among those with underlying conditions.

There have been concerns regarding the effects of propranolol on the central nervous system, such as sleep disturbance and agitation:

●A meta-analysis of 11 randomized trials (829 participants) comparing propranolol with placebo or other treatments found an overall incidence of neurologic adverse effects of 7 percent in both propranolol and other treatment groups [73]. An analysis of five of the included trials found a tendency toward an increased risk of sleep disturbances in children treated with propranolol compared with other treatments, although the association was not statistically significant (pooled relative risk 1.67, 95% CI 0.91-3.07).

●A cohort study that compared the sleep behavior at three and six months of age in 54 infants treated with propranolol and 54 untreated infants demonstrated a modest increase in the number of nighttime awakenings per hour and a decrease of sleep efficiency in the propranolol group at six months compared with the control group [74]. Although statistically significant, these differences were likely not clinically relevant. Only 3 of 54 infants were switched from propranolol to atenolol therapy due to severe sleep problems.

Other beta blockers — A few small trials suggested that atenolol, a selective B-1 blocker, and nadolol may be as effective as propranolol for the treatment of proliferative hemangiomas, potentially with a lower rate of adverse effects such as bronchoreactivity and sleep disturbances [75-79]. In a subsequent, large, randomized, open-label trial, 377 infants (mean age 10 weeks) with problematic hemangiomas were treated with propranolol 2 mg/kg per day in three divided doses or atenolol 1 mg/kg per day in a single dose for at least six months and then followed up for two years [80]. At six months, the primary outcome of "any response" was achieved in 93.7 percent of infants in the propranolol group and 92.5 percent in the atenolol group (difference 1.2 percent, 95% CI -4.1 to 6.6 percent) in the intention-to-treat population. At 96 weeks, a complete or nearly complete response was noted in 82.1 percent of infants in the propranolol group and 79.7 percent in the atenolol group (difference 2.4 percent, 95% CI -5.5 to 10.4 percent). Adverse events occurred more frequently in the propranolol group than in the atenolol group (70 versus 44 percent) and included diarrhea, sleep disturbance, cool extremities, and bradycardia.

These results suggest that atenolol is an effective alternative to propranolol. However, its use is limited by the lack of a widely available oral formulation suitable for infants.

Second-line therapies

Systemic corticosteroids — Treatment with systemic corticosteroids for complicated hemangiomas has been largely supplanted by systemic beta blockers. However, systemic corticosteroids remain a treatment option for patients with complicated hemangiomas for whom treatment with beta blockers is contraindicated. (See 'Contraindications' above.)

Systemic corticosteroids were compared with propranolol in a small, noninferiority, randomized trial [81]. In this study, 34 children aged 0.3 to 8.2 months with hemangiomas located predominantly on the face were randomly assigned to treatment with propranolol 2 mg/kg per day in three divided doses or prednisolone 2 mg/kg/day in a single dose for 16 weeks. A response to treatment, broadly defined as stop of progression and volume decrease, was achieved by 96 and 92 percent of patients in the propranolol and systemic corticosteroid groups, respectively. Adverse effects were generally mild and occurred with equal frequency in both groups.

Dosing — The usual starting dose for prednisolone is 2 to 3 mg/kg per day, although some clinicians advocate higher starting doses of up to 5 to 6 mg/kg per day. A single, morning dose is preferred to minimize adrenal suppression. A response (stabilization with or without regression) is usually seen within the first few weeks [82,83]. Treatment is generally continued for several months or more, depending upon the indications for treatment, the response, and the child's age at initiation [13]. Prednisone should be slowly discontinued since abrupt discontinuation or rapid tapering of glucocorticoids while a hemangioma is still in its active growth phase may result in rebound proliferation [12].

Adverse effects — Adverse effects of systemic corticosteroids are more likely to develop with higher doses and courses of six months or longer and resolve with drug tapering:

●The most common complication is the development of a cushingoid facies, which usually begins within the first one to two months of treatment [84].

●Personality changes (eg, depressed mood, agitation, insomnia, restlessness) develop in approximately one-third of infants, usually during the first two weeks of therapy [84].

●Delayed skeletal growth, which may be more readily apparent since a child grows most rapidly during the first year of life, results from a temporary inhibition of collagen synthesis. However, nearly all children catch up to the normal growth curve once therapy has been discontinued, usually by two years of age [84,85].

●Gastric upset occurs in at least 20 percent of infants and can be relieved with histamine 2 (H2) blockers or proton pump inhibitors, which many initiate routinely along with glucocorticoids [84].

●Serious corticosteroid complications, such as aseptic necrosis of the femoral head, hypertension, osteoporosis, and cataracts, are extremely rare in children [84].

Systemic corticosteroids have immunosuppressive effects and can increase the risk for infections [86]. There are at least two reports of Pneumocystis carinii pneumonia (PCP, but officially renamed Pneumocystis jirovecii pneumonia) developing in infants treated with glucocorticoids for hemangiomas [87,88]. While the true risk of PCP and the utility of antibiotic prophylaxis in this population are not known, some advocate that trimethoprim-sulfamethoxazole prophylaxis be considered [86], particularly in infants with airway involvement or other risk factors for PCP [87].

We do not routinely administer PCP prophylaxis to children being treated with systemic glucocorticoids for infantile hemangiomas. However, PCP prophylaxis may be warranted in infants who have other risk factors for PCP (eg, premature infants with significant concomitant medical problems). (See "Glucocorticoid effects on the immune system" and "Epidemiology, clinical manifestations, and diagnosis of Pneumocystis pneumonia in HIV-uninfected patients".)

Live-virus vaccines (eg, measles, mumps, rubella [MMR], varicella, rotavirus), should not be administered while infants are taking supraphysiologic glucocorticoid doses. In addition, because the varicella vaccine is not administered until children are at least one year of age, infants receiving glucocorticoid therapy should avoid exposure to individuals with varicella infection. (See "Standard immunizations for children and adolescents: Overview", section on 'Infants and children'.)

Immunization for diphtheria and tetanus may not be effective in some patients when administered during systemic glucocorticoid therapy [86]. Diphtheria and tetanus titers can be used to confirm protection.

Supraphysiologic doses of glucocorticoids may suppress the hypothalamic-pituitary-adrenal axis. "Stress doses" of glucocorticoids may be necessary for infants who require medical or surgical hospitalization while undergoing glucocorticoid therapy for infantile hemangiomas [89].

Vincristine and interferon alfa — Vincristine and interferon alfa are alternative systemic agents for the treatment of complicated hemangiomas but are rarely used since the advent of propranolol:

●Vincristine – Vincristine is used in the treatment of the Kasabach-Merritt phenomenon associated with the kaposiform hemangioendothelioma and tufted angioma [90,91] (see "Tufted angioma, kaposiform hemangioendothelioma, and the Kasabach-Merritt phenomenon"). Its use may rarely include more aggressive hemangiomas as an alternative therapy for life-threatening or severely life-altering hemangiomas unresponsive to propranolol or corticosteroids.

Vincristine is generally administered by a central venous catheter. Its administration is commonly overseen by a pediatric hematologist/oncologist [92-94]. Toxicities of vincristine include peripheral neuropathy, constipation, jaw pain, and rarely leukopenia and anemia.

●Interferon alfa – Interferon alfa, a potent inhibitor of angiogenesis, has been used in the past as an alternative therapy for aggressive hemangiomas not responsive to glucocorticoids [5,95-97]. The initial dose of interferon alfa is 3 million units/m² per day [4]. The interval between administration and response ranges from a few weeks to several months [13].

Adverse effects of interferon alfa that are usually transient include fever, irritability, neutropenia, and liver enzyme abnormalities [82]. The most worrisome adverse effect of interferon is severe neurotoxicity, including spastic diplegia.

In one meta-analysis including 441 infants with vascular lesions treated with interferon, 11 (2.5 percent) developed permanent spastic diplegia and 16 (3.6 percent) motor developmental complications that reversed upon discontinuation of therapy [98]. Because of this concerning adverse effect, interferon alfa is rarely used for the treatment of infantile hemangiomas.

Surgical therapies — When a hemangioma poses primarily cosmetic concerns, therapeutic intervention must be tailored on an individual basis. In addition to systemic, topical, and intralesional medications, therapeutic options include laser therapy and surgery. Cautery, irradiation, and cryotherapy may produce more scarring than untreated lesions and are thus not generally recommended.

Pulsed dye laser — The pulsed dye laser (PDL) cannot be expected to affect thicker, superficial hemangiomas or those with deep involvement, since the depth of laser penetration is only 1.2 mm. The most accepted use of PDL in the management of hemangiomas is the treatment of ulceration, post-involution erythema, and/or telangiectasias [5]. Small, thin, superficial hemangiomas early in the proliferative phase may also be appropriate candidates for laser, but which hemangiomas benefit most from laser therapy and what the optimal settings are remain areas of controversy [99]. Indications, efficacy, and adverse effects of PDL therapy for infantile hemangiomas are discussed in detail elsewhere. (See "Laser and light therapy for cutaneous vascular lesions", section on 'Infantile hemangiomas'.)

Excisional surgery — Surgical excision is often reserved for involuted lesions with residual scars or loose skin; hemangiomas with inadequate involution by age four; pedunculated cutaneous hemangiomas (because of the risk of scarring); small, localized periorbital hemangiomas; and slowly involuting lesions in cosmetically concerning locations [8,82,100]. Excisional surgery may also be considered for large periocular hemangiomas, refractory ulcerated hemangiomas, and nasal-tip hemangiomas, but only if medical therapy is thought to pose a greater risk and the resultant scar is likely to be acceptable. In cases without complication, but for which there is uncertainty about the outcome, the benefits and risks of surgical intervention must be carefully considered since the surgical scar may be worse than the results of spontaneous involution [83,101].

Embolization — As a last resort, large visceral (especially hepatic) hemangiomas have been treated with arterial embolization after failure of medical therapy [100]. The results may be temporary.

SPECIAL SITUATIONS

Periocular hemangiomas — Periocular hemangiomas, and especially those that are larger than 1 cm, involve the upper eyelid, have a deep component, can compromise vision, and cause amblyopia, astigmatism, or strabismus [102]. These hemangiomas should be evaluated by an ophthalmologist experienced with hemangiomas and their treatment [26]. Superficial periocular hemangiomas have been successfully treated with topical beta blockers [15,103]. Surgical excision also may be an option for small, localized lesions [104-107].

Vision-threatening cases are generally treated systemically with propranolol or, less commonly, with intralesional corticosteroids [25,46,108-111]. Intralesional corticosteroids should be managed by a specialist, most often an ophthalmologist with knowledge and experience in this area. Rare but serious side effects, including eyelid necrosis, central retinal artery occlusion, and adrenal suppression, have been reported [112-116].

Ulcerated hemangiomas

Wound care and topical agents — Gentle and meticulous local wound care is the mainstay of ulcer therapy and is particularly important for lesions in locations subject to trauma and infection, such as the perineum (picture 3). Local wound care reduces pain and helps to prevent secondary infection [117]. Commonly used therapies include topical antibiotics, barrier creams, and nonstick dressings [118]. Very gentle debridement of crusted wounds with saline soaks two to three times daily may also be helpful since crusting prevents re-epithelization and favors infection.

There are a few reports of successful use of topical timolol for the treatment of ulcerated hemangiomas [18,119-121]. In one retrospective analysis of 30 children with hemangiomas with focal to 3 cm ulcerations predominantly located in intertriginous areas, treatment with one drop twice daily of timolol 0.5% gel led to ulcer resolution after an average of 93 days [18]. (See 'Topical beta blockers' above.)

Topical metronidazole gel, often used in combination with topical mupirocin, has proved to be safe and efficacious for ulceration, particularly in intertriginous or moist areas such as the lip and perineum [117]. When clinically indicated, broad-spectrum oral antibiotics are also occasionally used.

Becaplermin, a synthetic form of platelet-derived growth factor, is approved by the US Food and Drug Administration for treatment of lower-extremity diabetic neuropathic ulcers. It has been reported to be effective as a second-line topical therapy in the treatment of ulcerated hemangiomas that are refractory to standard care [122,123]. Becaplermin prescribing information contains a boxed warning about the possible risk of death from cancer in patients who receive repeated treatment with becaplermin [124]. The studies that prompted the warning were performed in adult patients with diabetes. No cases of cancer have been reported in children who were treated with becaplermin for hemangioma ulceration.

Oral propranolol — We suggest oral propranolol in addition to meticulous wound care and appropriate analgesia for the treatment of ulcerated hemangiomas that may cause permanent disfigurement; interfere with daily life activities (eg, diaper changes, bathing, feeding, sleeping); or are unresponsive to wound care and pain and infection control. (See 'Propranolol' above.)

A beneficial effect of propranolol on ulcerated hemangiomas has been reported in several case series [125-128]:

●In two studies, treatment with oral propranolol (2 to 2.5 mg/kg per day) was associated with a shorter time to pain control and healing (mean time to healing of 4.3 and 8.7 weeks compared with 22.4 weeks in a group of historical controls treated only with supportive measures) [125,126].

●In another study, 64 infants with ulcerated hemangiomas of the head and neck region were treated with oral propranolol 2 mg/kg per day in three divided doses or a combination of ibuprofen 10 mg/kg and paracetamol 16.2 mg/kg every eight hours for up to six months [129]. A complete or partial response was achieved in 24 of 28 patients in the propranolol group and in 12 of 24 patients in the ibuprofen/paracetamol group, with a mean time to healing of 18 and 28 days, respectively.

Analgesia — The pain associated with ulceration can be severe. Affected infants commonly suffer from sleep disturbance and increased irritability. Use of oral acetaminophen (without codeine) or a topical anesthetic agent (ie, lidocaine hydrochloride 2 to 5% ointment) may be warranted. To avoid the risk of lidocaine toxicity, parents should be instructed to apply only a pea-sized amount of lidocaine to the affected area no more than four times per day. (See "Evaluation and management of pain in children", section on 'Pharmacologic therapy'.)

Eutectic mixture of local anesthetics (EMLA) should be avoided in infants less than three months of age because it contains prilocaine hydrochloride, which has been associated with infantile methemoglobinemia. Infants younger than three months have low levels of methemoglobin reductase. The risk of methemoglobinemia is increased when EMLA is used concomitantly with other methemoglobinemia-associated drugs (table 1). (See "Methemoglobinemia", section on 'Topical anesthetics'.)

Pulsed dye laser — Pulsed dye laser (PDL) 595 nm can be used as an adjunctive treatment for ulcerated hemangiomas that fail to heal after medical therapy and optimal wound care [1]. Treatment can be repeated at two- to four-week intervals. (See "Laser and light therapy for cutaneous vascular lesions", section on 'Infantile hemangiomas'.)

Airway hemangiomas — Because of the small caliber of the infant airway, a growing airway hemangioma can lead to life-threatening airway obstruction. (See "Infantile hemangiomas: Epidemiology, pathogenesis, clinical features, and complications", section on 'Airway hemangiomas'.)

Systemic propranolol is generally the first line of therapy for children with symptomatic airway hemangiomas [45,130]. Laser ablation is an occasional second-line therapy [131]. Rarely, tracheotomy may be required.

In a multicenter study, 27 infants aged one to five months with airway hemangiomas were treated with oral propranolol 2 mg/kg per day for a median time of 15 months (range 7 to 34 months) [132]. Eleven children were treated with propranolol alone, whereas 16 received intralesional corticosteroid injection at the time of propranolol initiation. The symptoms of stridor generally resolved within a day of initiation of propranolol treatment. However, additional therapy, including systemic steroids, laser ablation, or surgical excision, was required in 16 children because of recurrence of respiratory symptoms.

High-output failure — Infants with significant hepatic or very large cutaneous hemangiomas may rarely develop high-output heart failure within the first several months of life. Treatment in such cases may include: systemic propranolol and/or glucocorticoids; vincristine or interferon in unresponsive, life-threatening cases; hepatic arterial embolization in selected hepatic cases; and/or treatment of heart failure (with fluid restriction, diuretics, and digoxin as indicated) [133,134].

PHACE syndrome — The presence of severe arterial anomalies may restrict the use of propranolol in a small subset of patients with PHACE (posterior fossa anomalies, hemangioma, arterial anomalies, cardiac anomalies, and eye anomalies) syndrome (MIM 606519) [135]. In addition to large facial hemangiomas, patients with this disorder exhibit coarctation of the aorta and abnormalities of the cerebral and cervical vasculature and vessels of the aortic arch. It is known that a small percentage of patients with severe cerebral or cervical anomalies develop acute arterial ischemic stroke, most often during infancy or toddlerhood [136]. Thus, there is at least theoretical concern that propranolol-induced hypotension and reduced cerebrovascular perfusion in patients with already compromised cerebral vasculature could increase the risk of stroke in this population [135]. (See "PHACE syndrome".)

Consensus guidelines recommend that infants with PHACE syndrome be thoroughly evaluated with magnetic resonance imaging/magnetic resonance angiography (MRI/MRA) of the head and neck and cardiac imaging to include the aortic arch before starting propranolol treatment [40]. MRA findings that confer the highest risk of stroke include severe, long-segment narrowing or nonvisualization of major head or neck arteries without adequate collateral/compensatory circulation, especially in the presence of concomitant cardiac and aortic arch anomalies [136]. (See "PHACE syndrome".)

The risks and benefits of propranolol treatment for patients with PHACE syndrome who have high-risk MRA features should be discussed in consultation with neurology and/or cardiology specialists [40]. If the potential benefits of propranolol treatment are deemed to outweigh the risks, propranolol should be given at the lowest possible dose, with slow upward dose titration and three-times-daily dosing [40]. This schedule is aimed at minimizing abrupt changes in systolic blood pressure, which is a known risk factor for stroke. (See "PHACE syndrome", section on 'Propranolol'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Infantile hemangiomas and PHACE syndrome".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Hemangioma (The Basics)")

SUMMARY AND RECOMMENDATIONS

●The approach to the treatment and the choice of treatment modality for infantile hemangiomas should be individualized depending upon the size of the lesion(s), location, presence of complications, potential for scarring or disfigurement, the age of the patient, the rate of growth or involution at the time of evaluation, the potential risk(s) and benefits of treatment, the availability of the various modalities, and the experience of the treating clinician. (See 'General approach' above.)

●Treatment is usually required for complicated hemangiomas that may interfere with a vital structure or function and for lesions at increased risk of ulceration, scarring, and disfigurement. The goals of treatment include prevention or reversal of life- or function-threatening complications; prevention or minimization of disfigurement, bleeding, infection, and pain; and minimization of psychosocial distress for the patient and family. (See 'Risk stratification and indications for referral/intervention' above.)

●We suggest active nonintervention for uncomplicated hemangiomas that are not disfiguring (Grade 2C). Active nonintervention requires regular monitoring of the clinical course and attention to the psychosocial implications for the child and family. (See 'Active nonintervention' above.)

●We recommend oral propranolol as the first-line agent for the treatment of complicated hemangiomas with the potential to impair function or cause disfigurement (eg, periorbital hemangiomas) (Grade 1A). Treatment is started with 0.5 to 1 mg/kg per day and then gradually increased to the target dose of 2 mg/kg per day (algorithm 1). (See 'Propranolol' above.)

●Systemic glucocorticoids, vincristine, and interferon alfa are alternative agents for aggressive hemangiomas but are rarely needed since the advent of propranolol. (See 'Systemic corticosteroids' above and 'Second-line therapies' above.)

●Children with periorbital hemangiomas should be evaluated by an ophthalmologist who is experienced in the treatment of hemangiomas. (See 'Periocular hemangiomas' above.)

●We suggest oral propranolol in addition to meticulous wound care and appropriate analgesia for the treatment of ulcerated hemangiomas that may cause permanent disfigurement, interfere with daily life activities, or do not respond to wound care measures (Grade 2C). (See 'Ulcerated hemangiomas' above.)