INTRODUCTION

Infantile cutaneous hemangioma is a frequent benign tumor that regresses spontaneously. The life-threatening, functional, or cosmetic nature of some forms indicates the need for treatment. Although the efficacy of propranolol for the treatment of infantile hemangiomas (IH) has been well documented, there is limited clinical data regarding the safety and tolerability of propranolol in neonates. The aim of this study was to evaluate the safety of oral propranolol in this indication and to study the sequelae after regression of IH in a Moroccan population over a fourteen-year period.

MATERIALS AND METHODS

A prospective, observational study was conducted from September 2008 to September 2022 by the dermatology and pediatrics departments of the Hassan II University Hospital Center, located in Fez, Morocco. Data was collected from 215 patients treated for hemangioma with propranolol. The inclusion criteria were hemangiomas with functional risks, namely orificial locations, hemangiomas complicated by hemorrhage or ulceration, and those larger than 25 mm in non-risk locations. The exclusion criteria were medical contraindications to beta-blockers and hemangiomas smaller than 25 mm in non-risk locations.

The patients were closely monitored intra-hospital for known significant risks associated with propranolol treatment (hypoglycemia, hypotension, bradycardia, and bronchospasm) for four hours after the initial dosing. Follow-ups were scheduled once a month for the first year, once every three months for the second year, and after three years of completion.

Post-medication adverse events were assessed and managed accordingly, and the parents were informed about precautionary measures.

RESULTS

We collected 215 children treated with propranolol for hemangioma, among whom 170 patients completed their treatment three years ago. A female predominance was noted. Eighty percent of our patients began treatment after four months. The median duration of treatment was twelve months. The indications for treatment were periorificial localizations in 55% of the cases, forms larger than 25 mm in 45%, and ulcerations in 13% (Fig. 1) (Table 1).

Figure 1: (a) Anetodermal skin noted at the end of treatment. (b and c) Sequelae telangiectasia noted at the end of treatment. (d) Unsightly scars noted at the end of treatment.

Table 1: Clinical and therapeutic characteristics.

Thirty-eight patients (16%) experienced side effects after treatment with beta-blockers (Table 2).

Table 2: Tolerance side effects.

Two cases of bronchospasm occurred one week after the introduction of treatment at a dose of 3 mg/kg/day. Therefore, oral propranolol was permanently stopped in this patient.

The rest of the adverse side effects were transient, transient on the initiation of therapy, or off-dose escalation and did not require the modification of therapy.

Residual telangiectasias (39% of the cases) (Fig. 1a), anetodermal skin (15%) (Figs. 1b and 1c), and unsightly scars (24%) (Fig. 1d) were the main sequelae noted (Table 3).

Table 3: Sequelae noted at the end of treatment.

DISCUSSION

In the literature, around 10% of cases of IH require systemic treatment, usually with propranolol [1–3]. In our study, it was noted that more than 50% of IH required systemic treatment. This may be explained by the recruitment bias at the university hospital of IH in the proliferative phase because most of them consulted at an age older than four months.

The exact mechanism of action of propranolol in HI is not fully understood. The possible actions include peripheral vasoconstriction (rapid effects), the inhibition of pro-angiogenic factors (intermediate effects mediated by several pathways leading to VEGF depletion, among others), and the activation of apoptosis (long-term effects) [4].

Young infants may have a greater likelihood of intolerance to hemodynamic changes than older children and adults. This may be explained by the pharmacological action of propranolol in inhibiting the sympathetic nervous system by blocking b-receptors on the nerves of the sympathetic system and reducing cardiac contractility, thus causing bradycardia and reduced blood pressure and bronchospasm [5-7]. Although rare, symptomatic hypoglycemia may be a serious complication of propranolol therapy. Recent studies have shown that propranolol may block catecholamine-induced lipolysis, glycogenolysis, and gluconeogenesis, which may facilitate hypoglycemia in children. In this respect, we noted only two cases of bronchospasm when treatment was instituted at 3 mg/kg/day, the treatment was permanently interrupted, and four cases of bronchiolitis in which treatment was temporarily stopped and resumed without an incident.

However, we noted no other serious effects, such as hypoglycemia, bradycardia, and hypotension. In our series, serious effects such as hypoglycemia, bradycardia, hypotension were not noted because the age of initiation of treatment was advanced and the use of treatment at the usual dose did not exceed 3 mg/kg/day and because of the adequate education of parents or guardians on the importance of administering propranolol as prescribed (that is, during or shortly after feeding).

Recent studies raise concerns about the potential effects of propranolol on neurodevelopment because propranolol is lipophilic, crosses the blood-brain barrier with the possibility of blocking neuronal pathways essential for learning and memory and also sleep disturbances with long-term psychological problems [7–9]. However, in our series, we noted mainly sleep disorders and no cases of memory and intelligence disorders.

The risk factors for these sequelae include mixed, segmental, ulcerated hemangiomas, late age of onset of treatment. Indeed, recent studies have shown that propranolol may inhibit endothelial cell homing and, thus, early treatment, especially when initiated during the proliferative phase, it is associated with better long-term outcomes [4,10]. However, most of our patients initiated treatment after four months, which explains the sequelae noted in 40%, such as residual telangiectasias, anetodermal skin, and unsightly scars. These sequelae required other therapies, such as surgery or laser treatment.

The late introduction of treatment in our context is explained, on the one hand, by socio-cultural ideas and, on the other, by the lack of knowledge about therapeutic opportunities of some clinicians.

CONCLUSION

Propranolol for infantile hemangiomas (IH) has been shown to be effective and relatively safe. Our data showed that propranolol was generally well tolerated in young infants. We noted mostly minor side effects that were not serious, transient, and manageable. However, major side effects were exceptional, with two cases of bronchospasm. However, we found sequelae, mainly telangiectasias and anetodermal skin, in 40% of the cases linked essentially to the late introduction of treatment. We, therefore, propose to introduce the treatment during the first weeks of life with simple follow-up.