consensus document for the treatment of infantile haemangiomas · these benign tumours do not...

Radboudumc Nijmegen C.J.M. van der Vleuten, DermatologistB.H. Verhoeven, Paediatric surgeon L.J. Schultze Kool, Interventional radiologist UMC Utrecht/ WKZC.C. Breugem, Plastic surgeon M. de Graaf, Dermatologist A. van Dijk, Paediatrician ErasmusMC RotterdamP.C.J. de Laat, Paediatrician S.G.M.A. Pasmans, Dermatologist M.F. Raphael, Paediatrician AMC AmsterdamC.M.A.M. van der Horst, Plastic surgeonM.A. Middelkamp Hup, Dermatologist O. Lapid, Plastic surgeon

HEVAS Patient Organisation Vascular Anomalies M.P. Jongma, Chair HevasC.T. van den Bosch, Vice chair Hevas

Consensus document for the treatment of infantile haemangiomasDetermined on 5 July 2017 in collaboration by four - recognised by the Minister of Health, Welfare and Sports centres of expertise in the field of congenital vascular anomalies together with patient organisation HEVAS.

2017

ContentI. Introduction 4

ll. Why is a consensus document needed? 4

III. The role of centres of expertise in infantile haemangiomas 4

IV. About infantile haemangiomas 5 A. Incidence and risk factors 5 B. Evolution, complications, and associated syndromes 5 Evolution 5 Complications 6 Associated syndromes 7 C. History, physical examination, and differential diagnosis 7 History, general paediatric and specific anamnesis 7 Physical examination 8 Differential diagnosis 8 D. Additional research 8 Photographic recording 8 Echo-Doppler / duplex 8 MRI/MRA 9 Blood tests 9 Biopsy 9

V. Management of infantile haemangiomas 9 A. Indicaties voor behandeling 10 B. Treatment options 10 I. Systemic drug therapies 10 II. Topical treatments 13 III. Surgical treatment options 14 IV. Management of ulcerated IH 14

VI. Patient information 15

VII. References 16

CONSENSUS DOCUMENT FOR THE TREATMENT OF INFANTILE HAEMANGIOMAS | 3

4 | CONSENSUS DOCUMENT FOR THE TREATMENT OF INFANTILE HAEMANGIOMAS

I. Introduction

Congenital vascular anomalies are divided into vascular tumours and vascular malformations.1 Infantile haemangioma (IH) is the most common vascular tumour in children, with an incidence of 5-10%2, 3 in all infants, and is characterized by abnormal proliferation of endothelial cells and abnormal vascular architecture. 3-5 IH shows a characteristic nonlinear growth pattern with rapid growth in the first weeks / months of life, followed by a plateau phase with spontaneous regression in the following years. IH is always benign. However, due to the location of the IH and complications, the course in 5-10% of the children may be complicated and an active approach is needed to prevent short-term and long-term damage.

IH present themselves in different ways. We distinguish different types: superficial, deep and mixed IH, and also IH that remain flat (reticular / abortive / minimal growth). On the basis of the pattern, there are also differences between IH (focal, multifocal, segmental and indeterminate).1 Visceral localisation is also known, particularly in the liver1. Despite the differences in appearance, IH all have the same basic, clinical and biological characteristics.

II. Why is a consensus document needed?

IH is very common: 5-10% of children 2, 3. These benign tumours do not always need to be treated; but a policy must be made for every IH. This is mainly due to the fact that:

• It may be a different fast-growing tumour / anomaly that may initially resemble an IH. It is crucial to exclude other, benign or possibly malignant (vascular) tumours 6. • IH may lead to (early and late) complications; these are not always predictable; timely treatment can possibly prevent complications.• Many IH do not disappear without residue. Timely treatment can potentially reduce residual defects.7 • The visibility of the IH can have psychosocial impact on parents and children, both in the young and older age groups.• IH may be associated with other anomalies in the context of a syndrome.

An expectative policy is in many cases a good policy, but only after the correct diagnosis has been made, an assessment of possible complications or residual lesions has been done, and an explanation has been given to parents about the expected course of the disease. It is also important to create a safety net for the parents during the growth phase of the IH, as rapid growth of the IH can bring a lot of uncertainty.

Treatment has significantly changed and been simplified since the discovery of the beta-blocker’s effectiveness in 2008, whereby an active approach may be acted upon more promptly. As a result, the perspective on the policy for IH has changed in recent years and is still subject to change, based on new insights and new studies.

III. The role of centres of expertise in infantile haemangiomas

This revised consensus document for IH, drawn up by specialists from the four centres of expertise for (congenital) vascular anomalies, recognised by the NFU and the Ministry of Health, Welfare and Sport, together with Patient Organisation HEVAS, aims to provide more clarity on the question in which IH there are indications for further diagnostics, treatment, and/ or (digital) consultation of one of the recognised centres of expertise? Ideally, each patient with an IH with risk of complications or associations should be referred to (a member of) a multidisciplinary team for evaluation, specific diagnosis, and assessment or start of treatment.8

It may be possible to have consultations based on photos, by means of telemedicine. Consultation with one of the centres of expertise before the start of beta-blocker or other treatment, and at the end of a treatment program should always be considered.

Experience has shown that treatment by doctors with specific experience with IH in a centre provides added value for patients and parents through the multidisciplinary approach of dermatologists, paediatricians, (paediatric and plastic) surgeons, and other medical specialists.

CONSENSUS DOCUMENT FOR THE TREATMENT OF INFANTILE HAEMANGIOMAS| 5

IV. About infantile haemangiomas

A. Incidence and risk factors IH is the most common benign tumour in childhood. Fifty percent of the IH is located in the head and neck area.

The main risk factors for the development of IH are the female gender, low birth weight, and premature birth.2-4, 9-11 Low birth weight seems to be the most important risk factor: for every 500 g decrease in birth weight, the relative risk of IH rises to 25-40%.4, 12 Other risk factors are: multiple pregnancy, trans-cervical chorionic villus sampling, high maternal age, breech presentation, 1st child, in vitro fertilisation, preeclampsia and placental anomalies (e.g. placenta praevia, placental release, and abnormal insertion of the umbilical cord).2, 3, 11, 13 A first-degree relative with an IH also doubles the probability of IH 12. Usually, IH is not hereditary. In certain families where IH occurs more often, there are indications that heredity does play a role. In genealogical research in families with IH, at least two possible mechanisms for IH heredity have been proposed: autosomal dominant and maternal transmission. Additional genetic studies are needed to further investigate this.14

B. Evolution, complications, and associated syndromes

EvolutionIH shows a characteristic nonlinear growth pattern: they usually manifest themselves during the first or second week of life, but not later than the age of 12 weeks.3 Up to 65% of children, precursor lesions are observed at birth (pale, erythematous or telangiectatic maculae).15 Most growth occurs before the age of 12 weeks.15 The growth rate then drops and the growth usually comes to a standstill between the ages of 4 and 9 months.8 Flat, segmental IH, and large focal IH (predominantly deep, and predominantly in the parotid area located, IH) may experience a prolonged growth phase into the second and third year of life.16

IH undergo spontaneous involution between the 2nd and 6th (and sometimes up to the 10th) years of life.4, 5 Some IH disappear without leaving a residual lesion, but a significant number leaves skin change, including: atrophy, telangiectasia, skin surplus, fibro-fatty tissue, pigmentation changes, and scars (after ulceration).17-19


ComplicationsSome IH-patients develop complications and may need treatment.11 Typical complications include ulceration, disability (sometimes life-threatening), and (potential or actual) deformation.

UlcerationUlceration is the most common complication and is seen in about 10% of all IH and 15-25% of patients with IH in specialised centres.20, 21 Locations prone to ulceration are the lower lip, the neck, and the anogenital region. Large, segmental, superficial (plaque-shaped) IH are more prone to ulceration than small, focal, or deep IH.22-24 Ulceration occurs at a median age of 4 months, usually in the proliferation phase, and can give rise to bleeding or infection, but pain is usually the main symptom.

(Vitale) functional disabilityPeri-ocular and / or intra-orbital IH can threaten vision and be the cause of amblyopia, astigmatism, or strabismus. An increased risk of amblyopia occurs in particular in IH larger than 1 cm in diameter, to the nasal side of the eye, IH giving pressure to the eyeball, IH causing ptosis, or IH at the eyelid margin.25-29

IH at the nose may threaten the airway. Airway involvement of subglottic IH, often associated with cutaneous (segmental) IH in the beard area, can lead to life-threatening airway obstruction.30-32 Lip IH or peri-oral IH can affect dietary intake, either or not due to ulceration.33 Voluminous IH in the neck may affect neck mobility. Children with multiple cutaneous IH (defined as ≥ 534 IH and certainly at > 10 IH 35) have an increased risk of clinically relevant liver and visceral IH, and therefore have to be screened by ultrasound of the abdomen 35. In rare cases, multifocal liver IH and / or large IH elsewhere in the body are the cause of high output congestive heart failure36 and / or thyroid dysfunction (hypothyroidism).37

DeformationDeformation can be the result of large IH, central in the face, especially at the location of the nose, lips, forehead, cheeks and ears.17, 38

In cases of nose and lip IH, it is known that regression can be slow and often incomplete. IH of the parotid region are often large and tend to regress more slowly than other IH. In more than 50% of the children referred for treatment of the IH, cosmetically disturbing residual symptoms will remain after involution.18, 19


Associated syndromesFor a small part of the IH, the IH may be a feature / part of an underlying disorder and / or structural anomaly, and the physician must realize that further additional examination / imaging is required. This concerns in particular the larger, segmental, plaque-shaped, flat IH in the face or in the lumbo-sacral / peri-anal / genital area.

The following structural disorders / syndromes need to be considered here:

PHACES syndrome This acronym PHACES stands for: Posterior fossa malformation (posterior part of the brain), Haemangiomas, Arterial vascular anomalies, Cardiac anomalies, Eye and Sternum anomalies.To diagnose PHACES, criteria were established during a consensus discussion in 2009, at which it was decided that there should be at least a segmental IH in the face or scalp (or an IH > 5 cm) in combination with one or more of the other characteristics. In all children with a segmental IH, even if this is not in the face, referral is recommended to a centre of expertise, specialised in vascular anomalies for further analysis.39,40 Larger segmental IH on the upper half of the body may also be associated with the structural anomalies of PHACES; the ‘PHACE-without-face’ phenomenon.41

LUMBAR syndrome and spinal dysraphismMidline IH in the lumbo-sacral or perineal area, formerly summarised under acronyms such as LUMBAR 42, PELVIS43 of SACRAL syndrome8, 44, are similar to PHACES and can also be an indication of associated, underlying problems. The acronym LUMBAR stands for Lower body IH and other cutaneous defects, Urogenital anomalies / Ulceration, Myelopathy, Bone deformities, Anorectal malformations / Arterial anomalies and Renal anomalies.42 Lumbo-sacral or perineal IH in the midline can thus be associated with urogenital, anorectal and vascular anomalies, but also spinal defects such as tethered cord, spinal dysraphism, and lipomeningocele.45

In children with a segmental IH (> 2.5 cm) in the lumbo-sacral, genital and peri-anal area referral to a centre of expertise for further analysis is advisable.45

C. History, physical examination, and differential diagnosisMost IH can be easily distinguished from (other) vascular anomalies by the typical growth and regression pattern of IH. However, it is very important to realize that a rapid growing tumour / abnormality in the neonatal phase may be another rapid-growing tumour / anomaly that may initially resemble an IH. It is crucial to exclude other benign or possibly malignant vascular lesions.

In 95% of the cases, the diagnosis can be made on the basis of the history, anamnesis, and physical examination. The following topics are important here:

History, general paediatric and specific anamnesisa. General medical history of the child and his / her family historyb. History, specifically regarding pregnancy c. Premature birth, neonatal complicationsd. Birth weighte. Appearance of the vascular lesion after birthf. Identify precursor places like pale patches resembling naevus anemicus, telangiectasia on livid surfaces or areas of erythema which resemble wine stains or hematomag. Disproportionate growth of the spot or spotsh. Painful, ulcerated, inflamed or bleeding spots i. Prior treatment(s) and the reaction of the skin lesion thereonj. Sudden growth, tense sensation of the spot, tenderness, and purple discolouration in a large ‘hemangioma’ may indicate the presence of the Kasabach-Merritt phenomenon, a consumption coagulopathy with thrombocytopenia, low fibrinogen, and increased dimers. This syndrome does not occur with normal IH but with other vascular tumours namely kaposiform hemangioendothelioma or tufted angioma.k. Breathing difficulties or stridor (progressive biphasic inspiratory and expiratory stridor between the ages of 6-12 weeks). IH in the beard area have a higher risk of associated airway IH.30-32


Physical examinationa. Skin and mucosal examination for the presence of other IH b. Presence of lumbo-sacral IH located in the midlinec. Measuring the superficial component of the IH (in mm) d. The examination of the liver can give an indication of the presence of hepatic IH (usually in conjunction with multiple (≥ 5) IH of the skin)e. Signs of high output heart failure (occasionally occurring in very large IH)f. Low threshold examination by ophthalmologist (and possibly orthoptist) if the IH is located in the peri-orbital region or between the eyes and / or nasal bridge.

Differential diagnosis: 8, 46, 47

Present at or arising immediately after birth• Congenital haemangioma (RICH, NICH of PICH)• Kaposiform hemangioendothelioma or tufted angioma • Capillary malformations (port wine stain)• Vascular malformation (venous, lymphatic, or mixed) 1

• Other: myofibromatosis, dermoid cyst, teratoma, sarcoma (fibro sarcoma), neuroblastoma, leukaemia (‘blueberry muffin baby’)

Arising after birth• Telangiectatic / pyogenic granuloma • Vascular malformation (venous, lymphatic or mixed)1

• Kaposiform hemangioendothelioma • Malignant tumours (sarcoma, lymphoma, cutaneous localization of neuroblastoma or leukaemia)• Others: hamartoma, benign tumours (pilomatrixoma, Spitz naevus, myofibromatosis, neurofibroma, facial granuloma, myxoma, lipoblastoma)

D. Additional researchIH is usually clinically diagnosed. Additional research is rarely indicated. The following diagnostic tests may be useful in atypical cases. But also as an addition, to assess possible potential complications or to better assess the extent of the IH.

In the case of an unclear diagnosis or atypical course, additional diagnostics and follow-up in a specialized expertise centre is necessary to prevent unnecessary diagnostics, interventions, and delay.The following additional (imaging) studies may be indicated.

Photographic recording for follow up (if possible by Medical Photographer)

Echo-Doppler / duplex• For large subcutaneous IH, especially in the parotid, supraglottic or paratracheal region, Doppler (or duplex) is recommended. The high-flow pattern combined with the typical course of an IH makes the diagnosis IH probable. In deeper IH in the growth phase, Doppler / doptone makes it relatively easy to differentiate with a venous malformation (low flow).


• An ultrasound of the liver (and total abdomen) should be performed to exclude visceral IH in children with 5 or more cutaneous IH, in particular those younger than 6 months of age, (diffuse neonatal haemangiomatosis versus benign cutaneous haemangiomatosis).34 • Consultation with a paediatric cardiologist and echocardiography may be considered in children with bulky IH, due to the increased risk of high output heart failure. Also, due to possible cardiac anomalies in large segmental IH (suspected PHACES), consultation with a paediatric cardiologist and echocardiography is indicated, ideally before the onset of (beta-blocker) treatment.40

• In case of a segmental, sacral IH in the midline, an ultrasound to exclude a myelodysplasia (e.g. tethered cord) may be sufficient (before the age of 2-3 months this is still a reliable investigation to be carried out, after which an MRI is often indicated).48

MRI/MRA• An MRI / MRA is only performed on indication in specialized centres (special MRI protocols with dynamic series). Usually, anaesthesia is required for this. An MRI can be performed without anaesthesia in the first weeks after birth.• An MRI may be necessary to exclude a myelodysplasia (e.g. tethered cord) at a lumbo-sacral IH.

Blood tests • Coagulation tests > No coagulation problems have been described in IH. Therefore, there is no indication for coagulation tests. • Hypothyroidism > Children with large intrahepatic IH have to be screened for hypothyroidism.37

Biopsy (rarely necessary)• Only in a (recognised) centre of expertise, a biopsy can be performed in some cases to distinguish atypical IH from other tumours as mentioned in the differential diagnosis. Glut-1 immunohistochemical staining is always positive in IH and not in vascular malformations.49

V. Management of infantile haemangiomas

To treat or not to treat? Due to heterogeneity of the condition with complications and the unique, natural development pattern, care and treatment of IH is complex. Most IH will regress without treatment. But IH can cause functional disorders, temporary or permanent deformation, and psychosocial distress. After involution, a significant part of the IH leaves scars, fibro-fatty tissue, telangiectasia, and other skin deformations. The final size, the rate of involution and the results after natural involution are difficult to predict in the first months / years, even for the most experienced doctors. This complicated relationship between growth, possible complications and associations, spontaneous involution, and possible residual lesions plays an important role in any decision about whether or not, when and how to treat.

Active non-interventionIn case it has been decided NOT to start treatment, the patient with an IH with possible risks / complications, especially during the proliferation phase of the IH, should be regularly monitored. Monitoring intervals should be adapted according to the age of the child, which is inversely proportional to the growth rate of the IH. The recommended interval for the follow-up of an ‘at risk’ IH can be determined as follows, taking age into account:

Age in months = follow-up interval in weeks50

Photo documentation is recommended (taking photos at each follow-up consultation).50


Active intervention

A. Indications for treatment For the following IH, treatment may be necessary or considered:

• Life and function threatening IH: (e.g. IH that can cause vision problems, cause breathing difficulties due to localisation in the airway, cause congestive heart failure, or when the liver is affected. IH causing hypothyroidism.)• IH in certain anatomical locations that often leave permanent scars or deformations, especially at the nose, lips, ear, eyes, in the area between the eyebrows, around the nipple (especially in girls).• IH with (impending) ulceration• Pedunculated IH, because they may result in fibro-fatty tissue/ skin-surplus after involution• Peri-anal / genital IH with (impending) ulceration• Large bulky IH (in the face), especially those with a prominent superficial component. They often give fibro-fatty tissue and / or cutis laxa later on.18 • In the case of smaller and superficial IH in visible areas, for example in the face and on hands, topical treatment can be considered for a cosmetic indication.

Furthermore, there are a number of factors that influence the choice of treatment:• Phase in which the IH is: proliferation phase, plateau phase, or involution phase• Location and type of IH• Parents’ preference• Experience of the physician and availability of certain treatment methods

B. Treatment options With the advent of beta-blockers in the treatment of IH, many classic therapeutic options have become less common or obsolete. This concerns various topical, intra-lesional and systemic treatments that have been used for decades, including imiquimod, interferon and cytostatics, radiotherapy and cryotherapy.51 Actually, there is hardly any indication in IH for these treatment options.Below is an overview of the current treatment arsenal for IH.

I. Systemic drug therapies

Systemic corticosteroidsUp until 2008, systemic corticosteroids were the first choice for complicated IH. The effectiveness was variable. Due to long-term use, side effects were commonly seen: hypertension, infections, growth retardation, intracranial hypertension, diabetes mellitus, osteoporosis, skin dilution, poorer wound healing fluid retention, Cushing’s syndrome, and gastric ulcers.Since the discovery of the efficacy of beta-blockers in IH, oral corticosteroids have been mostly disregarded.51, 52 53 Corticosteroids can be considered in patients with complex IH who do not respond to beta-blockers, for example in ulceration 54, or in patients with contraindications or who suffer side effects of beta-blockers55. However, the combination of oral corticosteroids and propranolol increases the risk of hypoglycaemia.56

Beta-blockers In 2008 it was discovered serendipitously that the non-selective beta-blocker propranolol is effective in the treatment of IH.57 Since then, beta-blockers are the first choice in IH.

Introduction of beta-blockersDue to the impressive observations on efficacy and tolerance, propranolol remarkably fast became the worldwide first choice treatment for IH, in first instance without official introduction or RCT. This is certainly due to the fact that propranolol has been available as a generic medicine for over 40 years, but for entirely different indications.Since 2008, a large variability of protocols has been made, which sometimes led to a lack of clarity among doctors about the prescription of propranolol, about investigations before start of treatment and dosage of the medication. Recently a RCT58 was published providing advice on dosage and duration of treatment.


Hand in hand, a specialty for propranolol (Hemangiol®, Pierre Fabre) has been developed and propranolol is officially (EMA / FDA) registered for the treatment of IH in young children, with clear guidelines for treatment. Hemangiol® also has a so-called PUMA registration.59 The start of Hemangiol® in children between 5 weeks and 5 months is on-label as a result of the registration. The start of Hemangiol® / propranolol in children younger than 5 weeks and children older than 5 months is off-label. Generic propranolol treatment is also off-label in the treatment of IH. Propranolol is a lipophilic, non-selective beta-blocker.

Preliminary, small studies with a hitherto limited ‘strength of evidence’60 show promising effectiveness of hydrophilic beta-blockers, such as nadolol (hydrophilic, non-selective)61 and atenolol (hydrophilic, ß1- selective). 62-65 Due to their hydrophilic character, nadolol and atenolol may have fewer side effects. The selective nature of atenolol leads to fewer pulmonary side effects. Hydrophilic beta-blockers such as atenolol and nadolol are off-label treatments for IH.

Both propranolol and atenolol are included in the Dutch children’s formulary “Kinderformularium”66 for the treatment of IH.

Working mechanism of beta-blockersThe working mechanism of beta-blockers in IH is not yet fully understood. The effect of beta-blockers can most probably be explained by: • Vasoconstriction of the capillaries, which changes the colour and consistency of the vascular tumour. • Decreased expression of vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF), leading to a decrease in proliferation of the endothelial cells • Induction of apoptosis in the capillary endothelial cells by blocking GLUT-1 receptors • Reduced renin activity, with a reduced angiotensin II and VEGF leading to involution .

Side effects of beta-blockersVarious case reports, case series, RCTs and registries of thousands of IH patients treated with propranolol show a clear picture of side effects that are generally considered to be mild and reversible.67

The following side effects of beta-blockers have been described in the literature: hypoglycaemia, bronchial hyper-responsiveness, hypotension, hyperkalaemia, diarrhoea, cold extremities, and restless sleep.

To prevent hypoglycaemia, it is important to administer the beta-blockers during or after feeding. Patients are at increased risk of hypoglycaemia when fasting (tachycardia, sweating and anxiety may be masked by beta-blockers and may not always be present). Especially young children with a low birth weight have a higher risk of hypoglycaemia due to illness, reduced food intake and after use of corticosteroids. If this is taken into account, the risk is small. Side effects of beta-blockers may lead to (temporary) discontinuation of the treatment.58, 67, 68

Propranolol is a highly lipophilic non-selective beta-blocker; there is some concern about potentially relevant neurological or cognitive side effects due to passage of the blood-brain barrier.69 69, 70 So far, there seem to be no long-term effects in children who use beta-blockers for cardiological reasons 69. In children with IH who are using beta-blockers, the long-term effects are still unknown, although there are no indications of concern so far.67, 69, 71, 72

Atenolol is a hydrophilic selective ß1- blocker and has a different side effect profile.63-65 Due to the hydrophilic nature, the side effects on the central nervous system are expected to be less. The selective ß1- blocking character of atenolol leads to fewer pulmonary side effects.


Investigations before start of beta-blocker treatment The indication for oral beta-blocker treatment is preferably made by physicians with experience with IH (and who work in a recognised centre of expertise).

Protocols of investigations prior to start of treatment vary between expertise centres. The minimum requirement is a focused history with cardiac history and family history along with complete physical examination with heart rate and blood pressure measurement.

ECG, echocardiography and paediatric cardiologist consultation are only performed on the basis of clinical indication.73-75 Baseline glucose values (and values during treatment) are only necessary in premature or dysmature infants and in infants with failure to thrive or a history of hypoglycaemia

Contraindications for beta-blockers 50, 74

Before starting the use of beta-blockers, contraindications for beta-blocker treatment must be checked.• Absolute contraindication for beta-blockers > Sick sinus syndrome including sino-atrial block, second and third degree AV block, cardiogenic shock.• Relative contraindications for propranolol and / or atenolol > Pulmonary symptoms in the patient’s history (bronchial obstruction, asthma, IRDS, BPD. Note: this is less strict for atenolol). > (Congenital) heart defects: always in consultation with a paediatric cardiologist > Hypotension (child 0-3 months < 65/45 mmHg, child 3-6 months < 70/50 mmHg, child 6-12 months < 80/55 mmHg). > Bradycardia (child 0-3 months < 100 bpm, child 3-6 months < 90 bpm, child 6-12 months < 80 bpm). > Severe disturbances of the peripheral arterial circulation. > Premature infants who have not reached the corrected age of 5 weeks (the corrected age is calculated by subtracting the number of weeks of prematurity from the real age) > Children at risk of hypoglycaemia.


Treatment with beta-blockers in daily practiceThis varies per centre. In general, the following applies:

• Start treatment before the age of 4-6 months Preferably, oral intake of beta-blockers is started in (or before) the growth / proliferative phase of the IH, if possible before the age of 4-6 months, so that complications of the IH can be (partially) prevented. Often, (too) late referral (‘IH is benign and automatically disappears ... without residue...’) is the main reason for delay. Effectiveness of propranolol in children older than 1 year has been described.76, 77 • Start-up inpatient, outpatient or during day-care? Whether a child is admitted at the start of the treatment varies per specialised centre. Consideration can be given to initiate propranolol either clinically or in day-care in children younger than 1-2 months, premature or dysmature children and children with ulcerated and very painful IH, and children with severe comorbidity or contraindications. Other children can start outpatient treatment. • Dosage Hemangiol® 3 mg/ kg/ day at 2 per day Propranolol (off-label) 2-3 mg/ kg/ day at 2 per day Atenolol (off-label) 1 mg/ kg at 1 per day • Check-ups during (initiation of) beta-blocker use Check-up schedules vary per specialised centre. For example, a check-up can take place during the initiation of treatment (blood pressure and heartbeat) during the first 2 hours after the first administration of beta-blocker and at dose elevation. During the treatment process, checks are carried out on side effects (anamnesis and / or physical examination) and effectiveness of the medication.• Duration of treatment In practise, treatment time is more customised than in the RCT58 (treatment duration of 6 months). Treatment is generally stopped between the age of 12-18 months (usually around the child’s age of 1 year), depending on the indication; shorter in an ulcerated (in the meantime cured) IH; longer in a peri-ocular IH. The use of beta-blockers can be terminated instantly. The recently reported regrowth of an IH after adequate beta-blocker treatment, results in the drug being decreased more slowly in some patients and being continued at a low dose until the age of 2, so that the chance of regrowth decreases.78

• What to do about side effects? In case of (probability of) threatening side effects (hypoglycaemia due to reduced intake, wheezing or shortness of breath with respiratory infection), a beta-blocker can be temporarily reduced or stopped. Then carefully restart in consultation with the prescriber; possibly switch propranolol to atenolol.

Beta-blockers in children with PHACES syndrome Children with PHACES are at risk for cardiovascular anomalies. Narrowing of the large cerebral or cervical vessels without collateral formation gives an increased risk of a stroke.79 It is therefore strongly advised to take a number of precautionary measures before starting beta-blocker treatment in children with a segmental IH:• Preferably MRI / MRA of the brain and echocardiography before the start of treatment with beta-blockers.74, 79

• It is recommended to start propranolol with a low dose of 0.5 mg / kg / day and to increase the dose (at 0.5 mg / kg intervals).• Dose interval: 3 times a day dosing is currently thought most advisable, so that critical changes in blood pressure are minimized 74, 79

• Intensive follow-up by multidisciplinary expertise team, including a paediatric neurologist.40

II. Topical treatments Topical beta-blockersDifferent case reports, case series 80-84, and RCTs show effectiveness of topical beta-blockers, such as propranolol or timolol.85, 86 Timolol is intrinsically more potent than propranolol.87

Due to the circumvented first-pass-effect in the liver in topically applied drugs, elevated serum levels may occur, and bioavailability is not always clear. Transcutaneous resorption may lead to systemic effects.88

Topical treatment with timolol was shown to be safe for IH in full-term infants at a dose of less than 0.2 mg/kg/day. But topical beta-blocker treatment of a-term, non-premature infants still requires alertness. In the case of premature infants, preference is given to (low-dose) oral beta-blockers over topical beta-blockers if the treatment indication is good.89


In children without risk factors with a superficial (< 1-2 mm high) IH, timolol can be safely applied (off-label): timolol eye drops (0.5%) up to twice a day 2 drops on the IH. For safety reasons, the maximum ophthalmic dose of twice per day 1 drop in each eye has been chosen, i.e. a maximum of 2 drops, twice per day.

It is recommended that the parent / guardian puts a drop on their own finger and smears it on the IH. Cave irritating eczema: apply or protect with a zinc oxide-containing preparation, such as zinc oxide cream (zinc oil), zinc oxide ointment 10%, zinc oxide vaseline (petrolatum) cream, or Sudocrem®. Topical beta-blockers are only effective at IH that remain relatively flat. The growth of IH in depth (deep IH) is not inhibited.85

III. Surgical treatment optionsFor many years, surgical treatment was a very important therapeutic option in complicated IH. Due to drug therapy (beta-blockers), the indication area for early surgery is getting smaller. Retrospective studies show that oral propranolol is more effective than (laser and cryo) surgery.90

Conventional (early) surgery is indicated if the IH does not respond to beta-blockers (or corticosteroids). Surgery can also be considered for pedunculated, ulcerated IH in the early phase and / or when there is insufficient (expected) effect of drug treatment. Ulcerated IH always leave a scar. This sometimes makes the consideration of surgical intervention easier.Late (plastic) surgery has traditionally played an important role in the reconstruction of residual lesions of an IH after regression (excess skin or scars).7 The effect of early beta-blocker treatment on the severity of residual lesions will become clear in the coming years. The moment of surgery can be determined in consultation with surgeon and (parents of) patient. If possible, efforts can be made to plan (plastic) surgery before the age of 4, before the child goes to primary school. In general, the tumour has then completed most of its regression.52, 91

Pulsed dye laser (595 nm) and Intense Pulsed Light (IPL) can be used after involution of the IH in the treatment of persistent telangiectasia. In some cases, additional treatment with the Nd:YAG laser may be required.92-94

IV. Management of ulcerated IH51

Ulceration occurs often around the age of 4 months. A precursor of ulceration can be grey or white discoloration at the age of 3-4 months, with the IH still feeling solid. This is also referred to as ‘white haemangioma’.95 This in contrast to the grey discolouration that occurs with the initial involution of the IH, with the IH feeling softer.

Ulceration in IH causes pain and scars. Bleeding is rare in ulcerated IH95. Ulceration is more often seen with large plaque-shaped segmental IH, larger voluminous (combined deep and superficial) IH, IH of the lips, IH with maceration in skinfolds, and IH in the diaper area or with a beginning diaper dermatitis. IH in the diaper area or in skinfolds should therefore from the beginning be treated with a protective zinc oxide-containing preparation, such as zinc oxide cream (zinc oil), zinc oxide ointment 10%, zinc oxide vaseline (petrolatum) cream, or Sudocrem®.

It is not always possible to prevent ulceration. Early onset of systemic beta-blocker therapy may potentially prevent ulceration and result in faster healing.96 It is not clear whether topical treatment with timolol may prevent ulceration.The first signs of ulceration are necrosis of the skin and pain (scaling on a convex IH, light brown to black crustae).

In case of ulceration, the following policy is advised. This requires customisation and often creativity from care providers and parents. Sometimes admission can be indicated because of pain.

• Pain relief: paracetamol/ acetaminophen drink. Other medicaments/ measures, if necessary (during care of the ulcer), in consultation with a paediatrician.• Wound care: goal is moist wound environment > In the case of very superficial ulceration, a mechanical barrier by means of zinc oil, ZOK ointment (zinc oxide alkaline ointment), zinc oil with silver sulfadiazine in equal parts, or Sudocrem®, may be sufficient. > Debridement of (large) necrotic crustae (i.e. hot compress) > Silicone mesh as non-adhesive bandage, if necessary combined with alginate gel, cleaning the wound. > Silicone dressing as non-adhesive foam dressing – also provides protection. > Thin hydrocolloid plasters or polyurethane plaster97 sometimes provide added value in ulcers in the diaper area, so that the wound is protected against urine / faeces. Cave softening – this may cause bleeding.


• Treatment of the IH itself, with systemic beta-blockers, often has added value and is particularly effective in voluminous ulcerated IH in the growth phase. Less effect with flat, ulcerated IH.• In cases of (suspected) infection: antibiotic treatment with empirical preference for Augmentin, if needed on the basis of cultivation, dosage according to the Kinderformularium.66 Clindamycin as second choice.66 Diarrhoea as a side effect can complicate the treatment, especially in ulcerated IH in the diaper area.• Surgery: in some cases, excision and primary closure with ulcerated IH can be useful, for example, on the scalp. It is known that an ulcerated IH can leave scars or alopecia.

VI. Patient information

Information to parents should include the following • What is an IH and what is the expected natural course with and without treatment.• If possible, show ‘before and after’ photos of other children of both natural involution and the results of the treatment that is considered.• Written information and instructions about the proposed treatment (your own leaflets, Hemangiol® leaflet / website, or HEVAS leaflets)• The risks and potential benefits of and alternatives for the treatment being considered.• In cases where the IH is in a visible location, for example in the face, a preparation for the way in which parents can deal with comments and questions from family and others.• Possibly referral (via general practitioner) for psychological counselling.• Mention of Hevas parent and patient support association for IH and vascular malformations (www.hevas.eu)


1. Wassef M, Blei F, Adams D, et al. Vascular Anomalies Classification: Recommendations From the International Society for the Study of Vascular Anomalies. Pediatrics. 2015;136(1):e203-214.2. Hoornweg MJ, Smeulders MJ, Ubbink DT, et al. The prevalence and risk factors of infantile haemangiomas: a case-control study in the Dutch population. Paediatric and perinatal epidemiology. 2012;26(2):156-162.3. Munden A, Butschek R, Tom WL, et al. Prospective study of infantile haemangiomas: incidence, clinical characteristics and association with placental anomalies. The British journal of dermatology. 2014;170(4):907-913.4. Dickison P, Christou E, Wargon O. A prospective study of infantile haemangiomas with a focus on incidence and risk factors. Pediatric dermatology. 2011;28(6):663-669.5. Luu M, Frieden IJ. Haemangioma: clinical course, complications and management. The British journal of dermatology. 2013;169(1):20-30.6. Hoornweg MJ, Theunissen CIJM, Hage JJ, et al. Malignant Differential Diagnosis in Children Referred for Infantile Hemangioma. Annals of plastic surgery. 2015;74(1):43-46.7. Perkins JA, Chen BS, Saltzman B, et al. Propranolol therapy for reducing the number of nasal infantile hemangioma invasive procedures. JAMA Otolaryngol Head Neck Surg. 2014;140(3):220-227.8. Leaute-Labreze C, Harper JI, Hoeger PH. Infantile haemangioma. Lancet. 2017.9. Filippi L, Cavallaro G, Bagnoli P, et al. Oral Propranolol for retinopathy of prematurity: risks, safety concerns, and perspectives. The Journal of pediatrics. 2013;163(6):1570-1577 e1576.10. Hemangioma Investigator G, Haggstrom AN, Drolet BA, et al. Prospective study of infantile haemangiomas: demographic, prenatal, and perinatal characteristics. The Journal of pediatrics. 2007;150(3):291-294.11. Haggstrom AN, Drolet BA, Baselga E, et al. Prospective study of infantile haemangiomas: clinical characteristics predicting complications and treatment. Pediatrics. 2006;118(3):882-887.12. Drolet BA, Swanson EA, Frieden IJ, et al. Infantile haemangiomas: an emerging health issue linked to an increased rate of low birth weight infants. The Journal of pediatrics. 2008;153(5):712-715, 715 e711.13. Bauland CG, Smit JM, Bartelink LR, et al. Hemangioma in the newborn: increased incidence after chorionic villus sampling. Prenat Diagn. 2010;30(10):913-917.14. Castren E, Salminen P, Vikkula M, et al. Inheritance Patterns of Infantile Hemangioma. Pediatrics. 2016;138(5).15. Tollefson MM, Frieden IJ. Early growth of infantile haemangiomas: what parents’ photographs tell us. Pediatrics. 2012;130(2):e314-320.16. Brandling-Bennett HA, Metry DW, Baselga E, et al. Infantile haemangiomas with unusually prolonged growth phase: a case series. Archives of dermatology. 2008;144(12):1632-1637.17. Yanes DA, Pearson GD, Witman PM. Infantile Haemangiomas of the Lip: Patterns, Outcomes, and Implications. Pediatric dermatology. 2016;33(5):511-517.18. Bauland CG, Luning TH, Smit JM, et al. Untreated haemangiomas: growth pattern and residual lesions. Plastic and reconstructive surgery. 2011;127(4):1643-1648.19. Chen TS, Eichenfield LF, Friedlander SF. Infantile haemangiomas: an update on pathogenesis and therapy. Pediatrics. 2013;131(1):99-108.20. Chamlin SL, Haggstrom AN, Drolet BA, et al. Multicentre prospective study of ulcerated haemangiomas. The Journal of pediatrics. 2007;151(6):684-689, 689 e681.

21. Hermans DJ, Boezeman JB, Van de Kerkhof PC, et al. Differences between ulcerated and non-ulcerated haemangiomas, a retrospective study of 465 cases. Eur J Dermatol. 2009;19(2):152-156.22. Kim HJ, Colombo M, Frieden IJ. Ulcerated haemangiomas: clinical characteristics and response to therapy. Journal of the American Academy of Dermatology. 2001;44(6):962-972.23. Shin HT, Orlow SJ, Chang MW. Ulcerated haemangioma of infancy: a retrospective review of 47 patients. The British journal of dermatology. 2007;156(5):1050-1052.24. Weitz NA, Bayer ML, Baselga E, et al. The “biker-glove” pattern of segmental infantile haemangiomas on the hands and feet. Journal of the American Academy of Dermatology. 2014;71(3):542-547.25. Jockin YM, Friedlander SF. Periocular infantile hemangioma. International ophthalmology clinics. 2010;50(4):15-25.26. Schwartz SR, Blei F, Ceisler E, et al. Risk factors for amblyopia in children with capillary haemangiomas of the eyelids and orbit. Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus. 2006;10(3):262-268.27. Dubois J, Milot J, Jaeger BI, et al. Orbit and eyelid haemangiomas: is there a relationship between location and ocular problems? Journal of the American Academy of Dermatology. 2006;55(4):614-619.28. Frank RC, Cowan BJ, Harrop AR, et al. Visual development in infants: visual complications of periocular haemangiomas. Journal of plastic, reconstructive & aesthetic surgery : JPRAS. 2010;63(1):1-8.29. Reem RE, Golden RP. Periocular haemangiomas and lymphangiomas. Pediatr Clin North Am. 2014;61(3):541-553.30. Orlow SJ, Isakoff MS, Blei F. Increased risk of symptomatic haemangiomas of the airway in association with cutaneous haemangiomas in a “beard” distribution. The Journal of pediatrics. 1997;131(4):643-646.31. Haggstrom AN, Skillman S, Garzon MC, et al. Clinical spectrum and risk of PHACE syndrome in cutaneous and airway haemangiomas. Archives of otolaryngology--head & neck surgery. 2011;137(7):680-687.32. O TM, Alexander RE, Lando T, et al. Segmental haemangiomas of the upper airway. The Laryngoscope. 2009;119(11):2242-2247.33. Yan AC. Pain management for ulcerated haemangiomas. Pediatric dermatology. 2008;25(6):586-589.34. Horii KA, Drolet BA, Frieden IJ, et al. Prospective study of the frequency of hepatic haemangiomas in infants with multiple cutaneous infantile haemangiomas. Pediatric dermatology. 2011;28(3):245-253.35. Vredenborg AD, Janmohamed SR, de Laat PC, et al. Multiple cutaneous infantile haemangiomas and the risk of internal haemangioma. The British journal of dermatology. 2013;169(1):188-191.36. Bosemani T, Puttgen KB, Huisman TA, et al. Multifocal infantile hepatic haemangiomas--imaging strategy and response to treatment after Propranolol and steroids including review of the literature. European journal of pediatrics. 2012;171(7):1023-1028.37. Vergine G, Marsciani A, Pedini A, et al. Efficacy of Propranolol treatment in thyroid dysfunction associated with severe infantile hepatic hemangioma. Horm Res Paediatr. 2012;78(4):256-260.38. Haggstrom AN, Beaumont JL, Lai JS, et al. Measuring the severity of infantile haemangiomas: instrument development and reliability. Archives of dermatology. 2012;148(2):197-202.

VII. References


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57. Leaute-Labreze C, Dumas de la Roque E, Hubiche T, et al. Propranolol for severe haemangiomas of infancy. N Engl J Med. 2008;358(24):2649-2651.58. Leaute-Labreze C, Hoeger P, Mazereeuw-Hautier J, et al. A randomized, controlled trial of oral Propranolol in infantile hemangioma. N Engl J Med. 2015;372(8):735-746.59. Paediatric Use Marketing Authorisation (https://www.cbg-meb.nl)60. Diagnosis and Management of Infantile Hemangioma, Executive Summary; Comparative Effective Review, nr 168; https://www.effectivehealthcare.ahrq.gov/ehc/ products/593/2170/infantile-hemangioma-report-160115.pdf.61. Pope E, Chakkittakandiyil A, Lara-Corrales I, et al. Expanding the therapeutic repertoire of infantile haemangiomas: cohort- blinded study of oral nadolol compared with Propranolol. The British journal of dermatology. 2013;168(1):222-224.62. Abarzua-Araya A, Navarrete-Dechent CP, Heusser F, et al. Atenolol versus Propranolol for the treatment of infantile haemangiomas: a randomized controlled study. Journal of the American Academy of Dermatology. 2014;70(6):1045-1049.63. Ji Y, Wang Q, Chen S, et al. Oral atenolol therapy for proliferating infantile hemangioma: A prospective study. Medicine. 2016;95(24):e3908.64. de Graaf M, Raphael MF, Breugem CC, et al. Treatment of infantile haemangiomas with atenolol: comparison with a historical Propranolol group. Journal of plastic, reconstructive & aesthetic surgery : JPRAS. 2013;66(12):1732-1740.65. Raphael MF, de Graaf M, Breugem CC, et al. Atenolol: a promising alternative to Propranolol for the treatment of haemangiomas. Journal of the American Academy of Dermatology. 2011;65(2):420-421.66. https://www.kinderformularium.nl/.67. Leaute-Labreze C, Boccara O, Degrugillier-Chopinet C, et al. Safety of Oral Propranolol for the Treatment of Infantile Hemangioma: A Systematic Review. Pediatrics. 2016.68. Hermans DJ, Bauland CG, Zweegers J, et al. Propranolol in a case series of 174 patients with complicated infantile haemangioma: indications, safety and future directions. The British journal of dermatology. 2013;168(4):837-843.69. Langley A, Pope E. Propranolol and central nervous system function: potential implications for paediatric patients with infantile haemangiomas. The British journal of dermatology. 2015;172(1):13-23.70. Hoeger PH. Propranolol for infantile haemangiomas: certain chances, potential risks. The British journal of dermatology. 2015;172(1):3-4.71. Moyakine AV, Hermans DJ, Fuijkschot J, et al. Propranolol treatment of infantile haemangiomas does not negatively affect psychomotor development. Journal of the American Academy of Dermatology. 2015;73(2):341-342.72. Moyakine AV, Kerstjens JM, Spillekom-van Koulil S, et al. Propranolol treatment of infantile hemangioma (IH) is not associated with developmental risk or growth impairment at age 4 years. Journal of the American Academy of Dermatology. 2016;75(1):59-63 e51.73. Blei F, McElhinney DB, Guarini A, et al. Cardiac screening in infants with infantile haemangiomas before Propranolol treatment. Pediatric dermatology. 2014;31(4):465-470.74. Drolet BA, Frommelt PC, Chamlin SL, et al. Initiation and use of Propranolol for infantile hemangioma: report of a consensus conference. Pediatrics. 2013;131(1):128-140.75. Raphael MF, Breugem CC, Vlasveld FA, et al. Is cardiovascular evaluation necessary prior to and during beta-blocker therapy for infantile haemangiomas?: A cohort study. Journal of the American Academy of Dermatology. 2015;72(3):465-472.


76. Zvulunov A, McCuaig C, Frieden IJ, et al. Oral Propranolol therapy for infantile haemangiomas beyond the proliferation phase: a multicentre retrospective study. Pediatric dermatology. 2011;28(2):94-98.77. Vivas-Colmenares GV, Bernabeu-Wittel J, Alonso-Arroyo V, et al. Effectiveness of Propranolol in the treatment of infantile hemangioma beyond the proliferation phase. Pediatric dermatology. 2015;32(3):348-352.78. Shah SD, Baselga E, McCuaig C, et al. Rebound Growth of Infantile Haemangiomas After Propranolol Therapy. Pediatrics. 2016;137(4).79. Metry D, Frieden IJ, Hess C, et al. Propranolol use in PHACE syndrome with cervical and intracranial arterial anomalies: collective experience in 32 infants. Pediatric dermatology. 2013;30(1):71-89.80. Semkova K, Kazandjieva J. Topical Timolol maleate for treatment of infantile haemangiomas: preliminary results of a prospective study. Clinical and experimental dermatology. 2013;38(2):143-146.81. Moehrle M, Leaute-Labreze C, Schmidt V, et al. Topical Timolol for small haemangiomas of infancy. Pediatric dermatology. 2013;30(2):245-249.82. Oranje AP, Janmohamed SR, Madern GC, et al. Treatment of small superficial haemangioma with Timolol 0.5% ophthalmic solution: a series of 20 cases. Dermatology. 2011;223(4):330-334.83. Ni N, Langer P, Wagner R, et al. Topical Timolol for periocular hemangioma: report of further study. Archives of ophthalmology. 2011;129(3):377-379.84. Chakkittakandiyil A, Phillips R, Frieden IJ, et al. Timolol maleate 0.5% or 0.1% gel-forming solution for infantile haemangiomas: a retrospective, multicentre, cohort study. Pediatric dermatology. 2012;29(1):28-31.85. Puttgen K, Lucky A, Adams D, et al. Topical Timolol Maleate Treatment of Infantile Haemangiomas. Pediatrics. 2016;138(3).86. Chan H, McKay C, Adams S, et al. RCT of Timolol maleate gel for superficial infantile haemangiomas in 5- to 24-week-olds. Pediatrics. 2013;131(6):e1739-1747.87. Achong MR, Piafsky KM, Ogilvie RI. Comparison of cardiac effects of Timolol and Propranolol. Clinical pharmacology and therapeutics. 1975;18(3):278-286.88. McMahon P, Oza V, Frieden IJ. Topical Timolol for infantile haemangiomas: putting a note of caution in “cautiously optimistic”. Pediatric dermatology. 2012;29(1):127-130.89. Frommelt P, Juern A, Siegel D, et al. Adverse Events in Young and Preterm Infants Receiving Topical Timolol for Infantile Hemangioma. Pediatric dermatology. 2016;33(4):405-414.90. Kagami S, Kuwano Y, Shibata S, et al. Propranolol is more effective than pulsed dye laser and cryosurgery for infantile haemangiomas. European journal of pediatrics. 2013;172(11):1521-1526.91. Mulliken JB, Fishman SJ, Burrows PE. Vascular anomalies. Current problems in surgery. 2000;37(8):517-584.92. Smit JM, Bauland CG, Wijnberg DS, et al. Pulsed dye laser treatment, a review of indications and outcome based on published trials. British journal of plastic surgery. 2005;58(7):981-987.93. Zhong SX, Tao YC, Zhou JF, et al. Infantile Hemangioma: Clinical Characteristics and Efficacy of Treatment with the Long-Pulsed 1,064-nm Neodymium-Doped Yttrium Aluminum Garnet Laser in 794 Chinese Patients. Pediatric dermatology. 2015;32(4):495-500.

94. Kaune KM, Lauerer P, Kietz S, et al. Combination therapy of infantile haemangiomas with pulsed dye laser and Nd:YAG laser is effective and safe. Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG. 2014;12(6):473-478.95. Maguiness SM, Hoffman WY, McCalmont TH, et al. Early white discoloration of infantile hemangioma: a sign of impending ulceration. Archives of dermatology. 2010;146(11):1235-1239.96. Hermans DJ, van Beynum IM, Schultze Kool LJ, et al. Propranolol, a very promising treatment for ulceration in infantile haemangiomas: a study of 20 cases with matched historical controls. Journal of the American Academy of Dermatology. 2011;64(5):833-838.97. Oranje AP, de Waard-van der Spek FB, Devillers AC, et al. Treatment and pain relief of ulcerative haemangiomas with a polyurethane film. Dermatology. 2000;200(1):31-34.

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