Clinical Practice Guideline for the Management of Infantile Hemangiomas

CLINICAL PRACTICE GUIDELINE

Guidance for the Clinician in Rendering Pediatric Care

Daniel P. Krowchuk, MD, FAAP,​a Ilona J. Frieden, MD, FAAP,b​ Anthony J. Mancini, MD, FAAP,c​ David H. Darrow, MD,Clinical DDS, FAAP,​d Francine Practice Blei, MD, MBA, FAAP,​e Arin K.Guideline Greene, MD, FAAP,f​ Aparna Annam, for DO, FAAP,the​ g Cynthia N. Baker, MD, FAAP,h​ Peter C. Frommelt, MD, FAAP,​i Amy Hodak, CPMSM,​j Brian M. Pate, MD, FHM, FA AP,​k Janice L. Pelletier, MD, FAAP,l​ Deborah Sandrock, MD, FAAP,​m Stuart T. Weinberg, MD, FAAP,​n Mary AnneManagement Whelan, MD, PhD, FAAP,​o SUBCOMMITTEE of ON THEInfantile MANAGEMENT OF INFANTILE Hemangiomas HEMANGIOMAS

Infantile hemangiomas (IHs) occur in as many as 5% of infants, making them abstract the most common benign tumor of infancy. Most IHs are small, innocuous, self-resolving, and require no treatment. However, because of their size or location, a significant minority of IHs are potentially problematic. These include IHs that may cause permanent scarring and disfigurement (eg, facial IHs), hepatic or airway IHs, and IHs with the potential for functional Departments of aPediatrics and Dermatology, Wake Forest School impairment (eg, periorbital IHs), ulceration (that may cause pain or of Medicine, Winston-Salem, North Carolina; Departments of scarring), and associated underlying abnormalities (eg, intracranial and bDermatology and Pediatrics, School of Medicine, University of California, San Francisco, San Francisco, California; Departments aortic arch vascular abnormalities accompanying a large facial IH). This of cPediatrics and Dermatology, Feinberg School of Medicine, Northwestern University and Ann and Robert H. Lurie Children’s clinical practice guideline for the management of IHs emphasizes several Hospital of Chicago, Chicago, Illinois; Departments of dOtolaryngology key concepts. It defines those IHs that are potentially higher risk and should and Pediatrics, Eastern Virginia Medical School and Children’s Hospital of the King’s Daughters, Norfolk, Virginia; eDonald and prompt concern, and emphasizes increased vigilance, consideration of Barbara Zucker School of Medicine, Northwell Health, New York City, active treatment and, when appropriate, specialty consultation. It discusses New York; fDepartment of Plastic and Oral Surgery, Boston Children’s Hospital and Harvard Medical School, Harvard University, Boston, the specific growth characteristics of IHs, that is, that the most rapid and Massachusetts; gDepartment of Radiology, University of Colorado School of Medicine, Children's Hospital Colorado, Aurora, Colorado; significant growth occurs between 1 and 3 months of age and that growth hDepartment of Pediatrics, Kaiser Permanente Medical Center, Los is completed by 5 months of age in most cases. Because many IHs leave Angeles, California; iDepartment of Pediatrics, Cardiology, Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, behind permanent skin changes, there is a window of opportunity to treat Wisconsin; jAmerican Board of Pediatrics, Chapel Hill, North Carolina; kDepartment of Pediatrics, University of Kansas School of Medicine- higher-risk IHs and optimize outcomes. Early intervention and/or referral Wichita, Wichita, Kansas; lDepartment of Pediatrics, Northern Light (ideally by 1 month of age) is recommended for infants who have potentially Health, Bangor, Maine; mSt Christopher’s Hospital for Children and College of Medicine, Drexel University, Philadelphia, Pennsylvania; problematic IHs. When systemic treatment is indicated, propranolol is the Departments of nBiomedical Informatics and Pediatrics, School of drug of choice at a dose of 2 to 3 mg/kg per day. Treatment typically is Medicine, Vanderbilt University, Nashville, Tennessee; and oCollege of Physicians and Surgeons, Columbia University, New York City, New York continued for at least 6 months and often is maintained until 12 months of This document is copyrighted and is property of the American age (occasionally longer). Topical timolol may be used to treat select small, Academy of Pediatrics and its Board of Directors. All authors have thin, superficial IHs. Surgery and/or laser treatment are most useful for the filed conflict of interest statements with the American Academy of Pediatrics. Any conflicts have been resolved through a process treatment of residual skin changes after involution and, less commonly, may approved by the Board of Directors. The American Academy of Pediatrics has neither solicited nor accepted any commercial be considered earlier to treat some IHs. involvement in the development of the content of this publication.

To cite: Krowchuk DP, Frieden IJ, Mancini AJ, et al. Clinical Practice Guideline for the Management of Infantile Hemangiomas. Pediatrics. 2019;143(1):e20183475

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 143, number 1, January 2019:e20183475 FROM THE AMERICAN ACADEMY OF PEDIATRICS INTRODUCTION IHs are potentially high risk and when IHs independently on the basis of their This is the first clinical practice guideline intervention is needed. knowledge and expertise. It does not address the management of vascular (CPG) from the American Academy In the broadest sense, the goal of this CPG malformations, congenital hemangiomas, of Pediatrics (AAP) regarding the from the AAP is to enhance primary care or other vascular tumors. The CPG management of infantile hemangiomas providers’ ability to confidently evaluate, encourages enhanced communication (IHs). Similar consensus statements triage, and manage IHs, employing an between primary care clinicians and have been published by European1 evidence-based approach. Specifically, hemangioma specialists to ensure early and Australasian expert groups.2 In the CPG will: addition, a recent AAP clinical report assessment and treatment of infants in provide an approach to risk provided a comprehensive review of •• whom active intervention is indicated, stratification and recognition of the pathogenesis, clinical features, and to improve patient outcomes, and to potentially problematic IHs; treatment of IH; it is available at http://​ enhance anticipatory guidance. It is not pediatrics.​aappublications.​org/​content/​ •• emphasize that early and frequent intended to be a sole source of guidance 136/​4/​e1060.‍3 monitoring in the first few weeks and in the management of children with months of life is crucial in identifying IHs, to replace clinical judgment, or to IHs occur in approximately 4% to 5% of those IHs that require intervention establish a protocol for all infants with infants, making them the most common because IHs may change rapidly during IHs. Rather, it provides a framework for benign tumor of childhood. They are this time period; clinical decision-making. more common in girls, twins, infants born preterm or with low birth weight •• review the role of imaging in patients (up to 30% of infants born weighing <1 who have IHs; and METHODS kg are affected), and white neonates. The methods of this CPG are discussed The pathogenesis of IHs has yet to be •• offer evidence-based guidance for in detail in the Methods section of the fully defined. A leading hypothesis is that the management of IHs, including Supplemental Information. Briefly, circulating endothelial progenitor cells indications for consultation, a comparative effectiveness review migrate to locations in which conditions referral and possible intervention, of potential benefits and harms of (eg, hypoxia and developmental field pharmacologic options for therapy, diagnostic modalities and pharmacologic disturbances) are favorable for growth.3 the role of surgical modalities, and ongoing management and monitoring and surgical treatments was conducted Knowledge about IHs has advanced (including parent education). on behalf of the Agency for Healthcare dramatically in the past decade, Research and Quality (AHRQ). The particularly regarding the unique This CPG is intended for pediatricians literature search strategy employed timing and nature of proliferation and and other primary care providers who Medline via the PubMed interface, the involution, risks of sequelae, and newer (1) manage IHs collaboratively with Cumulative Index to Nursing and Allied treatment options. As a result, pediatric a hemangioma specialist (defined Health Literature (CINAHL), and Excerpta providers have an opportunity to improve below), (2) care for children with Medica Database (Embase). Searches care and reduce morbidity in infants IHs being managed primarily by a were limited to the English language and with IHs by promptly recognizing which hemangioma specialist, or (3) manage to studies published from 1982 to June

TABLE 1 Highlights of This CPG •• IH growth characteristics are different than once taught. ⚬⚬ Most rapid IH growth occurs between 1 and 3 months of age. ⚬⚬ Although IHs involute, this process may be incomplete, leaving permanent skin changes that may be life altering. This is especially true for IHs that are thick. ⚬⚬ There is a window of opportunity to treat problematic IHs. Consult early (by 1 month of age) for lesions that are potentially high risk because of the following associations (Table 3): ◾◾ potential for disfigurement (the most common reason treatment is needed); ◾◾ life-threatening complications; ◾◾ functional impairment; ◾◾ ulceration; and ◾◾ underlying abnormalities. •• Oral propranolol is the treatment of choice for problematic IHs that require systemic therapy. •• Topical timolol may be used to treat some thin and/or superficial IHs. •• Surgery and/or laser treatment are most useful for the treatment of residual skin changes after involution. They may be used earlier to treat selected IHs.

Downloaded from www.aappublications.org/news by guest on September 30, 2021 2 FROM THE AMERICAN ACADEMY OF PEDIATRICS TABLE 2 Definitions Hemangioma specialist: Unlike many diseases, management of IHs is not limited to 1 medical or surgical specialty. A hemangioma specialist may have expertise in dermatology, hematologyoncology, pediatrics, facial plastic and reconstructive surgery, ophthalmology, otolaryngology, pediatric surgery, and/or plastic surgery, and his or her practice is often focused primarily or exclusively on the pediatric age group. Hemangioma specialists •• understand the time-sensitive nature of IHs during the growth phase and be able to accommodate requests for urgent should: evaluation; •• have experience with accurate risk stratification and potential complications associated with IHs; •• be able to provide recommendations for various management options, including observation, medical therapies, and surgical or laser procedures, and provide counseling regarding the potential risks and benefits of these interventions for specific patients; and •• have a thorough knowledge of past and emerging medical literature regarding IHs. •• Such specialists often have 1 or more of the following characteristics: ⚬⚬ participated in a vascular anomalies program during previous medical training; ⚬⚬ devotes a significant part of his or her clinical practice to IHs; ⚬⚬ is a member of or collaborates with a multidisciplinary vascular anomalies center; ⚬⚬ maintains membership in professional organizations or groups with a special interest in IHs; ⚬⚬ participates in research studies in the field of IHs; or ⚬⚬ publishes medical literature in the field of IHs. IHs: infantile hemangiomas Benign vascular tumors of infancy and childhood with unique clinical and histopathologic characteristics that distinguish them from other vascular tumors (eg, congenital hemangiomas) or malformations. These characteristics include development during the first weeks or months of life, a typical natural history of rapid growth followed by gradual involution, and immunohistochemical staining of biopsy specimens with erythrocyte-type glucose transporter protein and other unique markers not present on other benign vascular tumors. Many other entities are also called hemangiomas. Some are true vascular tumors, and others are vascular malformations. Therefore, it is important to use the adjective “infantile” when referring to true IHs. IHs are classified on the basis of soft-tissue depth and the pattern of anatomic involvement (see Supplemental Figs 5–10 for photographic examples). Soft-tissue depth: •• Superficial: red with little or no evidence of a subcutaneous component (formerly called strawberry” hemangiomas); •• Deep: blue and located below the skin surface (formerly called “cavernous” hemangiomas); and •• Combined (mixed): both superficial and deep components are present. Anatomic appearance: •• Localized: well-defined focal lesions (appearing to arise from a central point); •• Segmental: IH involving an anatomic region that is often plaque-like and often measuring at >5 cm in diameter; •• Indeterminate (undetermined): neither clearly localized or segmental (often called partial segmental); and •• Multifocal: multiple discrete IHs at disparate sites.

2015. Because the therapy of IHs has been DEVELOPMENT OF THE CLINICAL on Conflict of Interest and Voluntary evolving rapidly, the CPG subcommittee PRACTICE GUIDELINE Disclosure. Subcommittee members performed an updated literature review repeated this process at the time of the In December 2016, the AAP convened for the period of July 2015 to January publication of the guideline. All potential a multidisciplinary subcommittee 2017 to augment the original search. conflicts of interest are listed at the end composed of IH experts in the fields of of this document. The project was funded This most recent search employed dermatology, cardiology, hematology- by the AAP. only Medline because previously, oncology, otolaryngology(head and neck virtually all relevant articles had been surgery), plastic surgery, and radiology. The final recommendations were based accessed via this database. The search The subcommittee also included general on articles identified in the AHRQ and was concentrated on pharmacologic pediatricians, a parent representative, updated systematic reviews. Decisions interventions, including topical timolol an implementation scientist, a and the strength of recommendations (an emerging therapeutic alternative for representative from the Partnership were based on a systematic grading of which limited data were available at the for Policy Implementation (https://www​ .​ the quality of evidence by independent time of the original search). The original aap.​org/​en-​us/​professional-​resources/​ reviewers. Expert consensus was methodology and report, including the quality-​improvement/​Pages/​Partnership-​ used when definitive data were not evidence search and review, are available for-​Policy-​Implementation.​aspx), and available. Key action statements (KASs), in their entirety and as an executive an epidemiologist and methodologist. summarized in Table 4, were generated summary at www.​effectivehealthca​re.​ All panel members declared potential by subcommittee members authoring ahrq.​gov/​reports/​final.​cfm.‍4 conflicts on the basis of the AAP policy individual components of the CPG using

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 143, number 1, January 2019 3 TABLE 3 High-Risk IHs IH Clinical Findings IH Risk Life-threatening “Beard-area” IH Obstructive airway hemangiomas ≥5 cutaneous IHs Liver hemangiomas, cardiac failure, hypothyroidism Functional impairment Periocular IH (>1 cm) Astigmatism, anisometropia, proptosis, amblyopia IH involving lip or oral cavity Feeding impairment Ulceration Segmental IH: IH of any size involving any of the following sites: lips, Increased risk of ulceration columella, superior helix of ear, gluteal cleft and/or perineum, perianal skin, and other intertriginous areas (eg, neck, axillae, inguinal region) Associated structural anomalies Segmental IH of face or scalp PHACE syndrome Segmental IH of lumbosacral and/or perineal area LUMBAR syndrome Disfigurement Segmental IH, especially of face and scalp High risk of scarring and/or permanent disfigurement Facial IH (measurements refer to size during infancy): nasal tip or lip (any Risk of disfigurement via distortion of anatomic landmarks and/or scarring size) or any facial location ≥2 cm (>1 cm if ≤3 mo of age) and/or permanent skin changes Scalp IH >2 cm Permanent alopecia (especially if the hemangioma becomes thick or bulky); profuse bleeding if ulceration develops (typically more bleeding than at other anatomic sites) Neck, trunk, or extremity IH >2 cm, especially in growth phase or if Greater risk of leaving permanent scarring and/or permanent skin changes abrupt transition from normal to affected skin (ie, ledge effect); thick depending on anatomic location superficial IH (eg,≥ 2 mm thickness) Breast IH (female infants) Permanent changes in breast development (eg, breast asymmetry) or nipple contour Categorization of IH as high risk is based on published literature (including the AHRQ review and hemangioma severity scores) and consensus of CPG subcommittee members. Given the wide variation in IH location, size, and age at presentation, the subcommittee acknowledges that there may be situations in which an IH meets high-risk criteria and, therefore, merits consultation or referral, but the practitioner and parents do not believe this is necessary or practical. Clinical judgment is always involved in such decisions, and any plan of action needs to be individualized on the basis of a number of factors, including location of the lesion, age of child, family preferences, and geographic access to care. the results of the literature review. These subcommittee as experts in the field IHs.24 For example, because IHs involute sections were reviewed and refined before formal approval by the AAP. spontaneously, many that are small, by the subcommittee chairperson and All comments were reviewed by the are superficial, occur in areas covered co-chairperson and ultimately by all subcommittee and incorporated into the by clothing, and/or are unlikely to subcommittee members. final guideline when appropriate. cause disfigurement do not require hemangioma specialist evaluation or Evidence-based guideline treatment. However, some IHs may be recommendations from the AAP may RISK STRATIFICATION, TRIAGE, AND considered high risk, and depending be graded as strong, moderate, weak REFERRAL on the clinician s comfort level and on the basis of low-quality evidence, or ’ local access to specialty care, require a weak on the basis of balance between Key Action Statement 1A (‍Table 6) higher level of experience and expertise benefits and harms. Strong and Clinicians should classify an IH as to determine if additional intervention moderate recommendations usually are high risk if there is evidence of or is indicated. These high-risk IHs and associated with should and should potential for the following: (1) life- “ ” “ their associated clinical findings are not recommendation statements, threatening complications, (2) functional ” summarized in Table 3 and illustrated whereas some moderate and all weak impairment or ulceration, (3) structural in Figs 2–4, Supplemental Table 22, recommendations may be recognized by anomalies (eg, in PHACE syndrome or and Supplemental Fig 11. Of particular use of may or need not,​ signifying LUMBAR syndrome), or (4) permanent “ ” “ ” note and as discussed later, segmental that moderate recommendations are disfigurement (grade X, strong hemangiomas, those that cover an based on a range of evidence strengths recommendation). anatomic territory arising from 1 or more within the boundaries of the definition The purpose of this statement is to developmental units, confer a higher (Table 5, Fig 1). ensure timely identification of IHs risk of morbidity and life-threatening The CPG underwent a comprehensive that may require early intervention. complications than those that are review by stakeholders (including AAP Clinicians in the primary care setting localized, that is, seeming to arise from councils, committees, and sections), caring for infants with IH face 2 major a central focal point.5 At the same time, selected outside organizations, challenges: disease heterogeneity and smaller IHs in particular anatomic and individuals identified by the the unique growth characteristics of locations, such as the cheek, tip of the

Downloaded from www.aappublications.org/news by guest on September 30, 2021 4 FROM THE AMERICAN ACADEMY OF PEDIATRICS TABLE 4 Summary of Key Action Statements (KASs) for the Management of IHs In Managing IH, Recommendations for Clinicians Evidence Quality; Strength of Recommendation 1. Risk stratification 1A. Classify an IH as high risk if there is evidence of or potential for the following: (1) life-threatening complications, X; strong (2) functional impairment or ulceration, (3) structural anomalies (eg, in PHACE syndrome or LUMBAR syndrome), or (4) permanent disfigurement 1B. After identifying an IH as high risk, facilitate evaluation by a hemangioma specialist as soon possible X; strong 2. Imaging 2A. Do not perform imaging unless the diagnosis of IH is uncertain, there are ≥5 cutaneous IHs, or associated B; moderate anatomic abnormalities are suspected 2B. Perform ultrasonography as the initial imaging modality when the diagnosis of IH is uncertain C; weak 2C. Perform MRI when concerned about associated structural abnormalities (eg, PHACE syndrome or LUMBAR B; moderate syndrome) 3. Pharmacotherapy 3A. Use oral propranolol as the first-line agent for IHs requiring systemic treatment A; strong 3B. Dose propranolol between 2 and 3 mg/kg per d unless there are comorbidities (eg, PHACE syndrome) or adverse A; moderate effects (eg, sleep disturbance) that necessitate a lower dose 3C. Counsel that propranolol be administered with or after feeding and that doses be held at times of diminished X; strong oral intake or vomiting to reduce the risk of hypoglycemia 3D. Evaluate patients for and educate caregivers about potential adverse effects of propranolol, including sleep X; strong disturbances, bronchial irritation, and clinically symptomatic bradycardia and hypotension 3E. May prescribe oral prednisolone or prednisone to treat IHs if there are contraindications or an inadequate B; moderate response to oral propranolol 3F. May recommend intralesional injection of triamcinolone and/or betamethasone to treat focal, bulky IHs during B; moderate proliferation or in certain critical anatomic locations (eg, the lip) 3G. May prescribe topical timolol maleate as a therapy for thin and/or superficial IHs B; moderate 4. Surgical management 4. May recommend surgery and laser therapy as treatment options in managing selected IHs C; moderate 5. Parent education 5. Educate caregivers of infants with an IH about the condition, including the expected natural history and its X; strong potential for causing complications or disfigurement

TABLE 5 Guideline Definitions for Key Action Statements Statement Definition Implication Strong recommendation A particular action is favored because anticipated Clinicians should follow a strong recommendation benefits clearly exceed harms (or vice versa), and unless a clear and compelling rationale for an quality of evidence is excellent or unobtainable. alternative approach is present. Moderate recommendation A particular action is favored because anticipated Clinicians would be prudent to follow a moderate benefits clearly exceed harms (or vice versa), and recommendation but should remain alert to new the quality of evidence is good but not excellent information and sensitive to patient preferences. (or is unobtainable). Weak recommendation (based on low-quality A particular action is favored because anticipated Clinicians would be prudent to follow a weak evidence) benefits clearly exceed harms (or vice versa), but recommendation but should remain alert to new the quality of evidence is weak. information and sensitive to patient preferences. Weak recommendation (based on balance of A weak recommendation is provided when the Clinicians should consider the options in their benefits and harms) aggregate database shows evidence of both decision-making, but patient preference may have benefit and harm that appears to be similar in a substantial role. magnitude for any available courses of action. PHACE indicates posterior fossa defects, hemangiomas, cerebrovascular arterial anomalies, cardiovascular anomalies including coarctation of the aorta, and eye anomalies; LUMBAR, lower body IH and other cutaneous defects, urogenital anomalies and ulceration, myelopathy, bony deformities, anorectal malformations, and arterial anomalies and renal anomalies. nose, and perioral and periocular skin, 2. functional impairment or risk Life-threatening Complications can confer a high risk of complications as thereof; Life-threatening lesions include well (see discussion below). 3. ulceration or risk thereof; obstructing IHs of the airway, liver IHs associated with high-output congestive There are 5 major indications for 4. evaluation to identify important heart failure and severe hypothyroidism, consideration of early treatment or need associated structural anomalies; and for further evaluation of IHs: and, rarely, profuse bleeding from an 5. risk of leaving permanent scarring or ulcerated IH. Obstructing IHs of the 1. life-threatening complications; distortion of anatomic landmarks airway typically involve the subglottis,

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 143, number 1, January 2019 5 Hepatic hemangiomas have been characterized as occurring in 3 patterns: focal, multifocal, and diffuse; the latter 2 are attributable to IHs, whereas focal lesions more often represent congenital hemangiomas.7,‍8​ Most multifocal hepatic IHs are asymptomatic and do not require treatment. However, a minority of these lesions are associated with macrovascular shunting, causing high flow that can, in rare cases, result in high-output cardiac failure. So-called “diffuse” hepatic IHs are another rare subset that confers an even greater risk for morbidity and mortality. Infants who are affected typically present before 4 months of age with severe hepatomegaly, which can lead to potentially lethal abdominal compartment syndrome attributable to compromised ventilation, renal failure attributable to renal vein compression, or compromised inferior vena cava blood flow to the heart.7,‍8​ A consumptive FIGURE 1 form of hypothyroidism caused by the AAP rating of evidence and recommendations. inactivation of thyroid hormones by type 3 iodothyronine deiodinase present in TABLE 6 Key Action Statement 1A: Clinicians should classify an IH as high risk if there is evidence of IH tissue can also be a complication or potential for the following: (1) life-threatening complications, (2) functional impairment of multifocal or diffuse hepatic IHs.9 or ulceration, (3) structural anomalies (eg, in PHACE syndrome or LUMBAR syndrome), or Although liver IHs can occasionally (4) permanent disfigurement (grade X, strong recommendation). be seen in infants with 1 or no IH of Aggregate Evidence Grade X the skin, the greatest risk for liver Quality IHs is in infants who have 5 or more Benefits Early recognition of high-risk, potentially problematic IHs facilitates early cutaneous IHs,10​ for whom screening specialist evaluation and management and potential avoidance of complications ultrasonography is recommended 11,30​ Risks, harm, cost Unnecessary parental concern regarding lesions inappropriately characterized (see KAS 2A). ‍ Other sites of as high-risk IHs extracutaneous hemangiomas can Benefit-harm The benefits of identifying high-risk IHs outweigh the harm occur, including the gastrointestinal assessment tract, brain, and other organs. However, Intentional None vagueness such involvement is rare and occurs Role of patient None mostly in association with large preference segmental IHs, and screening for these Exclusions Vascular lesions that are not true IHs extracutaneous hemangiomas is not Strength Strong recommendation recommended unless signs or symptoms Key references ‍5–‍23 are present.31,32​ Severe bleeding, although often feared by parents, is further compromising the narrowest biphasic stridor and barky cough as the an extremely rare complication of portion of the pediatric airway. Although IH enlarges. Approximately half of infants ulcerated IHs (see discussion of the mean age at the time of diagnosis in whom an airway IH is diagnosed also ulceration). Another potentially life- is about 4 months, symptoms usually will have a cutaneous IH. Segmental IH of threatening complication is severe present much earlier but are often the lower face (“beard distribution”) or coarctation of the aorta not attributable mistaken as infectious or inflammatory anterior neck and oral and/or pharyngeal to IHs but rather to structural anomalies croup or reactive airway disease.25‍–‍27 mucosal IHs are the greatest risk factors seen in association with IHs in PHACE Most children who are affected develop for an airway IH.6,​27‍–‍29 syndrome.

Downloaded from www.aappublications.org/news by guest on September 30, 2021 6 FROM THE AMERICAN ACADEMY OF PEDIATRICS younger than 4 months, during the period of active IH proliferation. Certain types of IHs are at higher risk, including superficial and mixed types, segmental IHs, and those involving the scalp, neck, and perioral, perineal, perianal, and intertriginous sites, the latter likely caused by maceration and friction. In addition, protuberant IHs can ulcerate as a result of trauma. Although concern for potential bleeding in IHs is common among caregivers and providers, most IH bleeding is minor and easily controllable with pressure. In rare cases, particularly IHs involving the scalp or with deep ulceration, bleeding can be more profuse, even life- threatening.14,​‍15

Associated Structural Anomalies

A small subset of children with IHs have associated congenital anomalies. The best known phenomenon is PHACE syndrome (OMIM 606519).39 The acronym “PHACES” is sometimes used instead to include potential ventral midline defects, specifically sternal cleft and/or supraumbilical raphe. Cerebrovascular anomalies, present in more than 90% of patients with PHACE syndrome, are the most common extracutaneous feature of the syndrome, followed by cardiac anomalies (67%) and structural FIGURE 2 High-risk IHs involving the face and neck. brain anomalies (52%). The hallmark of PHACE syndrome is a large (often Functional Impairment either the perioral region or the airway. >5 cm in diameter) segmental IH that Infants with ulcerated lip IHs may have typically involves the face, scalp, and/ Examples of functional impairment feeding difficulties secondary to severe or neck, although in rare cases, the face include visual disturbance and pain.36 Airway IHs may complicate or scalp are spared, with a segmental interference with feeding because of breathing and swallowing, leading also to IH located on the torso and upper IH involvement of the lips or mouth. impaired feeding.37 extremity instead.5,‍16​ The risk of PHACE IHs occurring in the periocular region syndrome in an infant presenting with have the potential to cause mechanical a large segmental IH of the head or ptosis, strabismus, anisometropia, or Ulceration neck is approximately 30%.5 Revised astigmatism, which can quickly lead to Skin or mucosal ulceration of the IH consensus criteria for the diagnosis of the development of amblyopia.12,‍13,​ ‍33​ surface occurs with an estimated PHACE syndrome and the care of infants Specific characteristics that place an incidence of 5% to 21% in referral who are affected have recently been infant at a higher risk for amblyopia populations.14,​‍38 Ulceration can lead published.16 include an IH size of >1 cm, upper eyelid to significant pain, bleeding, and involvement, associated ptosis, eyelid secondary infection and virtually always LUMBAR syndrome may best be margin changes, medial location, and results in scarring. Depending on the viewed as the “lower half of the body” segmental morphology or displacement anatomic site of involvement, it can equivalent of PHACE syndrome.17 IHs of the globe.13,​34,‍35​ Feeding impairment result in disfigurement. Ulceration in LUMBAR syndrome are almost can occur in infants with IHs involving occurs most frequently in infants invariably segmental, involving the

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 143, number 1, January 2019 7 This indication for treatment represents a paradigm shift from the hands-off approach of the late 1950s through 1980s, when many experts recommended treatment only for those IHs causing functional impairment.41 One reason for this change is an increased recognition that although IHs involute, they often leave behind permanent skin changes that, although not life or function threatening, are potentially life altering.19,‍20​ Moreover, with the advent of β-blocker therapies for IHs, there are now better treatment options with greater efficacy and lower potential toxicity than oral corticosteroids, the previous gold standard. There is also increased recognition that parental and patient quality of life can be adversely affected by visible birthmarks and resultant scarring, particularly in areas that cannot be easily covered with clothing, such as the face, neck, arms, and hands, as well as other emotionally sensitive areas, such as the breasts and genitalia.42‍–44

The precise risk of a patient in a primary care setting having permanent skin changes from an IH is not known, but in a referral setting, such changes are seen in 55% to 69% of those with untreated IHs.19,‍20​ This risk is greatest in IHs with a prominent and thick superficial (strawberry) component, especially when there is a steep step-off (ie, ledge effect) from affected to surrounding normal skin. However, the degree of superficial FIGURE 3 thickening may be difficult to predict in High-risk IHs involving the trunk, extremities, and perineum. early infancy. Thus, even in IHs that do not initially appear to be high risk, it is lumbosacral or perineal skin and spinal dysraphism, is the most common prudent to serially follow lesion growth often extending onto 1 leg. Many IHs extracutaneous anomaly.17 and establish a means for prompt in LUMBAR syndrome are minimally evaluation if ongoing or rapid growth proliferative morphologically, Disfigurement is observed because this could alter management. with telangiectatic vascular stains IHs can lead to permanent disfigurement predominating over bulkier superficial either via scarring of the skin or Key Action Statement 1B (‍Table 7) hemangiomas. In such cases, ulceration distortion of anatomic landmarks (see 17 can be an early clue to the diagnosis. ‍Table 3 for specific information). The risk After identifying an IH as high risk, Rarely, undergrowth or overgrowth of disfigurement is much higher than clinicians should facilitate an evaluation of an affected limb may be present. the risk of functional or life-threatening by a hemangioma specialist as Like PHACE syndrome, the cutaneous consequences. The majority of infants soon as possible (grade X, strong IH and underlying anomalies in who receive treatment of IHs do so to recommendation). LUMBAR syndrome reveal regional prevent uncontrolled growth leading to The purpose of this statement is correlation. Myelopathy, particularly permanent disfigurement.1,‍18,​ ‍40​ to ensure timely evaluation by a

Downloaded from www.aappublications.org/news by guest on September 30, 2021 8 FROM THE AMERICAN ACADEMY OF PEDIATRICS have completed growth by 5 months of age.22 In a study in which parents’ photographs were used, early IH growth was found to be nonlinear, with an accelerated period of rapid growth between 5 and 7 weeks of age, and the optimal time for referral or initiation of treatment was 1 month of age, a time far earlier than the time most infants with IHs are typically referred to (or seen by) hemangioma specialists.21,‍22​

These observations regarding growth are helpful, but their impact in individual case management is limited by the tremendous degree of disease heterogeneity of IHs. Even for the most experienced clinicians, it can be difficult to predict the degree of IH growth until several weeks to months after the lesion is first noticed. By that time, damage to the dermis and subcutaneous tissues as well as permanent distortion of important anatomic landmarks, such as the nose or lips, may already have occurred.19,‍20,​ ‍44​ Hence, decisions regarding intervention must be based on risk stratification, including the age of the child (in anticipation of possible IH growth), health considerations (like prematurity), anatomic site, the size of the IH, any actual or potential complications, and parental preferences. In high-risk IHs, a wait-and-see approach can result in a missed window of opportunity to prevent adverse outcomes. FIGURE 4 IHs involving the posterior trunk. The rate of growth and ultimate size of an IH can vary dramatically from patient to patient. Predicting the growth of a hemangioma specialist of an IH cell proliferation continues, the IH particular IH is, therefore, difficult and identified as high risk. IH is a disease enlarges, becomes more elevated, and made even more challenging by the develops a rubbery consistency. IHs with a window of opportunity in which minority of lesions that do not exhibit the typically have their clinical onset before to intervene and prevent poorer typical pattern of proliferation followed 4 weeks of age.21,22​ outcomes, and this critical time frame by slow involution.23,‍45​ Differences for optimizing outcomes can be missed Several studies have helped to better in growth can even be evident when if there are delays in referral or characterize the proliferative phase of comparing 1 IH to another on the same treatment. Recent literature suggests IHs. Although IHs proliferate for variable patient. For example, in patients who have that the presence and growth of IHs is periods of time and to varying degrees, 2 or more IHs, 1 lesion may become large apparent much earlier than originally the most rapid growth of superficial and problematic, and others may barely thought.21,‍22​ Premonitory findings IHs typically occurs between 1 and 3 grow. A subset of IHs known as infantile appear in the skin during early infancy, months’ chronological age.21 IHs reach hemangiomas with minimal or arrested including localized blanching or macular 80% of their ultimate size by 3 months growth (IH-MAGs) typically present as telangiectatic erythema.21 As endothelial of age, and the large majority of IHs a patch of fine or coarsely reticulated

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 143, number 1, January 2019 9 TABLE 7 Key Action Statement 1B: After identifying an IH as high risk, clinicians should facilitate may be difficult. Clinical history, response an evaluation by a hemangioma specialist as soon as possible (grade X, strong to therapy, and imaging characteristics recommendation). considered together are extremely Aggregate Evidence Grade X important in this differentiation. In rare Quality cases, a tissue biopsy may be needed to Benefits Potential for early intervention for IH at a high risk of causing complications confirm the diagnosis. Risks, harm, cost Potential for delay in intervention if specialist evaluation cannot be arranged promptly or is unavailable in the geographic region; costs associated with Clinicians should use imaging, specifically specialist evaluation for IH incorrectly identified as high risk abdominal ultrasonography, if 5 or more Benefit-harm The benefits of specialist evaluation outweigh harms and costs cutaneous IHs are present to screen assessment 30 Intentional The subcommittee recognizes the multidisciplinary nature of IH management and for hepatic IH. Ultrasonography has a vagueness the diverse level of expertise among individuals in this field. As a result, the sensitivity of 95% for detection of hepatic definition of a specialist with expertise in vascular birthmarks is vague. The hemangiomas and avoids the need subcommittee also recognizes that the time frame “as soon as possible” is for sedation and exposure to ionizing vague. radiation.46 Early detection of these Role of patient Parental preference should be considered in the decision to see a specialist and preference in the choice of specialist lesions may lead to improved monitoring Exclusions IHs not considered high risk and initiation of appropriate treatment, Strength Strong recommendation resulting in decreased morbidity and Key references ‍19–​ 23 mortality.8,‍46,​ ​49 Imaging also is indicated if concern telangiectasias, often within a zone of appointments, including the education exists for structural anomalies, as would vasoconstriction.23 They may be mistaken of office staff to give young infants with be the case in infants at risk for PHACE for a port-wine stain or other vascular high-risk IHs priority appointments. syndrome or LUMBAR syndrome. These birthmark. Although they lack the robust In-person consultation may not always infants would typically have large (eg, >5 proliferative phase characteristic of be possible or mandatory. Clinicians cm in diameter) segmental facial or scalp many IHs, IH-MAGs may be associated may also use telemedicine (either IHs or segmental IHs of the perineum, with complications, such as ulceration or, live interactive or store and forward gluteal cleft, or lumbosacral area, with or if segmental, structural anomalies. The of photographs taken in the office) without lower extremity IHs (see KAS 2C growth trajectory of deeper IHs or those to assist with triage, evaluation, and for further discussion).16,‍17,​ ‍47,​ ‍48​ with deeper soft-tissue components also management. differs from that of localized superficial Key Action Statement 2B (‍Table 9) IHs, often presenting at a later age Key Action Statement 2A (‍Table 8) Clinicians should perform (eg, 1–2 months and, occasionally, Clinicians should not perform imaging ultrasonography as the initial 22 even later). unless the diagnosis of IH is uncertain, imaging modality when the diagnosis there are 5 or more cutaneous IHs, or of IH is uncertain (grade C, weak On the basis of this information, the associated anatomic abnormalities recommendation). consensus recommendation of the are suspected (grade B, moderate subcommittee is that patients with IHs Ultrasonography (with Doppler imaging) recommendation). identified as high risk have expedited is the initial imaging modality of choice consultation and/or referral to a The purpose of this statement is to when the diagnosis of IH is uncertain. hemangioma specialist (Supplemental provide guidance to clinicians regarding The study can be performed without Table 22, Supplemental Fig 11). The the indications for imaging of IHs. Most sedation and does not necessitate type of hemangioma specialist may IHs can be diagnosed clinically. Therefore, exposure to ionizing radiation, which depend on the specific concern (eg, a imaging of IHs is not indicated for can be risky, particularly in young hemangioma specialist experienced diagnostic purposes unless the lesion infants. On ultrasonography, most IHs in airway management will be needed has an atypical appearance (ie, the appear as a well-defined mass with high- if concern exists for a subglottic diagnosis is uncertain) or it behaves flow vascular characteristics and no hemangioma). Because the time to in a manner that is inconsistent with arteriovenous shunting (an exception to appointment with a hemangioma the expected proliferative growth and the latter is that hepatic IHs may exhibit specialist may exceed the window of involution phases within the expected arteriovenous shunting). This may change opportunity during which evaluation time frame.46,‍47​ Noninvasive imaging as the IH involutes and has a more fatty and possible treatment would be of may be used to monitor response to appearance with decreased vascularity.47,‍50​ maximum benefit, those who care treatment but typically is not required.47 Doppler ultrasonography is also the for infants with IHs should have Occasionally, differentiating an IH from modality of choice when screening for mechanisms in place to expedite such a highly vascularized malignant tumor hepatic IHs and can be used to monitor

Downloaded from www.aappublications.org/news by guest on September 30, 2021 10 FROM THE AMERICAN ACADEMY OF PEDIATRICS TABLE 8 Key Action Statement 2A: Clinicians should not perform imaging unless the diagnosis of IH best studies to detect PHACE syndrome. is uncertain, there are 5 or more cutaneous IHs, or associated anatomic abnormalities are MRI does not use ionizing radiation but suspected (grade B, moderate recommendation). may require sedation given the duration Aggregate Evidence Grade B of the examination.51,‍52​ The duration Quality of imaging is important because it Benefits Avoid the cost, risk of sedation, and radiation associated with unnecessary has been theorized that prolonged imaging (>3 hours) or repeated exposures to Risks, harm, cost Potential misdiagnosis if imaging is not performed general anesthetic and sedative drugs Benefit-harm Benefits outweigh harm assessment in children younger than 3 years may 53,54​ Intentional None negatively affect brain development. vagueness Single, brief exposures are unlikely to Role of patient Minimal; when parental anxiety is significant, ultrasonography is a low-cost and have similar effects. As more rapid MRI preference low-risk means of confirming the diagnosis scanning protocols are developed, the Exclusions None Strength Moderate recommendation need for sedation may diminish. As an Key references ‍8,‍4​ 6–‍48 alternative to sedation, young infants fed immediately before an MRI and swaddled may sleep through the procedure. TABLE 9 Key Action Statement 2B: Clinicians should perform ultrasonography as the initial imaging Discussion between the radiologist, modality when the diagnosis of IH is uncertain (grade C, weak recommendation). ordering clinician, and sedation team is Aggregate Evidence Grade C critical to determine the optimal imaging Quality and sedation protocols.55 Benefits Select the appropriate imaging study to aid in diagnosis and identify associated abnormalities; avoid ionizing radiation and sedation In patients in whom there is a Risks, harm, cost Risk that ultrasonography may not be sufficiently diagnostic or may result in the risk of LUMBAR syndrome, spinal misdiagnosis of a lesion believed to represent an IH ultrasonography (for those with a Benefit-harm Benefits outweigh harms corrected age of less than 6 months) assessment Intentional None and Doppler ultrasonography of the vagueness abdomen and pelvis can be used as an Role of patient Minimal initial screen for abnormalities.56‍–‍58 preference Ultimately, however, MRI likely Exclusions None will be required to provide greater Strength Weak recommendation Key references ‍47,‍50​ definition. For example, if a high suspicion for spinal abnormalities remains despite normal ultrasonography progression of disease and response to For patients with segmental IHs of the (ie, there are associated markers of 47 treatment. perineum, gluteal cleft, or lumbosacral dysraphism [eg, sacral dimple, skin area (with or without lower extremity appendage, tuft of hair, and lipoma]), Key Action Statement 2C (‍Table 10) IHs), imaging for LUMBAR syndrome MRI is a more sensitive diagnostic 17,48​ Clinicians should perform MRI when should be considered. ‍ If there is modality.47 concerned about associated structural uncertainty about whether there is a Computed tomography is not the abnormalities (eg, PHACE syndrome or risk of associated structural anomalies, modality of choice for imaging IHs LUMBAR syndrome) (grade B, moderate consultation with a hemangioma because it involves ionizing radiation, recommendation). specialist or other appropriate expert (eg, pediatric neurologist, which should be avoided in children, Imaging for associated structural neurosurgeon, or radiologist) can particularly young infants, unless anomalies is indicated in infants at be helpful to determine if imaging is absolutely necessary. Advantages of risk for PHACE syndrome or LUMBAR required and which studies should be computed tomography are that it can be syndrome. For example, an infant performed. rapidly performed and may not require with a large (eg, >5 cm in diameter) sedation. segmental facial or scalp IH is at risk MRI is the optimal imaging modality for PHACE syndrome, and further to define underlying structural evaluation with MRI and/or magnetic abnormalities, and contrast is needed MANAGEMENT: PHARMACOTHERAPY resonance angiography (MRA) of the to assess vascular components.46 MRA Key Action Statement 3A (‍Table 11) head and neck (including the aortic can illustrate the vascular anatomy. arch and brachiocephalic origins) and Thus, MRI and MRA, with and without Clinicians should use oral propranolol echocardiography is advisable.16,‍47​ contrast of the head and neck, are the as the first-line agent for IHs requiring

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 143, number 1, January 2019 11 TABLE 10 Key Action Statement 2C: Clinicians should perform MRI when concerned about associated mean estimate of expected clearance structural abnormalities (eg, PHACE syndrome or LUMBAR syndrome) (grade B, moderate for oral propranolol was 95%, which recommendation). was superior to other interventions.46 Aggregate Evidence Grade B Ten studies compared propranolol Quality versus another modality, including Benefits Select the appropriate imaging study to aid in diagnosis and identify associated steroids, pulsed-dye laser (PDL), abnormalities; avoid ionizing radiation and sedation bleomycin, or other treatments (Table Risks, harm, cost Risk of sedation or general anesthesia 12). Propranolol was more effective Cost of MRI (but offers greater diagnostic sensitivity) Benefit-harm Benefits outweigh harms in 3 studies, effectiveness did not assessment differ significantly in 2 other studies, Intentional None and studies comparing propranolol vagueness versus steroids to reduce IH size had Role of patient Minimal conflicting results. Harms are discussed preference Exclusions None in subsequent KASs, but in the AHRQ Strength Moderate recommendation analysis, propranolol’s superior safety Key references ‍46,‍5​ 1–‍55 profile is confirmed.

The subcommittee’s additional TABLE 11 Key Action Statement 3A: Clinicians should use oral propranolol as the first-line agent for review yielded another 19 studies, 4 IHs requiring systemic treatment (grade A, strong recommendation). of which met inclusion criteria for Aggregate Evidence Grade A benefits of interventions (and 9 of Quality which met inclusion criteria for harms Benefits Improve IH treatment; avoid adverse effects associated with oral steroid therapy of interventions). These 4 studies Risks, harm, cost Occurrence of adverse effects associated with propranolol use (see KAS 3D); evaluated propranolol versus placebo medication cost and cost of hospitalization if drug is initiated while infant is an inpatient or observation. Propranolol was Benefit-harm Benefits outweigh harms associated with significantly greater assessment clearance of IH compared with the Intentional None control group in all studies. The strength vagueness Role of patient Parents should be involved in shared decision-making regarding treatment. of evidence (SOE) was considered high preference for greater effectiveness of propranolol Exclusions Caution (but not exclusion) in infants <5 wk of age, postconceptional age of <48 versus placebo or observation. The wk; potential exclusions that require appropriate subspecialty evaluation review also confirmed the superiority and/or clearance; evidence of cardiogenic shock or heart failure; sinus of oral propranolol over a variety of bradycardia; heart block greater than first degree; known or suspected PHACE syndrome, including presence or risk of coarctation of the aorta and comparators. Propranolol was superior cerebrovascular anomalies; known asthma and/or reactive airway disease; to ibuprofen and paracetamol in treating known hypersensitivity to propranolol ulcerated hemangiomas71 and to oral Strength Strong recommendation captopril in patients with problematic Key references ‍3,​46,​59 61 – IHs.72 In a randomized controlled trial (RCT) of oral propranolol compared with systemic treatment (grade A, strong induction of apoptosis, inhibition of observation for IHs, the overall efficacy recommendation). nitric oxide production, and regulation of propranolol (defined as excellent, of the renin-angiotensin system.61‍–‍69 Oral The purpose of this statement is to good, or medium response) was 98.97%, propranolol hydrochloride (Hemangeol) advise clinicians that oral propranolol is compared with 31.25% in the observation was approved by the US Food and Drug 73 74 the current treatment of choice for IHs group (P < .05). Last, Aly et al Administration (FDA) in March 2014 requiring systemic therapy. After the compared oral propranolol alone versus for use in proliferating IHs requiring serendipitous observation of its utility oral propranolol combined with 2 weeks systemic therapy. This therapy has now in treating IHs,59​ propranolol, a nonselective of “priming” with oral prednisolone. replaced the previous gold standard antagonist of both -1 and -2 adrenergic Those in the prednisolone-primed β β therapy for threatening IHs, systemic or receptors, has evolved to become propranolol group showed a statistically intralesional corticosteroids.70 the treatment of choice for IHs.1,‍3,​ ‍60​ superior reduction in IH size at weeks 2, The precise mechanisms of action of In the AHRQ review, 18 studies were 4, and 8 compared with the propranolol propranolol on IHs are unclear but have included in a network meta-analysis group, but the 6-month response was been hypothesized to be attributable to of the effectiveness and harms of equivocal for both groups regarding all vasoconstriction, angiogenesis inhibition, corticosteroids and β-blockers. The assessed variables.74

Downloaded from www.aappublications.org/news by guest on September 30, 2021 12 FROM THE AMERICAN ACADEMY OF PEDIATRICS TABLE 12 AHRQ Summary of Comparative Efficacy of Various reatmentsT for IHs growth during tapering or after stopping Drug Mean Estimate of Expected 95% Bayesian Credible Interval, % the medication may occur in 10% to Clearance, % 25% of patients and can occur even 18,76​ Propranolol 95 88–99 after 6 months of therapy. ‍ A large Topical timolol 62 39–83 multicenter retrospective cohort study Intralesional triamcinolone 58 21–93 found the greatest risk of rebound Oral steroid 43 21–66 Control 6 1–11 occurred in those in whom therapy was discontinued at <12 months of age (and especially before 9 months), and the lowest risk was in those in whom Limited data exist on the utility of placebo arm (P < .0001).76 The FDA treatment was discontinued between β-blockers other than propranolol approval of propranolol hydrochloride 18 or different delivery mechanisms for oral solution (4.28 mg/mL) recommends 12 and 15 months of age. Risk factors propranolol. The AHRQ review included a starting dose of 0.6 mg/kg twice daily, for rebound growth noted in this study 3 small studies comparing propranolol with a gradual increase over 2 weeks were the presence of mixed or deep versus nadolol or atenolol and 1 study to a maintenance dose of 1.7 mg/kg morphology and female sex. These comparing oral, intralesional, and twice daily (3.4 mg/kg per day based observations have led many experts to topical propranolol. Atenolol and nadolol on expression as the hydrochloride salt recommend continuing therapy until at each demonstrated effectiveness on of propranolol). As noted in the AHRQ least 1 year of age. lesion size, with little difference in review, other studies typically reported Dosing may need to be modified in 46 efficacy between propranolol and dosing of 2 to 2.5 mg/kg per day,​ and certain situations. Patients with atenolol and greater efficacy of nadolol a multidisciplinary, multiinstitutional PHACE syndrome may have an in 1 small study. The review did not expert panel and a European expert increased risk of stroke, and this find differences in response with consensus group1,‍61​ support a starting risk may be greater if certain propranolol, nadolol, or atenolol, but dose of 1 mg/kg per day and a target neurovascular anomalies are present.16 the SOE in comparing these was low.46 dose of 2 to 3 mg/kg per day. Data In patients who merit systemic IH The subcommittee s additional review comparing 2 and 3 mg/kg per day are ’ therapy, the benefits and risks must be yielded 1 article on oral atenolol for IH, lacking. carefully weighed. Evaluation with which did not meet the AHRQ inclusion Similarly, available data do not permit MRI and/or MRA of the head and neck criteria for comparative effectiveness evidence-based recommendations on and echocardiography should be but revealed an excellent treatment dosing frequency (twice daily versus 3 performed before or shortly after response in 56.5% of patients.75 times daily), but both the FDA and the the initiation of therapy.61 If patients European Medicine Evaluation Agency who are at high risk require treatment Key Action Statement 3B (‍Table 13) labeling is for twice-daily dosing. with propranolol, it is advisable to Clinicians should dose propranolol The site for initiation of propranolol use the lowest effective dose, slowly between 2 and 3 mg/kg per day unless (outpatient versus inpatient) is evolving titrate the dose, and administer there are comorbidities (eg, PHACE as more evidence accumulates that the drug 3 times daily (to minimize syndrome) or adverse effects (eg, cardiovascular and other acute toxicities abrupt changes in blood pressure); sleep disturbance) that necessitate occur rarely. Although in both the comanagement with a pediatric a lower dose (grade A, moderate aforementioned consensus articles, neurologist is recommended.1,‍16,​ ​61,​ recommendation). initiation in an inpatient setting is ‍77 Other patients who may require favored for infants younger than 8 lower propranolol doses include those The purpose of this statement is to weeks, those with cardiovascular or with progressive IH ulceration while provide clinicians guidance in dosing respiratory comorbidities, and those receiving therapy and those who oral propranolol for IHs. To date, with poor social support, FDA labeling experience adverse effects (such as authors of most studies favor dosing sanctions initiation in an outpatient sleep disturbances). at 2 to 3 mg/kg per day. An RCT of 456 setting for infants >5 weeks’ corrected infants compared a placebo versus 1 of gestational age. 4 propranolol regimens (1 mg/kg per Key Action Statement 3C (‍Table 14) day or 3 mg/kg per day for 3 or A duration of 6 months of therapy was Clinicians should counsel that 6 months duration). The regimen of shown to be superior to 3 months in propranolol be administered with or after 3 mg/kg per day for 6 months was the large RCT conducted by Léauté- feeding and that doses be held at times superior, with complete or nearly Labrèze et al.76 In the AHRQ review, of diminished oral intake or vomiting to complete resolution in 60% of patients, the duration of propranolol treatment reduce the risk of hypoglycemia (grade X, compared with 4% of patients in the ranged from 3 to 13 months.46 Rebound strong recommendation).

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 143, number 1, January 2019 13 TABLE 13 Key Action Statement 3B: Clinicians should dose propranolol between 2 and 3 mg/kg per experienced hypoglycemia (3 of these day unless there are comorbidities (eg, PHACE syndrome) or adverse effects (eg, sleep suffered hypoglycemic seizures in the disturbance) that necessitate a lower dose (grade A, moderate recommendation). setting of viral gastroenteritis and poor Aggregate Evidence Grade A oral intake).80‍–‍82 Quality In a large meta-analysis of oral Benefits The recommended doses have been associated with high clearance rates of IH Risks, harm, cost Response rates for higher or lower doses have not been well studied propranolol for IHs not included in Benefit-harm Benefits outweigh harms the AHRQ review, adverse events were assessment reported for 1945 of 5862 patients Intentional None who were treated.60 The investigators vagueness identified 24 cases of hypoglycemia Role of patient Parents will be involved in the decision about dosing in the setting of PHACE preference syndrome or the occurrence of adverse effects and 2 cases of hypoglycemic seizures Exclusions See KAS 3A; dosing may be modified if comorbidities exist among 3766 patients who were treated Strength Moderate recommendation with propranolol from their literature Key references ‍1,​46,​61,​76 review (some of whom are included in aforementioned studies). Of the 14 events TABLE 14 Key Action Statement 3C: Clinicians should counsel that propranolol be administered with with resolution details, 9 led to dose or after feeding and that doses be held at times of diminished oral intake or vomiting to adjustment or temporary discontinuation reduce the risk of hypoglycemia (grade X, strong recommendation). of propranolol, and 1 led to permanent discontinuation of treatment. The authors Aggregate Evidence Grade X Quality mention that 1 case of hypoglycemic seizure was related to overdose, and the Benefits Reduce the likelihood of adverse reactions Risks, harm, cost Risk that parents will decline therapy because of concerns about potential other was associated with diminished medication adverse effects oral intake because of infection.60 Benefit-harm assessment Benefits outweigh harms Intentional vagueness None Although the risk of hypoglycemia Role of patient None must be considered when prescribing preference oral propranolol for IHs, routine glucose Exclusions None screening is not indicated.1,‍61​ Strength Strong recommendation Hypoglycemia occurs infrequently and Key references ‍46,​60,​61,​76,​78–‍80 can be minimized with appropriate education of caregivers on the importance of administering propranolol during The purpose of this statement is The AHRQ review identified 24 or immediately after a feeding and of to reinforce the importance of comparative studies (4 good quality) temporarily withdrawing therapy during administering oral propranolol with and 56 case series (4 good quality) that periods of fasting (including poor oral feeds and of holding therapy at times reported harms data of β-blockers for intake because of illness or before general of restricted oral intake to prevent IHs. Rates of clinically important harms anesthesia) or vomiting.60 Prolonged hypoglycemia and hypoglycemia-induced (hypoglycemia, hypotension, bradycardia, fasting should be avoided, and parents seizures. The association between and bronchospasm) varied widely, and should be advised that hypoglycemia hypoglycemia and propranolol in infants the authors assigned a moderate SOE becomes more likely after ≥8 hours of and children is well established and for the association of propranolol with fasting in infants and young children.83,​84 is related to effects on glycogenolysis both clinically important and minor and gluconeogenesis.78 β-blockade harms (with high study limitations).46 Key Action Statement 3D (‍Table 15) by propranolol can affect these Harms overall did not cause treatment Clinicians should evaluate patients for processes, and infants and children discontinuation. and educate caregivers about potential may be particularly susceptible to adverse effects of propranolol, including this effect.78,‍79​ Early clinical features The subcommittee s additional review ’ sleep disturbances, bronchial irritation, of hypoglycemia in infants, which may yielded 8 reports that met inclusion and clinically symptomatic bradycardia be masqueraded by -adrenergic criteria for harms regarding oral β and hypotension (grade X, strong blockade, include sweating, tachycardia, propranolol for treatment of IHs. recommendation). shakiness, and anxious appearance, These reports provided more detailed whereas later manifestations (signs of information about the occurrence of The purpose of this statement is neuroglycopenia) may include lethargy, hypoglycemia. Three of the 8 articles to increase awareness of potential poor feeding, apnea, seizures, stupor, and reported hypoglycemia; these articles propranolol-associated adverse effects loss of consciousness.79 included 1021 patients, 10 of whom other than hypoglycemia for clinicians

Downloaded from www.aappublications.org/news by guest on September 30, 2021 14 FROM THE AMERICAN ACADEMY OF PEDIATRICS and caregivers of patients receiving this TABLE 15 Key Action Statement 3D: Clinicians should evaluate patients for and educate caregivers medical therapy for IHs. Propranolol about potential adverse effects of propranolol, including sleep disturbances, bronchial has been used in pediatric patients irritation, and clinically symptomatic bradycardia and hypotension (grade X, strong for decades, primarily in an off-label recommendation). fashion. In young infants, is has been Aggregate Evidence Grade X used primarily for cardiac disorders Quality and for the treatment of thyrotoxicosis Benefits Recognition of adverse effects of propranolol treatment at doses up to 6 to 8 mg/kg per day. Risks, harm, cost Risk of caregivers declining medical therapy because of concern about Despite this use, many pediatricians potential adverse effects Benefit-harm assessment Benefits outweigh harms will be unfamiliar with the drug, and Intentional vagueness None reviewing its possible adverse effects is Role of patient None warranted. preference Exclusions None As noted in the discussion of KAS 3C, Strength Strong recommendation the AHRQ review identified a number Key references ‍3,​46,​61,​76,​80,​85–‍88 of adverse effects during propranolol treatment. Adverse effects most respiratory events were mentioned, trial, with a recommendation for frequently reported included sleep including temporary discontinuation of in-office intermittent heart rate and disturbances, cold extremities, therapy80,‍82​ and decreased dosage of blood pressure monitoring for 2 hours gastrointestinal symptoms, bronchial propranolol.89 after the first dose of propranolol or irritation (classified as hyperreactivity, for increasing the dose for infants bronchospasm, bronchiolitis, and 5 weeks adjusted gestational age cold-induced wheezing), and a Although bradycardia and ’ or older.76 Monitoring for those who decrease in heart rate or blood hypotension are known to accompany are younger or for those with other pressure. Rates of clinically important propranolol-associated β-receptor comorbidities should be individualized harms (hypoglycemia, hypotension, blockade, both tend to be mild and and may require brief hospitalization bradycardia, and bronchospasm) asymptomatic in children treated for for medication initiation. These varied widely across the studies, and IHs who have no preexisting cardiac 3,84,​ 87,​ 88,​ ​91–93 recommendations may change over the authors assigned a moderate SOE comorbidities. ‍ ‍ ‍ ‍ ‍ In the time as more information becomes for the association of propranolol with subcommittee’s review, only 1 of the available now that the medication is in both clinically important and minor 8 reports mentioned hypotension or widespread use. harms (with high study limitations).46 bradycardia as an adverse event, with Overall, harms did not cause treatment 1 of 906 patients (0.1%) exhibiting discontinuation. bradycardia and 2 of 906 exhibiting Theoretical concerns about adverse asymptomatic hypotension.80 The use effects of propranolol on brain Our additional review yielded 8 reports of pretreatment electrocardiography development have been raised. As a that met inclusion criteria for harms (ECG) is controversial. Although this highly lipophilic β-blocker, propranolol of interventions. Sleep disturbance, initially was advocated by some, has the ability to cross the blood brain sleeping disorders, agitation during the several studies have revealed no barrier.94 Adult studies have revealed night, and nightmares or night terrors actionable findings with continuous impairments in short- and long- were mentioned in 6 of 8 reports and ECG monitoring, and researchers term memory, psychomotor occurred in 2% to 18.5% of patients have questioned its value.61,​91 FDA function, and mood, and prenatal who were treated.80,‍82,​ ‍85,​ ‍86,​ 89,​ ‍90​ In 3 of guidelines for patient monitoring do β-blockade has been associated with these 6 reports, propranolol treatment not include routine ECG.61 In their long-term cognitive impairment,95,​ ‍96​ was modified (reduction in dosage, consensus recommendations, Drolet leading some to question the potential earlier-evening dosing, and early et al61 suggest ECG screening only (1) central nervous system effects of discontinuation of therapy) in response in infants with a baseline heart rate this agent when used to treat young 80,82,​ 85​ to these effects. ‍ ‍ below normal for age, (2) in infants children with IHs.97,​98 In the large In 4 reports, possible respiratory with a family history of congenital heart prospective randomized propranolol adverse effects were mentioned, conditions or arrhythmias or with a trial conducted by Léauté-Labrèze et al,​76 including labored breathing in 0.9%,86​ maternal history of connective tissue no appreciable neurodevelopmental breathing-related problems in 11.5%,89​ disease, or (3) when there is a history differences were noted between the respiratory disorders in 3.4%,80​ of arrhythmia or one is auscultated propranolol-treated groups and the and wheezing or bronchiolitis in during examination. Currently, the FDA- placebo group at week 96. Four other 12.9%.82 In 3 of these series treatment approved administration guidelines studies addressing development in modifications in response to the mirror those used in the pivotal clinical infants treated with propranolol for

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 143, number 1, January 2019 15 IHs have yielded conflicting results. most frequently in the literature are injections are often administered, with In 2 case series (with a total of 272 between 2 and 5 mg/kg per day,3,​ ​70,‍104​ ‍–‍106 the number used ranging in most reports patients), gross motor delay was and most consider optimal dosing to be from 1 to 7.109‍–‍112 99,100​ reported in 4.8% to 6.9%. ‍ 2 to 3 mg/kg per day. Typical protocols The AHRQ review found that intralesional In contrast, a case series of 141 include treating at full dose for 4 to 12 triamcinolone had a mean estimate patients found psychomotor delay weeks followed by a gradual taper and of expected clearance of 58% (Table in only 1 child, and a controlled trial completion of therapy by 9 to 12 months 12).46,‍103​ Overall, the SOE was low for 3,​70,105,​ 106​ of 82 children found no increase in of age. ‍ ‍ Some have advocated for intralesional steroids having a modest the rate of developmental concerns shorter treatment durations (1–6 weeks), effect relative to control, with wide as assessed by the Ages and Stages with multiple intermittent courses as confidence bounds.46 The subcommittee’s 101,​102 107 Questionnaire. Although these needed. additional search yielded 1 report that latter studies are reassuring, further met inclusion criteria for benefits of prospective psychometric studies of In the AHRQ review, steroids were interventions as a comparative study. children treated with oral propranolol consistently associated with clinically This was a retrospective review of for IHs may be warranted. important harms, including Cushingoid patients with periocular IHs treated with appearance, infection, growth oral propranolol, who were compared Key Action Statement 3E (‍Table 16) retardation, hypertension, and mood with a cohort treated with intralesional changes. The authors considered the corticosteroid injection. Both groups Clinicians may prescribe oral SOE to be moderate for the association showed a reduction in astigmatism over prednisolone or prednisone to treat of steroids with clinically important 12 months, and neither experienced IHs if there are contraindications or an 46 harms. significant adverse effects necessitating inadequate response to oral propranolol dose reduction or treatment cessation.115 (grade B, moderate recommendation). The authors concluded that oral Key Action Statement 3F (‍Table 17) The purpose of this statement is propranolol (given its efficacy and safety to highlight the utility of systemic Clinicians may recommend intralesional profiles) has emerged as the treatment corticosteroid therapy for IHs in certain injection of triamcinolone and/or of choice for periocular IHs requiring settings, such as for patients in whom betamethasone to treat focal, bulky IHs therapy.115 β-blocker therapy is contraindicated, during proliferation or in certain critical poorly tolerated, or ineffective. Systemic anatomic locations (eg, the lip) (grade B, Steroids (oral and intralesional forms therapy with corticosteroids was moderate recommendation). were grouped together in the AHRQ harms considered the standard of care for analysis) were consistently associated several decades before being supplanted The purpose of this statement is to with clinically important harms, including by oral propranolol. highlight the utility of intralesional Cushingoid appearance, infection, corticosteroid injection for certain IH growth retardation, hypertension, In the AHRQ review, oral steroids had a subsets. Numerous studies have reported and mood changes. The authors mean estimate of expected clearance success in the use of steroid injections considered the SOE to be moderate for of 43% (Table 12).46,‍103​ The AHRQ for IHs, demonstrating it to be safe and the association of steroids with clinically report identified 24 studies (3 RCTs, 108–114 effective. ‍‍ This modality is most often important harms. The most commonly 1 cohort study, and 20 case series) reserved for IHs that are relatively small reported complications associated with reporting outcomes and/or harms after and well localized where proliferation intralesional steroid injection for IHs are corticosteroid use in children with IHs. is resulting in increased bulk and transient Cushingoid features, failure to One RCT was judged as good, 1 as fair, threatening anatomic landmarks (eg, the thrive, and local skin complications.109‍–‍112 and 1 as poor quality, and the cohort lip or nose). Larger or more extensive Local complications may include fat study was judged as fair quality (all case lesions are poorer candidates for this and/or dermal atrophy and pigmentary series were judged as poor quality for treatment modality given the larger 108–110 harms reporting). The steroids studied volume of steroids necessary (and the changes. ‍‍ Adrenal suppression is varied in terms of dose, type, route of inherent systemic risks), the difficulty of infrequently reported in association with administration, and patient ages. Children obtaining even distribution throughout intralesional steroid injections but has in steroid treatment arms typically had the tumor, and the potential for local been observed when large doses (eg, >4 modest improvement in lesion size, but complications in lesions that are mostly mg/kg) have been administered.116,​‍117 outcomes were difficult to compare flat or superficial.3 Most studies have There have been rare reports of central given differences in scales. The optimal used triamcinolone either alone or in retinal artery embolization, usually after dosing of systemic corticosteroids for conjunction with betamethasone, with injection into IHs of the upper eyelid, likely IHs remains unclear. Dose ranges of injections given on average every 4 to 6 related to high injection pressures and/or prednisone or prednisolone reported weeks (but with wide variability). Repeat volumes.118‍–‍121

Downloaded from www.aappublications.org/news by guest on September 30, 2021 16 FROM THE AMERICAN ACADEMY OF PEDIATRICS TABLE 16 Key Action Statement 3E: Clinicians may prescribe oral prednisolone or prednisone to 6 to 9 months of therapy. The greatest treat IHs if there are contraindications or an inadequate response to oral propranolol improvement was in color; however, (grade B, moderate recommendation). with a longer duration of treatment, Aggregate Evidence Grade B improvement in size, extent, and volume Quality were also observed. Best responses Benefits Modest benefit in IH clearance; medication cost is low were observed in thinner superficial IHs Risks, harm, cost Clinically important harms; cost associated with the evaluation and (ie, <1 mm thick) versus mixed or deep treatment of adverse effects IHs. The large majority of infants studied Intentional vagueness None Benefit-harm assessment Benefits outweigh harms were 6 months or younger at time of Role of patient preference Shared decision-making regarding treatment initiation of treatment, and 41% were ≤3 Exclusions None months of age. This suggests that early Strength Moderate recommendation topical timolol treatment may also inhibit Key references ‍46,​70,​103 IH growth. Only 7% of infants required subsequent treatment with a systemic 40 TABLE 17 Key Action Statement 3F: Clinicians may recommend intralesional injection of triamcinolone β-blocker. and/or betamethasone to treat focal, bulky IHs during proliferation or in certain critical anatomic locations (eg, the lip) (grade B, moderate recommendation). Although pharmacokinetic data are limited, evidence suggests that timolol Aggregate Evidence Grade B Quality maleate can be detected in the blood or urine of at least some infants Benefits Modest benefit in IH clearance 126,136​ Risks, harm, cost Clinically important harms; cost of medication, visits for injection; risk of treated topically. ‍ Additional anesthesia if used pharmacokinetic studies are needed Benefit-harm Benefits outweigh harms in selected clinical situations given occasional reports of systemic assessment toxicity.137‍–139 It should be noted that Intentional None timolol is significantly more potent than vagueness Role of patient Shared decision-making regarding route of drug delivery propranolol, and topical application preference avoids first-pass liver metabolism, as Exclusions None would occur with an oral β-blocker.127 Strength Moderate recommendation Pending the results of ongoing studies, Key references ‍3,​46,​103,​108–‍112 these factors should lead to caution when using timolol, especially if prescribing Key Action Statement 3G (‍Table 18) that their use of timolol exceeds that of more than 1 drop twice daily or when oral β-blockers.135 treating preterm or young infants. Clinicians may prescribe topical timolol maleate as a therapy for thin and/ In the AHRQ review, 2 RCTs and 4 cohort The AHRQ report emphasized that or superficial IHs (grade B, moderate studies were included. Topical timolol there were far more reports of recommendation). had a mean estimate of expected harms with oral β-blockers than The purpose of this statement is clearance of 62% (Table 12).46,‍103​ Timolol with timolol but did note 1 report of to highlight the potential utility of was significantly more effective than shortness of breath and insomnia.46 topical timolol in treating thin and/or observation or a placebo in 3 studies; 1 Subsequent to that report, tolerability superficial IHs. Topical timolol maleate, study comparing topical imiquimod with data have been reassuring overall, a nonselective β-adrenergic receptor timolol did not demonstrate superiority but some adverse events have been inhibitor, has been used in the treatment of either agent but was found to have reported.40,‍122,​ ‍124,​ 125,​ ‍131​ ‍–‍134,140​ In the large of pediatric glaucoma as a first-line agent insufficient SOE.46 Our subsequent review cohort study of 731 patients conducted for several decades.122,‍127,​ ‍128​ Treatment found 3 further reports meeting criteria by Püttgen et al,​40 adverse events were of IHs with ophthalmic timolol maleate for efficacy, including 1study comparing noted in 3.4% of patients and included was initially reported in 2010, and timolol to an ultrapotent corticosteroid local irritation (nearly half of the since that time, there have been many and 2 other studies of timolol alone.40,‍133,​ ‍134​ adverse events) and bronchospasm (in reports (including some with hundreds In the largest of these, a multicenter 3 patients); no cardiovascular events of patients), as well as an RCT, with retrospective cohort study of 731 were reported. No adverse events were positive findings. 40,​122‍–‍125,‍129​ ‍–‍134 On the patients, most infants were treated significant enough to necessitate drug basis of these reports showing efficacy with the 0.5% gel-forming solution. The discontinuation.40 In a retrospective case with minimal adverse effects, timolol study reveal improvement in nearly 70% series of 30 children with ulcerated IHs is increasingly being used for thin and of patients treated for 1 to 3 months treated with topical timolol maleate 0.5% superficial IHs, and many centers report and in 92.3% of patients who received gel-forming solution and evaluating for

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 143, number 1, January 2019 17 TABLE 18 Key Action Statement 3G: Clinicians may prescribe topical timolol maleate as a therapy for involving the ear or eyelid [causing thin and/or superficial IHs (grade B, moderate recommendation). ptosis]); (3) the lesion is well localized Aggregate Evidence Grade B in an anatomically favorable area; or Quality (4) resection is likely to be necessary in Benefit Modest benefit in IH clearance the future, and the resultant scar would Harm Low but possible risk of local irritation, sleep disturbance, cold extremities, be the same.142,‍143,​ ​145 The decision bronchospasm, and bradycardia, with more caution needed in preterm infants to undertake surgery during infancy and those without intact skin (ie, ulceration) should take into consideration current Cost Cost of medication Benefits-harm Benefits outweigh harms knowledge of the risks of general assessment anesthesia in this age group.53‍–‍55 Value judgments None Role of patient Parents have a significant role in decision-making regarding the desire to treat Surgery also is an important treatment preference small superficial lesions for which timolol may be effective option for IHs that, despite involution, Intentional None vagueness have left residual skin changes (eg, Exclusions Lesions that are large size, significantly elevated, or life-threatening thinned skin, scar, fibrofatty tissue, Strength Moderate recommendation telangiectasias, and/or anatomic Key references ‍40,​46,​85,​122–‍126 deformities in areas such as the nose, ear, or lip).19,‍20,​ ‍143​ In most cases, deferring surgery until the child is 3 to adverse events, sleep disturbance was made in consultation with a hemangioma 5 years of age is reasonable because: observed in 1 infant (who was treated specialist, especially in young infants. (1) the lesion may resolve significantly simultaneously with oral propranolol With the advent of β-blocker therapy, without leaving a deformity that and topical timolol) and a single episode surgical and laser approaches are used necessitates intervention; (2) the tumor of cold extremities was reported in less frequently. is smaller than it was during infancy, another. The remainder had no reported In general, surgical interventions are and thus, the operation is often easier, 141 adverse events. Bradycardia, both not performed in infancy. During this and the resultant scar may be smaller; symptomatic and asymptomatic, was time, anesthetic risks are of greater and (3) the IH primarily is adipose tissue reported in 4 of 22 young and preterm concern, and the tumor is highly instead of blood vessels, and thus, the infants given timolol for IHs. Two infants vascular, posing a higher risk of blood operation is safer.142,143,​ ‍145​ However, it had bradycardia that was mild and loss, iatrogenic injury, and an inferior is usually unnecessary to wait longer asymptomatic, but in 2 (both of whom outcome.142,‍143,​ ‍145​ than 3 to 5 years of age because the were born preterm and weighed less In certain locations, such as the previously accepted adage that 50% of than 2500 g at initiation of therapy) lip and nasal tip, the final cosmetic IHs complete involution by 5 years of there were associated symptoms.126 To result is superior when growth of the age, 70% by 7 years of age, and 90% address concerns regarding potential lesion has ceased and the number by 9 years of age has proven to be percutaneous absorption and toxicity, of surgical interventions can be kept incorrect.19,‍143,​ ‍149​ In fact, most IHs do not many authors have advocated using to a minimum. Furthermore, there is improve significantly after 3 to 4 years of limited amounts of medication (eg, 1 no psychosocial urgency to improve age.20,‍143​ Moreover, performing surgery drop 2–3 times per day),40​ and some a deformity caused by IHs in this age at this earlier age can be beneficial have cautioned against application to group because long-term memory and in minimizing stigma and impact on 127 ulcerated lesions. self-esteem are not established until a child’s self-esteem.143 There is less later in childhood.143,​146‍–‍148 There are urgency to correct a residual deformity certain clinical situations, however, in an area that is concealed by clothing SURGICAL MANAGEMENT in which early surgery can be an (eg, a lesion on the trunk). Some parents Key Action Statement 4 (‍Table 19) important treatment option. These may elect to wait until the child is older include IHs that ulcerate, obstruct or and able to help in decision-making, Clinicians may recommend surgery deform vital structures (such as the especially if the reason for surgery is and laser therapy as treatment options airway or orbit), or involve aesthetically the management of less disfiguring skin in managing selected IHs (grade C, sensitive areas. In these circumstances, changes.143 moderate recommendation). surgery may be indicated when (1) the The purpose of this statement is to lesion has failed to improve with local Laser Management support surgery and laser therapy wound care and/or pharmacotherapy; as treatment options for selected (2) the lesion is well localized, and PDL has been used for several decades IHs, although it is recommended that early surgery will simplify later to treat IHs. The AHRQ review noted decisions regarding their use should be reconstruction (eg, a prominent IH that most studies that were reviewed

Downloaded from www.aappublications.org/news by guest on September 30, 2021 18 FROM THE AMERICAN ACADEMY OF PEDIATRICS TABLE 19 Key Action Statement 4: Clinicians may recommend surgery and laser therapy as treatment ‍Figs 2–4, Supplemental Table 22, and options in managing selected IHs (grade C, moderate recommendation). Supplemental Fig 11). Aggregate Evidence Grade C Quality IHs That Do Not Raise Concern Benefits Early surgical intervention after infancy corrects residual deformities before the In a primary care setting, the majority child’s self-esteem develops Risks, harm, cost Risk of surgical complications and general anesthesia; costs associated with of IHs are not problematic and require operative intervention, anesthesia, and postoperative care no active intervention (ie, are low risk; Benefits-harm Preponderance of benefit Supplemental Table 22, Supplemental assessment Fig 11). However, given their appearance, Intentional None even nonproblematic (that is, low-risk) vagueness Role of patient Significant IHs may cause significant parental anxiety preference and concern. These emotions may be Exclusions Children with a nonproblematic IH amplified by information gleaned from Strength Moderate recommendation Internet searches that show photographs Key references ‍20,​142–‍144 emphasizing the more severe end of the disease spectrum as well as public reactions to the child’s IH if the lesion evaluated PDL (as opposed to other redness may be diminished, deeper is located at a site not easily covered lasers) and examined heterogeneous elements of the IH (that increase the by clothing.42,‍155,​ ‍156​ Formal educational end points (the latter factor limiting the risk of residual skin changes) are not efforts can reduce parental anxiety and ability to draw conclusions). However, affected.144,​152,‍153​ enhance comfort with a plan to observe there is low SOE that PDL is more effective the IH for any unexpected or worrisome Some authors advocate for using in reducing IH size when compared with changes.154 PDL as a treatment of ulceration. observation.46 There is evidence that PDL However, evidence supporting the use Parents should be educated about the is superior to other lasers. In contrast, of PDL for this indication comes from natural history of IHs. Specifically, they there is wide recognition that PDL is case reports and small case series. may be advised that, although growth effective and safe in removing residual Propranolol has been associated with characteristics vary from case to case, macular erythema and superficial faster healing of ulceration when most superficial IHs have a maximum telangiectasias in involuting or involuted compared with laser therapy and growth potential between 1 and 3 months IHs, but it often requires several antibiotics.46 of age3,‍21,​ ‍157​ and that the majority of treatments to achieve optimal results.1,​ growth is complete by 5 months of age.22 ‍142 Other lasers, such as erbium-yttrium- Deeper IHs may have a slightly later aluminum-garnet, have been reportedly onset and a more prolonged duration effective in ameliorating textural changes PARENT EDUCATION of growth. During the period of growth, in small case series.150 Harms associated Key Action Statement 5 (‍Table 20) clinicians should encourage parents to with laser therapy that were identified in call, schedule an office visit, or share the AHRQ review included skin atrophy, Clinicians should educate parents of photographs of the IH with them to bleeding, scarring, ulceration, purpura, infants with an IH about the condition, reassess if concerns exist about the and pigmentation changes.46 The AHRQ including the expected natural lesion s appearance, unexpectedly rapid review also noted that most studies of history, and its potential for causing ’ growth, ulceration, bleeding, or pain, all lasers reviewed evaluated lasers as a complications or disfigurement (grade X, findings that indicate that a lesion is no first-line treatment, a practice that is less strong recommendation). longer low risk. common since the advent of β-blocker The purpose of this statement is to treatment. ensure that parents are knowledgeable Parents should be advised that by age There is controversy regarding whether about their child’s IH and to provide 5 to 12 months, most IHs have stopped PDL should be used to treat IHs early clinicians with a framework for educating growing and are beginning to involute. in infancy (ie, during the proliferative those parents about IHs. The information For IHs with a superficial component, this phase). Several case reports and case provided by clinicians should be as appears as a gradual change in color series have revealed an increased specific to the patient’s IH as possible from red to milky-white or gray. Lesions risk of ulceration, scarring, and (eg, indicating whether and why an IH gradually flatten and shrink from the hypopigmentation when PDL is is low risk and, thus, likely to cause no center outward. Involution proceeds more used during this period.1,‍144,​ ‍151​ problems or sequelae or is potentially slowly than growth. Newer studies have Moreover, PDL penetrates only into the high risk and requires urgent evaluation demonstrated that 90% of IH involution superficial dermis, and thus, although or treatment; Table 3, illustrated in is complete by 4 years of age.20,‍143​ This

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 143, number 1, January 2019 19 is in contrast to traditional teaching that TABLE 20 Key Action Statement 5: Clinicians should educate parents of infants with an IH about involution proceeds at 10% per year (ie, the condition, including the expected natural history, and its potential for causing 50% of IHs resolve by 5 years of age and complications or disfigurement (grade X, strong recommendation). 90% by 9 years of age). Parents should Aggregate Evidence Grade X be advised that even after involution, Quality residual changes, such as telangiectasias, Benefits Promotes parent satisfaction and understanding, may reduce medication errors, redundant skin, or a scar,3,​ ‍19​ may be left. may improve clinical outcomes It is usually possible to tell whether such Risks, harm, cost May increase parental anxiety because of the need to administer medication; time spent in education, may increase health care costs because of the need changes are going to persist by 4 years for follow-up visits of age, and if concerning, consultation Benefit-harm Benefits outweigh harms for management of these skin changes, assessment particularly laser or surgical treatment, Intentional None may be pursued. vagueness Role of parental Essential; shared decision-making regarding the need for treatment is vital A collection of serial photographs preferences can be useful to demonstrate to Exclusions None parents the natural history of IHs Strength Strong recommendation Key references 21,‍ ​22,​154 and the process of spontaneous involution.154 Such photos are available on the Hemangioma Investigator to consult promptly with a hemangioma discussion about management can Group (https://​hemangiomaeducati​on.​ specialist unless they have the take place. If medical treatment is org/)​ and Yale Dermatology (http://​ experience and knowledge to manage recommended, the specialist will medicine.​yale.​edu/​dermatology/​patient/​ such patients independently. Because educate parents about the medication conditions/​hemangioma.​aspx) Web IH proliferation may occur early and and its dosing, its possible adverse sites. Information sheets (ie, handouts) be unpredictable and because there effects, and the expected duration of are available from the Society for is a window of opportunity for optimal treatment. If the medication selected Pediatric Dermatology Web site treatment, caregivers can be advised is propranolol, as often is the case, (http://​pedsderm.​net/​) under the that consultation should take place in a a patient information sheet (such “For Patients and Families” tab, timely manner. Unfortunately, this does as that developed by the Society for and adapted versions of their not always occur. Although caregivers Pediatric Dermatology or that provided hemangioma patient information first notice lesions by 1 month of age in the What Are Hemangiomas? and and propranolol sheets are included (on average, at 2 weeks) and the ideal Propranolol for Hemangiomas sections in the What Are Hemangiomas? time for consultation may be 4 weeks of of the Supplemental Information) or Propranolol for Hemangiomas, and age, 1 study found that the mean age at information from the article by Martin Medication Information sections of the presentation to a dermatologist was 5 et al160 may be provided. For families Supplemental Information. A video for months, by which time most growth is unable to travel to see a hemangioma parents is also available on the Society complete.21,‍22​ specialist, collaborative care may be for Pediatric Dermatology Web site considered. The hemangioma specialist (https://​pedsderm.​net/​for-​patients-​ Recognizing that it may be difficult can evaluate serial photographs and families/​patient-​education-​videos/​ to obtain an appointment with a provide the primary care clinician with #InfantileHemangi​omas). Information hemangioma specialist in a timely guidance on treatment. In this case, the also is available from the AHRQ (https://​ manner, caregivers and clinicians primary care clinician will assume a effectivehealthca​re.​ahrq.​gov/​topics/​ may need to advocate on behalf of the more active role in parent education. infantile-​hemangioma/​consumer/​),158​ infant. In settings where a hemangioma and answers to frequently asked specialist is not readily available, telemedicine triage or consultation, CHALLENGES TO IMPLEMENTING THIS questions are available on the CPG Hemangioma Investigator Group and using photographs taken by caregivers Several potential challenges exist to Yale Dermatology Web sites. or the clinician, can be helpful. In 1 academic center in Spain, implementing this CPG. The first is the teledermatology triage reduced the age dynamic nature of individual IHs with IHs That May Be Problematic at first evaluation of an infant with an IH a period of rapid growth, the degree When confronted with a potentially from 5.9 to 3.5 months.159 of which can be difficult to predict, problematic IH (ie, high risk; Table 3; particularly in young infants. There illustrated in Figs 2–4, Supplemental Once the hemangioma specialist are no surrogate markers or imaging Table 22, and Supplemental Fig 11), has an opportunity to meet with studies that have been shown to primary care clinicians are encouraged parents and evaluate the infant, a reliably predict growth. Hence, frequent

Downloaded from www.aappublications.org/news by guest on September 30, 2021 20 FROM THE AMERICAN ACADEMY OF PEDIATRICS in-person visits or a review of parental false reassurance can be given even in drug need referral versus which can photos may be needed, especially in high-risk cases; indeed, all hemangioma be observed without referral by the infants younger than 3 to 4 months. specialists have seen examples of lost pediatrician? However, this may be complicated by the opportunities to intervene and prevent Is outpatient in-office cardiovascular frequency and timing of well-child visits poor outcomes because of lack of •• monitoring for propranolol truly during this period. After the first-week or delayed referral. The availability needed in healthy infants 5 weeks or visit, an infant who is well, has regained of highly effective treatments for older? Is blood pressure monitoring birth weight, and has parents who are IHs makes it critical that this myth necessary, or is measuring heart rate experienced caregivers may not be seen is debunked and that practitioners sufficient? again until 2 months of age. As noted by become more comfortable with the Tollefson and Frieden,21​ most superficial concept of identifying high-risk IHs that •• What is the role of the pediatrician in IHs have accelerated growth between 5 require close observation or prompt managing infants placed on β-blocker and 7 weeks of age, and 4 weeks of age intervention. therapies (both topical and systemic), and are there specific time frames for may be the ideal time for referral if high- Last, some geographical locations lack specialty reevaluation? risk features are present. Thus, the most access to prompt specialty care from dramatic IH growth (and potentially hemangioma specialists. Lack of access •• How accurate are primary care permanent skin changes) may occur can also result in delays in referrals physicians in identifying high-risk during a time when an infant is not or prompt appointments. Possible IHs using parameters such as those scheduled to see a health care provider. solutions could include establishing outlined in this CPG? Although awareness of this issue does resources for the photographic triage Are pediatric trainees receiving adequate not justify altering the interval of well- •• of cases in which risk stratification is training in risk stratification and child visits for all infants, it heightens uncertain or in which triage to hasten management of IHs? the need for more frequent monitoring referral can be augmented by this Some of these questions may be in those with possible or definite IHs. methodology. Prompt evaluation, either in-person or answered by research that is currently via photographs, is warranted for any underway. Other studies will be needed infant reported by parents to have a EVIDENCE GAPS AND PROPOSED to identify and remedy remaining gaps. changing birthmark during the first 2 FUTURE DIRECTIONS Moreover, because there has been a tremendous accrual of information months of life. The proportion of IHs in primary care about IH management, there will settings that are truly high risk is not need to be periodic updates as new A second challenge is the wide known. Even in a referral setting, the information becomes available (and heterogeneity of IHs in terms of size, proportions needing active intervention possibly sooner than the 5 years location, patterns of distribution (ie, vary depending on referral patterns.3,‍161​ typical for CPGs). With such ongoing segmental versus localized), and This information would be useful to reassessment and revision, the depth (ie, superficial, mixed, or deep). pediatricians and other primary care subcommittee hopes this CPG will be This heterogeneity, particularly when providers and should be the subject of viewed as an effective guide to IH triage combined with the unpredictable future research. growth of any given IH, may lead and management and to minimize poor to uncertainty in management (ie, Scoring systems for IH severity outcomes from higher-risk IHs. One whether to treat or observe). Although have been proposed, and one in barrier to a better understanding of IHs this CPG provides guidance regarding particular, the Hemangioma Severity and to answering the questions posed risk stratification and growth Score, has gained some favor as here is the imprecision of current 162 164 characteristics, there is no one-size- a triage tool. ‍–‍ However, more diagnostic codes. For example, the fits-all approach. If uncertainty exists, research is needed to ensure that International Classification of Diseases, consultation with a hemangioma it can accurately be interpreted by 10th Revision code for “hemangioma of specialist (whether by an in-person visit primary care physicians and to find the skin and subcutaneous tissues” is or photographic triage) can be helpful. scores that capture the vast majority not specific to IHs and can include other of high-risk IHs requiring specialty care entities (eg, congenital hemangioma A third challenge is the long-held without overreferring. and verrucous hemangioma) that are tenet that IHs are benign and go away. not IHs. In addition, current diagnostic Other important evidence gaps should be Because of this myth, parents and codes do not contain sufficient detail highlighted, including the following: caregivers are often reassured that to permit appreciation of higher- the lesion will disappear, and this is •• How safe is topical timolol as a risk features, such as location or accurate in the vast majority of cases. treatment during early infancy, and multifocality. Advocacy for the creation However, there is ample evidence that which patients being treated with the of a unique and exclusive International

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 143, number 1, January 2019 21 Classification of Diseases, 10th Revision Stuart T. Weinberg, MD, FAAP code (and appropriate modifiers) for Mary Anne Whelan, MD, PhD, FAAP ABBREVIATIONS IHs would be an appropriate step in AAP: American Academy of Pediatrics addressing this issue. SUBCOMMITTEE ON THE MANAGEMENT OF AHRQ: Agency for Healthcare INFANTILE HEMANGIOMAS (‍OVERSIGHT BY Research and Quality Implementation tools for this guideline THE COUNCIL ON QUALITY IMPROVEMENT CPG: clinical practice guideline are available on the AAP Web site at AND PATIENT SAFETY) ECG: electrocardiography https://www.​ aap.​ org/​ en-​ us/​ professional-​ ​ Daniel P. Krowchuk, MD, FAAP, Chairperson, FDA: Food and Drug Administration resources/quality-​ improvement/​ Pages/​ ​ General Pediatrics and Adolescent Medicine IH: infantile hemangioma default.​aspx (this may leave or stay Ilona Frieden, MD, FAAP, Vice Chairperson, IH-MAG: infantile hemangioma with Pediatric Dermatology minimal or arrested growth depending on the Digital Transformation Aparna Annam, DO, FAAP, Pediatric Radiology Initiative). A useful resource for Cynthia N. Baker, MD, FAAP, General Pediatrics KAS: key action statement clinicians is the AAP Web page, Francine Blei, MD, MBA, FAAP, Pediatric LUMBAR: lower body infantile heman- “Diagnosis and Management of Infantile Hematology-Oncology giomas and other cutaneous Hemangiomas (https://www.​ aap.​ org/​ ​ David H. Darrow, MD, DDS, FAAP, Otolaryngology defects, urogenital ” Head and Neck Surgery anomalies and ulceration, en-us/​ advocacy-​ and-​ policy/​ aap-​ health-​ ​ Peter C. Frommelt, MD, Pediatric Cardiology initiatives/Infantile-​ Hemangiomas/​ ​ Arin K. Greene, MD, FAAP, Plastic Surgery myelopathy, bony deformi- Pages/default.​ aspx).​ Amy Hodak, CPMSM, Family Representative ties, anorectal malforma- Anthony J. Mancini, MD, FAAP, Pediatric tions, and arterial anomalies Dermatology and renal anomalies LEAD AUTHORS Brian M. Pate, MD, FHM, FAAP, Implementation MRA: magnetic resonance Scientist Daniel P. Krowchuk, MD, FAAP angiography Ilona J. Frieden, MD, FAAP Janice L. Pelletier, MD, FAAP, General Pediatrics Anthony J. Mancini MD, FAAP Deborah Sandrock, MD, FAAP, General PDL: pulsed-dye laser David H. Darrow, MD, DDS, FAAP Pediatrics PHACE: posterior fossa defects, Francine Blei, MD, MBA, FAAP Stuart T. Weinberg, MD, FAAP, Partnership for hemangiomas, cerebrovascu- Policy Implementation Representative Arin K. Greene, MD, FAAP lar arterial anomalies, car- Mary Anne Whelan, MD, PhD, FAAP, Epidemiologist Aparna Annam, DO, FAAP diovascular anomalies Cynthia N. Baker, MD, FAAP and Methodologist Peter C. Frommelt, MD (including coarctation of the Amy Hodak, CPMSM aorta), and eye anomalies STAFF Brian M. Pate, MD, FHM, FAAP RCT: randomized controlled trial Janice L. Pelletier, MD, FAAP Kymika Okechukwu, MPA, Senior Manager, SOE: strength of evidence Deborah Sandrock, MD, FAAP Evidence-Based Medicine Initiatives

The guidance in this report does not indicate an exclusive course of treatment or serve as a standard of medical care. Variations, taking into account individual circumstances, may be appropriate.

All clinical practice guidelines from the American Academy of Pediatrics automatically expire 5 years after publication unless reaffirmed, revised, or retired at or before that time.

DOI: https://​doi.​org/​10.​1542/​peds.​2018-​3475

Address correspondence to Daniel P. Krowchuk, MD, FAAP. E-mail: [email protected]

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2019 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: Dr Frieden is a member of the Data Monitoring Safety Board for Pfizer and the Scientific Advisory Board for Venthera/Bridge Bio; Dr Mancini has indicated that he has advisory board relationships with Verrica, Valeant, and Pfizer; the other authors have indicated they have no financial relationships relevant to this article to disclose.

FUNDING: No external funding.

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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Downloaded from www.aappublications.org/news by guest on September 30, 2021 28 FROM THE AMERICAN ACADEMY OF PEDIATRICS Clinical Practice Guideline for the Management of Infantile Hemangiomas Daniel P. Krowchuk, Ilona J. Frieden, Anthony J. Mancini, David H. Darrow, Francine Blei, Arin K. Greene, Aparna Annam, Cynthia N. Baker, Peter C. Frommelt, Amy Hodak, Brian M. Pate, Janice L. Pelletier, Deborah Sandrock, Stuart T. Weinberg, Mary Anne Whelan and SUBCOMMITTEE ON THE MANAGEMENT OF INFANTILE HEMANGIOMAS Pediatrics originally published online December 24, 2018;

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/early/2018/12/20/peds.2 018-3475 References This article cites 156 articles, 19 of which you can access for free at: http://pediatrics.aappublications.org/content/early/2018/12/20/peds.2 018-3475#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Current Policy http://www.aappublications.org/cgi/collection/current_policy Administration/Practice Management http://www.aappublications.org/cgi/collection/administration:practice _management_sub Standard of Care http://www.aappublications.org/cgi/collection/standard_of_care_sub Evidence-Based Medicine http://www.aappublications.org/cgi/collection/evidence-based_medic ine_sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on September 30, 2021 Clinical Practice Guideline for the Management of Infantile Hemangiomas Daniel P. Krowchuk, Ilona J. Frieden, Anthony J. Mancini, David H. Darrow, Francine Blei, Arin K. Greene, Aparna Annam, Cynthia N. Baker, Peter C. Frommelt, Amy Hodak, Brian M. Pate, Janice L. Pelletier, Deborah Sandrock, Stuart T. Weinberg, Mary Anne Whelan and SUBCOMMITTEE ON THE MANAGEMENT OF INFANTILE HEMANGIOMAS Pediatrics originally published online December 24, 2018;

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/early/2018/12/20/peds.2018-3475

Data Supplement at: http://pediatrics.aappublications.org/content/suppl/2018/12/19/peds.2018-3475.DCSupplemental http://pediatrics.aappublications.org/content/suppl/2019/03/04/peds.2018-3475.DC2 http://pediatrics.aappublications.org/content/suppl/2019/03/04/peds.2018-3475.DC1

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