Diagnosis and Treatment Decisions

Evaluation through the use of various diagnostic imaging modalities has generally been reserved for deep lesions to help understand their extent or to confirm the diagnosis of IH. Purely cutaneous lesions do not require imaging, but opinions regarding the initial diagnostic test of choice for more extensive IH, including deep, segmental, and syndromic lesions, are conflicting. Furthermore, different disease sites or extents may be best handled with different imaging modalities. The questions of imaging necessity and type are especially important because many imaging studies in infants often require general anesthesia and may be associated with adverse effects. Modalities such as computed tomography also involve exposure to radiation.

Specific disease characteristics, such as lesion size, location, rate of growth, and persistence as well as modifiers such as patient age, functional impact, and IH subtype influence whether children are treated with pharmacologic agents or surgically. Many lesions can be treated with pharmacologic agents; however, refractory lesions that possess immediate risk for morbidity or mortality, such as hemangiomas obstructing the airway or visual axis, may require more immediate surgical intervention. Lesion characteristics such as size, location, and type (e.g., superficial, deep) also influence the choice of specific pharmacologic agents. For example, small, superficial lesions may respond well to topical agents such as timolol, while deep lesions are less likely to respond.¹⁴ Both medical and surgical treatment paradigms contain significant variability and lack of consensus.

Contraindications to specific treatments vary. Contraindications to beta-blockers include asthma, significant bradycardia, heart block, concurrent illness such s viral gastroenteritis or respiratory infection, history of reactive airway disease, and hypoglycemia.¹⁵ Contraindications to steroids include diabetes, chronic or untreated infections, decreased bone density, immunodeficiency, and active wound healing, and contraindications to surgical approaches include personal or family history of adverse reactions to anesthesia.

In many cases of IH, early referral and intervention are crucial to a satisfactory outcome, such as ocular IH disrupting the development of neural pathways during infancy. Further, some lesions, such as nasal tip IH, may cause permanent structural changes to adjacent structures. This may result in severe functional and disfiguring sequelae, even with complete resolution of the IH itself. In addition to structural damage, the psychological complications of having facial differences must be considered when determining the need for referral or treatment. While well-recognized clinical signs such as ulceration, airway obstruction, or vision-threatening involvement indicate need for urgent referral, there are no discrete guidelines that help direct primary care providers when to refer patients with IH for subspecialty care.

Interventions

The beta-blocker propranolol was approved by the U.S. Food and Drug Administration (FDA) for use in IH in March 2014.^16–18 Propranolol was historically used in children for cardiac conditions and off-label to treat IH after the serendipitous discovery of its effects on IH lesions in 2008.¹⁹ Prior to this, corticosteroids were the drug of choice, but propranolol has become the typical choice for initial medical management in children without contraindications to beta-blockers. Steroids may be used in children with contraindications to beta-blockers or who do not respond to beta-blockers. Additionally, there is no clear consensus as to when alternative or adjunctive or historically used medications such as chemotherapeutic drugs are appropriate if first-line treatment is unsuccessful.^20,21

Surgical interventions for IH can be used for primary management of high risk lesions and include resection or ablation using laser or radiofrequency. Some confusion and disagreement exists about what type of surgical treatment to use, when in the disease course to treat, and how the disease site informs treatment decisions. Interventions for IH are varied, involved, and not without risk (e.g., risk of permanent hypopigmentation, scarring from pulsed dye laser therapy, potential harms of anesthesia); therefore, universal treatment is not recommended.²²

Scope of Review

This systematic review addresses the evidence for benefits and harms of commonly used treatments for children (ages 0–18 years) with IH: beta-blockers, corticosteroids, “second-line” drugs used after the failure of beta-blockers or steroids, and laser and surgical treatment. The decisional dilemmas that this review addresses are whether imaging modalities are useful both in diagnosis and for guiding treatment, and the expected comparative effectiveness (benefits and harms) of pharmacologic and surgical treatments, relative to observation or other active treatments. While pharmacologic and surgical interventions cannot be directly compared because of their inherent confounding by indication, we assess the comparative effectiveness of different options within both pharmacologic and surgical approaches.

We include both contextual and Key Questions. We systematically reviewed and assessed the risk of bias of the literature meeting our inclusion criteria for Key Questions, which address the comparative effectiveness of interventions. We provide a narrative review of relevant literature for contextual questions as few effectiveness studies address these questions, which are related to natural history of IH and markers for occult IH.

Key Questions

Key Questions (KQs) and Contextual Questions (CQs) were developed in consultation with Key Informants and the Task Order Officer and were posted for review to the AHRQ Effective Health Care Web site. Questions were as follows:

CQ1.

What is known about the natural history of infantile hemangiomas, by hemangioma site and subtype? What are the adverse outcomes of untreated infantile hemangiomas? What characteristics of the hemangioma (e.g., subtype, size, location, number of lesions) indicate risk of significant medical complications that would prompt immediate medical or surgical intervention?

CQ2.

What is the evidence that five or more cutaneous hemangiomas are associated with an increased risk of occult hemangiomas?

KQ1.

Among newborns, infants, and children up to 18 years of age with known or suspected infantile hemangiomas, what is the comparative effectiveness (benefits/harms) of various imaging modalities for identifying and characterizing hemangiomas?

1. Does the comparative effectiveness differ by location and subtype of the hemangioma?

KQ2.

Among newborns, infants, and children up to 18 years of age with infantile hemangiomas who have been referred for pharmacologic intervention, what is the comparative effectiveness (benefits/harms) of corticosteroids or beta-blockers?

KQ3.

Among newborns, infants, and children up to 18 years of age with infantile hemangiomas for whom treatment with corticosteroids or beta-blockers is unsuccessful what is the comparative effectiveness of second line therapies including immunomodulators and angiotensin-converting enzyme inhibitors?

KQ4.

Among newborns, infants, and children up to 18 years of age with infantile hemangiomas who have been referred for surgical intervention, what is the comparative effectiveness (benefits/harms) of various types of surgical interventions (including laser and resection)?