Beta Blockers Tamed Infantile Hemangiomas, But Ulceration Still Defies Doctors

Infantile hemangioma is the most common benign vascular tumor of infancy, affecting roughly two to ten percent of babies worldwide. For most families, these strawberry-colored birthmarks appear, grow for a few months, and then quietly fade without ever needing treatment. Yet for a significant minority, the story is far more painful. Ulceration, the breakdown of the skin overlying the tumor, remains one of the most feared complications of these lesions, causing intense pain, bleeding, secondary infection, feeding difficulties, disrupted diaper care, and permanent scarring. A comprehensive new review published in World Journal of Pediatrics by researchers at West China Hospital of Sichuan University argues that even in the age of beta blockers, the drugs that revolutionized hemangioma care, ulceration remains a stubborn and underappreciated clinical problem that demands earlier recognition and a fundamentally more integrated approach.

The so-called beta blocker era began in 2008, when the cardiac drug propranolol was serendipitously found to shrink problematic hemangiomas, a discovery that transformed pediatric dermatology and vascular anomaly care almost overnight. Before propranolol became standard therapy, ulceration was reported in approximately fifteen to thirty percent of infants with hemangiomas. Widespread beta blocker use has driven that figure down to around eleven percent, and a recent retrospective cohort study found that only about five percent of propranolol-treated patients developed a new ulcer after starting treatment. These are genuine gains, but the review’s authors are emphatic that the complication has not been eliminated. Ulcers still develop before therapy begins, and, perhaps counterintuitively, some emerge or even worsen after propranolol has been started, a paradox that the researchers trace back to the underlying biology of the tumors themselves.

Understanding who is at risk has become considerably more precise. Ulceration shows a strong predilection for specific lesion types and anatomical locations. Rapidly proliferating, large, superficial, mixed, and segmental lesions are the most vulnerable, particularly when they involve the lips, neck, diaper area, perineum, anogenital region, or skin folds, where friction, moisture, and mechanical stress relentlessly assault a fragile epidermal barrier. The numbers from referral cohorts are striking. In a multicenter study of 435 anogenital hemangiomas, more than half, 53.3 percent, developed ulceration, rising to 71.7 percent among segmental or partially segmental lesions. Among 69 lip hemangiomas, 53.6 percent ulcerated. Multivariate analyses have quantified these risks further: segmental morphology roughly doubled the odds of ulceration in anogenital lesions, mixed type more than tripled them, and a lower-lip location increased the odds more than eightfold compared with upper-lip disease.

Crucially, the review highlights that risk factors for ulceration after propranolol initiation may not mirror those before treatment. In a cohort of propranolol-treated infants, mixed, indeterminate, and segmental hemangiomas were independent risk factors for new ulcers, with segmental lesions carrying an odds ratio exceeding twenty-two, while trunk and extremity locations appeared protective. This distinction matters clinically, because it means that even after systemic beta blocker therapy has begun, physicians cannot assume that a lesion’s morphology has stopped mattering. Girls account for roughly three quarters of ulcerated cases, consistent with the overall female predominance of hemangiomas, though the evidence does not support sex as an independent risk factor once other variables are accounted for. Prematurity, black ethnicity, and lower socioeconomic status have also been linked to ulceration, though the latter associations may partly reflect delayed diagnosis and unequal access to specialist care rather than biology alone.

The pathogenesis of ulceration, the review argues, is best understood not as a simple surface wound but as a dynamic, multifactorial process rooted in tumor biology. During the rapid proliferative phase, the metabolic demands of tumor cells, endothelial cells, and stromal cells surge, yet the newly formed vessels feeding the lesion are structurally immature and often fail to deliver adequate oxygen. This supply-demand mismatch leaves the superficial tissues relatively hypoxic, priming them for necrosis and epidermal breakdown. One of the most clinically valuable insights concerns early white discoloration of the lesion, which histological studies have linked to upper dermal fibrosis and matrix remodeling. This pallor is now recognized as an important warning sign of impending ulceration, giving clinicians a window to intervene before the skin actually breaks down.

The review also delivers a sobering technical caveat about imaging. Conventional Doppler ultrasound, the workhorse for characterizing hemangiomas and monitoring treatment response, measures macroscopic blood flow rather than capillary perfusion or oxygen diffusion at the epidermal-dermal interface. Preserved intralesional flow on Doppler therefore does not exclude focal superficial ischemia, meaning that no Doppler parameter has been validated to predict ulceration. Ultrasound should complement, not replace, clinical risk assessment based on lesion morphology, location, growth pattern, and early whitening. In the diaper area, the authors describe a double-hit mechanism: intrinsic proliferative hypoxia weakens the barrier, while moisture, maceration, pH changes, enzymatic irritation, and microbial colonization continuously erode the stratum corneum, pushing the lesion from early ischemic whitening toward overt ulceration.

Once an ulcer has formed, molecular mechanisms may conspire to keep it open. Relative tissue hypoxia stabilizes hypoxia-inducible factor-1 alpha, drives vascular endothelial growth factor signaling that produces functionally immature vessels, and increases matrix metalloproteinase activity. The resulting degradation of the extracellular matrix and basement membrane amplifies barrier failure, promoting ulcer persistence, delayed healing, and scarring. The authors caution that direct evidence for this protease-inhibitor imbalance in hemangioma ulcers specifically remains limited, borrowing plausibility from the chronic wound literature, but the framework offers a coherent explanation for why some ulcers heal slowly, become infected, and leave prominent scars. Timing is also characteristic: approximately eighty to ninety-five percent of ulcers develop during the proliferative phase, most often between two and four months of age, with more than half occurring within the first four months of life.

On the treatment side, the review’s central message is that no single modality suffices. Oral propranolol remains the mainstay of systemic therapy, controlling tumor proliferation, relieving pain, and promoting wound healing, with reported median healing times of roughly six to seven weeks in multicenter cohorts. Yet the optimal dose remains unresolved. One analysis found that doses of one milligram per kilogram per day or less were associated with shorter healing times, while a prospective study using two milligrams per kilogram per day reported complete healing in a mean of 5.5 weeks. Because dose selection is confounded by age, ulcer severity, and clinician preference, the authors suggest that a cautious initial dose with individualized titration may be reasonable, while stressing that the question demands proper randomized trials. A small number of children experience worsening ulcers after propranolol initiation or escalation, particularly when tissue ischemia or barrier damage predates treatment, so dynamic reassessment during therapy is essential.

Around this systemic backbone, the review maps the supporting cast. Wound care, gentle cleansing, nonadherent dressings, barrier creams, hydrocolloids, and antimicrobial dressings, forms the cornerstone of management, though no single method has proven superior, and caregivers need clear written instructions and warning signs that warrant medical review. Pain should be assessed at every visit with age-appropriate behavioral scales, with acetaminophen preferred for systemic analgesia and topical lidocaine used sparingly under supervision. Topical timolol offers a local option for small, superficial, focal ulcers, with reported healing times ranging from about nineteen days in randomized study conditions to five weeks in broader cohorts. Pulsed dye laser therapy, which targets superficial vascular components, can accelerate healing of painful or bleeding superficial ulcers, with one randomized trial reporting a mean healing time of 19.22 days, but it is not effective for all lesions and should not be considered routine first-line therapy. For moderate to severe or complex ulcers, multimodal combinations are often necessary, though claims of synergy between propranolol and laser therapy rest on small, uncontrolled series.

Perhaps the review’s most important contribution is conceptual: ulcerated infantile hemangioma should be judged not by the size of the wound alone but across multiple dimensions, including pain, infection, anatomical function, healing trajectory, caregiver burden, and long-term cosmetic outcome. Even small ulcers under five square centimeters can devastate feeding, sleep, and diaper care when they sit on the lip, perineum, or periocular region. No validated ulceration-specific scoring system yet exists, and the authors call for prospective multicenter studies to standardize severity definitions, refine risk-stratified treatment algorithms, and test emerging therapies such as atenolol, nadolol, dual-wavelength lasers, and topical brimonidine-timolol combinations. Their proposed framework, connecting quantitative risk recognition, dynamic pathogenesis, lesion-directed therapy, wound care, and family-centered outcomes, aims to shift practice from reactive wound management toward earlier, individualized, multidisciplinary care. For the infants and families who bear the burden of this painful complication, that shift cannot come soon enough.

Subject of Research: Ulcerated infantile hemangioma: risk factors, pathogenesis, and management in the beta-blocker era

Article Title: Ulcerated infantile hemangioma in the β-blocker era: recent advances

Article References: Zhang, K.-Z., Guo, R.-M., Qiu, T., Yang, M., & Ji, Y. (2026). Ulcerated infantile hemangioma in the β-blocker era: recent advances. World Journal of Pediatrics. https://doi.org/10.1007/s12519-026-01101-x

Image Credits: AI Generated

DOI: 10.1007/s12519-026-01101-x

Keywords: infantile hemangioma, ulceration, propranolol, beta blockers, pediatric dermatology, wound care, topical timolol, pulsed dye laser, PHACE syndrome, LUMBAR syndrome, risk stratification, tissue hypoxia