Infantile hemangioma (IH) is the most common benign tumor in infants, with an incidence of up to 10% in white children and a male:female ratio of 1:3. The incidence in premature or low birth weight newborns can be as high as 22% to 30%. This is followed by a typical period of characteristic spontaneous regression, which can last up to 5-6 years. Finally, there is a recovery period lasting about 10 years, which is characterized by the gradual replacement of vascular tissue by fibrofatty tissue. Although hemangiomas are characterized by self-resolution, their need for treatment has been controversial. However, recent literature shows that, in fact, nearly 50% of patients with hemangiomas continue to have cosmetic sequelae such as capillary dilation, scar formation, residual fibrofatty tissue, and epithelial atrophy after adulthood. A very small number of rapidly proliferating hemangiomas with serious complications may also lead to severe functional impairment and even life-threatening conditions. According to the 2005 guidelines for the diagnosis and treatment of hemangiomas and vascular malformations of the Vascular Disease Group of the Oral and Maxillofacial Surgery Specialty Committee of the Chinese Oral Medical Association, active treatment should be provided immediately when: 1) IH grows rapidly and grows in important areas such as the oral cavity and face, endangering life or vital organ function; 2) IH with bleeding, infection or ulceration; 3) IH with thrombocytopenia syndrome Kasabach-Merritt syndrome . At present, the main methods of treatment for hemangioma are drug therapy, laser therapy and surgery. However, for large and severe IH with serious complications, pharmacological treatment is undoubtedly the most effective and rapid. This review mainly introduces the drugs commonly used in the field of IH treatment and their mechanism of action, and provides some reference for further rationalization of IH treatment in the future. 1.Glucocorticoid therapy Glucocorticoids have been the drug of choice for the treatment of severe IH since the treatment of IH in the 1960s. Hemangiomas with concomitant congestive heart failure, thrombocytopenia, affecting important functions such as vision or respiration, and lesions located in anatomical sites prone to malformation are all indications for oral hormone therapy. A retrospective study found that during treatment with glucocorticoids, one-third of children with IH had markedly regressed lesions, another third had stable lesions that did not progress, and the last third were insensitive to glucocorticoid therapy. There are currently two types of oral glucocorticoid therapy. The first is systemic oral high-dose prednisone, usually at a dose of 2-4 mg/kg/d, taken orally once daily in the morning. If the IH stops growing or becomes smaller within 2 weeks, the same dose is continued; if the efficacy is not obvious, the dose is increased to 5 mg/kg/d and the efficacy is evaluated again after 2 weeks. The dose will be gradually reduced during the 6th to 8th week until it is discontinued. Another method of glucocorticoid administration is local intra-lesional injection of IH. The most commonly used are tretinoin and betamethasone. The maximum dose of 20 mg of tretinoin and 3 mg of betamethasone can be used to reduce the side effects of glucocorticosteroids on the body. According to the pharmacokinetic principle of the drug, usually the mixture of tretinoin and betamethasone is injected again at an interval of 4-6 weeks after the first injection, and usually 3-4 injections are needed to effectively control the rapid development of IH. Some studies have shown that IH with lesions of different sizes have different efficiency rates for local injections of glucocorticoids, and about 30% of patients with IH have a tendency for further lesion enlargement during glucocorticoid tapering and require repeat treatment. Overall, the effectiveness of topical glucocorticoid injections for IH is over 60%. Even with short-term systemic glucocorticosteroid therapy, there are a number of common side effects due to the high dose of treatment. These include sleep disturbances, hyperexcitability, centripetal obesity, adrenocortical suppression, and growth retardation. Compared to systemic glucocorticoid therapy for IH, intra-lesional glucocorticoid injections are significantly less likely to cause systemic side effects. However, it is important to note that there is a risk of retinal artery occlusion when glucocorticosteroids are injected locally into periorbital IH. Glucocorticoid therapy for IH is effective primarily in promoting rapid apoptosis of IH vascular endothelial cells, which some studies suggest may be accomplished through upregulation of the mitochondrial cytochrome genome. Recently, it has been shown that glucocorticoids can induce differentiation of vascular endothelial cells by inhibiting the preadipocyte receptor, an inhibitor of adiposity, and cause progressive replacement of IH lesions with fat. Glucocorticoids can also be used to stimulate the conversion of mesenchymal tissue cells into adipocytes by inducing peroxidase-active receptors. Of course, after these mechanisms are more clearly defined, the individualized treatment of IH with glucocorticoids will make further development. 2. Treatment with interferon Interferon was mainly used for antiviral therapy in immunodeficient patients before it was used for the treatment of IH. It has been used for the treatment of IH and has become a second-line drug for IH treatment for nearly 20 years. Currently, there are two types of interferons: interferon-2α and interferon-2β. Interferon-2α is the main drug used for the treatment of IH. Interferon-2α is commonly used as a starting dose of 1 million U per square meter of body surface area injected subcutaneously once a day and then increased to 3 million U per square meter of body surface area injected subcutaneously once a day for 6-12 months. The use of interferon-2α in children with IH who have failed to respond to glucocorticoid therapy is more than 90% effective; however, the use of interferon-2α in most preterm infants with IH still results in rebound lesions in some children after discontinuation of the drug, resulting in the need for repeat treatment. Interferon-2α can also be administered intradermally by injecting 3 million U per square meter of body surface area once daily for the first week, and then once weekly for an average of 6 to 8 weeks. The advantages are short treatment duration and few complications. The side effects of interferon therapy include fever, flu-like symptoms, gastrointestinal reactions, rash, and transient increase in liver enzymes. All of these side effects are reversible after discontinuation of the drug. The most serious side effect of interferon therapy is its neurotoxicity, which occurs mainly in the central nervous cortex. The most serious complication is irreversible spasticity of both sides of the limb that occurs even after interferon-2α is discontinued, and peripheral neuropathy has also been reported. However, it has been observed that neurotoxic side effects tend to occur later in the course of treatment, so the occurrence of neurotoxicity may be related to the length of the course of drug use, but not significantly related to the maximum dose of the drug. Therefore, the use of interferon in the treatment of IH should be limited to second-line drugs, and neurological examinations and liver function tests must be routinely done during the course of use in order to detect its side effects early. Another drug, imiquimod, has been used externally in recent years to treat superficial forms of IH with good results. Imiquimod cream was the first immunomodulatory drug approved by the FDA for topical treatment of external genital warts in 1997. The use of imiquimod for the treatment of infantile hemangiomas was first reported by Martinez in 2002. According to the study, imiquimod mainly acts as an interferon inducer. In in vitro experiments, interferon-2α was found to inhibit the proliferation of hemangioma tumors by inhibiting the migration of vascular endothelial cells. Although interferon is effective in the treatment of severe IH where glucocorticoid therapy is ineffective, it can only be classified as a second-line drug for IH treatment because of its unpredictable potential side effects. 3.Anti-tumor drug treatment At present, the main anti-tumor drugs for the treatment of IH are pinyamycin and vincristine. The main mechanism of vincristine is to inhibit the mitosis of cell nucleus, which is commonly used in chemotherapy for various malignant tumors. Currently, some studies have confirmed that it can be used to treat IH that is ineffective with glucocorticoid therapy or cannot tolerate glucocorticoids. The dose of vincristine for IH treatment is 0.05 mg to 0.75 mg per square meter of body surface area, administered intravenously once every 2 to 3 weeks, and can be given 3 to 4 times consecutively. The main side effects of vincristine are its neurotoxicity, and some patients may experience diminished or absent deep tendon reflexes, paralytic intestinal obstruction and bone pain. It is important to note that infants and children tolerate vincristine neurotoxicity better than adults, so if neurotoxicity occurs in infants and children, it is not obvious. In addition, relatively rare side effects include alopecia and fever and rash. Vincristine has local tissue irritation, and the drug must not leak out, otherwise it may cause local necrosis. In view of these side effects, it is necessary to have a consultation with a pediatric oncologist, regular routine neurological examinations and whole blood tests when using vincristine for children with IH. Vincristine can inhibit vascular endothelial cell proliferation by suppressing nuclear mitosis, which is mainly implemented by preventing the polymerization of filamentous tubulin in mid-cell division and can eventually lead to apoptosis of vascular endothelial cells. Experimental models have shown that small doses of vincristine can inhibit angiogenesis, suggesting that vincristine may be involved in inducing the final apoptotic pathway of IH in the treatment of IH. The second antitumor drug for the treatment of IH is pingyangmycin. Pingyangmycin is an antitumor drug isolated from Actinomyces cultures. The main pharmacological mechanism is to inhibit DNA binding so that it is destroyed, and additionally it can break DNA single strands, possibly thus destroying DNA templates and preventing DNA replication. Especially in patients with poor oral hormone therapy and IH already in regression, intra-tumoral injection of Pingyangmycin can be used for treatment with an overall efficiency of 90%. The efficacy of local injection is similar to that of oral hormone therapy, but it can reduce the systemic adverse effects associated with oral hormone therapy. Intratumoral injection of Pingyangmycin is suitable for the treatment of small and medium-sized hemangiomas. The mass concentration of Pingyangmycin is 1~2 mg/mL, and each dose does not exceed 8 mg. Generally, IH with diameter less than 1.5 cm can be cured with one injection; for larger tumor or multiple lesions, the tumor is obviously reduced with 3~5 injections, and it is effective within 7~30 days after injection. The side effects of Pingyangmycin may include fever, gastrointestinal reaction, skin reaction pigmentation, keratinization thickening, etc.,, hair loss, limb numbness, etc. Its chance of causing chemical and pneumonia or pulmonary fibrosis is small, but attention should be paid to check the lungs during the use of the drug, and the drug should be stopped if pneumonia-like changes occur. 4, β-blocker treatment etc. In the treatment of children with obstructive hypertrophic cardiomyopathy, it was found by chance that propranolol could effectively control the proliferation of severe IH and promote its regression. Propranolol is a non-selective β-adrenergic receptor blocker. Oral propranolol is safe and effective in the treatment of proliferative IH, with far fewer adverse effects than glucocorticoids, and has become the drug of choice for some physicians. It may become the first-line drug for the treatment of severe IH in the near future . Some studies have found that propranolol can downregulate vascular growth factor, reduce the expression of metalloproteinases and induce apoptosis of vascular endothelial cells. However, its treatment of IH and the specific mechanism of action need to be further investigated. Most physicians believe that propranolol can be used in the treatment of IH with reference to the following treatment: 2-3 mg/kg/d, all divided into 2-3 oral doses. It is usually best to monitor their vital signs, especially blood pressure, heart rate, respiration and blood glucose, in hospital during the initial 24 hours of treatment. The course of treatment can last from 2 to 8 months. However, recent studies have shown that most children with IH are better controlled by giving only a small dose of propranolol 1-1.5 mg/kg/d, but in female children with IH, propranolol doses up to 2 mg/kg/d may be required [34]. In addition, another drug, vinblastine, has been started for the treatment of IH, and due to the small sample size, the specific dose and duration of treatment remain to be observed In addition to oral drugs, a gel made from 0.5% timolol maleate ophthalmic solution has also been used directly externally for the treatment of IH with some efficacy. Although beta-blockers have shown a good safety profile after long-term widespread use in children with cardiovascular disease, long-term use in many preterm infants with IH requires caution. Potential side effects of propranolol include bronchospasm (especially in patients with airway responsive disease), congestive heart failure, depression, nausea, vomiting, abdominal cramps, sleep disturbances, bradycardia, hypotension, and hypoglycemia, especially in people with usual hypotension or hypoglycemia. Some children with IH who have been treated with glucocorticoids for some time may have residual adrenal suppression which increases the risk of hypoglycemia. It has been found that the density of angiotensin receptors in the vessel wall is higher in skin lesions with IH than in normal skin vessels. And vascular beta-blockers can inhibit renin activity, while low renin activity can reduce angiotensin levels. It can be inferred that lowering the level of angiotensin can inhibit the proliferation of vascular endothelial cells and accelerate their apoptosis. Of course, this hypothesis needs to be confirmed by further studies. In conclusion, IH is the most common tumor in infants and children, and with the progress of modern medicine, the prognosis and treatment effect of IH will be further improved. Since most of the IH is found on the head and face, the psychological impact of IH that occurs on the face, especially the aesthetic one, supports the aggressive treatment of this group of children with IH. We should believe that although the efficacy of pharmacological treatment of IH is definite, there are few prospective studies on pharmacological treatment of IH. Therefore, these treatments require strict indications and close observation after treatment, as well as making the patient’s family aware of the characteristics of the disease and medications. For IH, if the indication for treatment is met, a specialist consultation with an experienced physician should be sought early in the evolution of the disease to decide on a treatment plan, rather than waiting for the lesion to progress to the point where it adversely affects the child before starting treatment.