Safety of oral propranolol for neonates with problematic infantile hemangioma: a study in an Asian population

Abstract

Purpose: The overriding goal of this study was to evaluate the safety of initiating and maintaining propranolol for problematic infantile hemangioma (IH) in neonates.

Methods: Clinical data of 112 infants with IH admitted from January 2016 to December 2020 Department of Plastic Surgery, Jiangxi Provincial Children's Hospital were analyzed retrospectively. All of patients were evaluated during the hospital at the beginning of the treatment and later in outpatient settings during the treatment. Each time, the following monitoring methods were applied: physical examination, ultrasound echocardiography (UCG), electrocardiography (ECG), blood pressure (BP), heart rate (HR), and basic laboratory tests included blood glucose (BG), liver function, blood potassium, thyroid function.

Results: There was a significant reduction in the BP and HR at the initiation of treatment. The incidences of bradycardia and hypoglycemia were observed to be increased with the prolong duration of treatment, but not prolonged PR interval. During the course of the therapy, the risk of hyperkalemia and hypothyroidism was reached maximum at the 2 months and 3 months, respectively. Physical growth index including average height, weight and head circumference was not influenced by the treatment. The observed adverse effects were majority mild and only 3 patients needed to rest for 7 days due to severe diarrhea before restarting treatment.

Conclusions: Propranolol is safe and well-tolerated by properly selected young infants with IH. No serious adverse events were observed. Larger, prospective studies are indicated to investigate propranolol in young infants.

What Is Known

• Propranolol administration has been considered to be the first-line therapy for problematic IH. 

• Based on available data, FDA approval of propranolol for treatment of IH is only for infants with a corrected age of at least 5 weeks.

What is New:

• Oral propranolol is safe and well-tolerated by properly selected neonates with IH. 

1. Introduction

With an incidence of 4–10%, infantile hemangioma (IH) that caused by the proliferation of vascular endothelial cells is the most common benign vascular tumor during childhood [1]. If not treated in time, these tumors have a characteristic evolution that includes a period of rapid proliferation, regression and completion of regression. IHs can occur on any body part, but primarily develop in the head-face-neck region. Although most of IHs could regress spontaneously, approximately 70% of children suffer from sequelae, such as telangiectasia, excessive fibrofatty tissue and skin laxity [2]. Furthermore, about 10% of patients could develop complications, including obstruction, functional impairment, ulceration and disfigurement [3]. Therefore, such cases are considered problematic and need prompt consultation to specialist and early intervention to withdraw the progression of IH. 

Historically, the various management options for problematic IHs included intralesional and systemic corticosteroids, chemotherapeutic agents, laser therapy and surgical intervention [4]. Unfortunately, these treatment options have potentially considerable side effects. In 2008, Leaute-Labreze et al. found that propranolol could promote the regression of infantile hemangioma when they applied propranolol in the treatment of a patient with tachycardia complicated by IH [5]. Since then, propranolol has become the main drug for the treatment of IH worldwide. Meanwhile, a growing body of research has further proved that propranolol can prevent growth and induce IH regression, which is more effective and safer than other treatment methods, including corticosteroids [6-10]. Currently, propranolol administration has been considered to be the first-line therapy for problematic IH.

The specific growth characteristics of IHs is that the rapidest and most significant growth occurs at the age of 1 - 3 months, and most of the growth is completed at the age of 5 months [11]. Further, Tollefson and colleagues reported that the most rapid IHs growth occurs between 5.5 and 7.5 weeks of ag, much earlier than previously appreciated [12]. The authors of this study proposed that there is a period of opportunity, prior to the rapid growth, rather than after growth has been accomplished, to treat high-risk IHs and optimize outcomes. Although it is efficacious that propranolol treatment starts at beyond the period of rapid proliferation, some irreversible consequences may have already resulted, such as permanent skin changes. Moreover, current researches have shown that early intervention, especially starting at the proliferative stage, is associated with an increased likelihood of excellent results and avoid functional impairment [13, 14]. Thus, for IHs requiring clinical intervention, the optimal timing of starting treatment is either before or as soon as appearing irreversible consequences, including permanent disfigurement or dysfunction.

Nevertheless, the drug of propranolol applied to children may cause a set of risks and side effects such as atrioventricular block, bradycardia, hypotension and hypoglycemia [15]. Pediatricians who are not positive about treating IHs with the drug of propranolol, especially for young infants, often emphasize the systemic effects of these drugs particularly on cardiovascular system, and argue that the US Food and Drug Administration (FDA) has not approved propranolol for "correcting premature infants < 5 weeks of age". 

Although, premature or young infants with IHs have been reported to successfully treated with propranolol, no comprehensive data regarding the basic laboratory tests, cardiovascular data, physical development and side events was offered [16, 17]. Inspired by this, a study to assess the safety of propranolol in young infants was conceived, hoping to provide evidence-based data for future treatment recommendations. The overriding goal of this study was to analyze the safety of initiating and maintaining propranolol for problematic IH in young infants in term of basic laboratory tests, cardiovascular data and physical development.

2. Materials And Methods

Clinical data of 112 infants with IH admitted from January 2016 to December 2020 Department of Plastic Surgery, Jiangxi Provincial Children's Hospital were analyzed retrospectively. The propranolol administration contraindications were excluded by basic laboratory and cardiac examinations. Basic laboratory tests included blood glucose, liver function, thyroid function, renal function and so on. Cardiac examinations included ECG, UCG. Inclusion criteria comprised: infants younger than 1 month (corrected actual age) at the time of propranolol initiation for treatment of IH. Exclusion criteria included: infants were treated for a diagnosis other than IH or 1 month older at the time of propranolol initiation. 

This research was granted by the Institutional Review Committee of ethics Committee of Jiangxi Provincial Children's Hospital, and all guardians signed informed consents. This study was conducted according to the ethical guidelines of the Declaration of Helsinki.

2.1 Methods

All infants were scheduled to be hospitalized for 24 hours monitoring at the first three days during the initial propranolol treatment. The initial dose of propranolol administration was twice daily at daily total dose of 0.5 mg/kg for day 1, and then the oral dose was increased to daily total dose of 0.75 mg/kg and 1mg/kg daily for day 2 and 3, respectively. Patients took the first dose of propranolol at 8:00 a.m. In order to avoid the risk of hypoglycemia, we asked patients to take propranolol within 30 minutes after feeding. During the outpatient follow-up, oral propranolol was adjusted to daily total dose of 2 mg/kg when patient was older than 1 month. 

Hypotension was defined as BP: 0-1month < 50/30 mmHg, 1-2 months < 60/35 mmHg, 2–3 months < 65/40 mmHg, 3–6 months < 70/45 mmHg, 6–12 months < 75/50 mmHg, 12–24 months < 75/50 mmHg [18, 19]. Bradycardia was defined as HR: 0-1 < 110 bpm, 1-2 months < 105 bpm, 2-3 months < 100 bpm, 3–6 months < 90 bpm, 6–12 months < 80 bpm, 12–24 months < 70 bpm [18, 19]. Hypoglycemia was defined as BG level < 40 mg/d (2.2mmol/L) before 1 month of age and < 3.89 mmol/L after 1 month of age [20].

2.1.1 during hospitalization

We arranged for the same nurse to measure BG, HR and BP. Noninvasive multi-parameter monitor was used for continuous bedside monitoring of all infants. HR and BP were measured at 8:00, 9:00, 10:00, 21:00 and 20:00 each day. Fingerstick blood glucose monitoring was used to measure the BG level before the first dose of propranolol (baseline) and 2h after administration. The oral dose of propranolol was not added on the next day, when infants occurred hypotension or bradycardia.

2.1.2 during follow-up

At 1, 2, 3, 5, 7, 10, 13, 16 and 19 months after the beginning of therapy, the parents and children returned to the clinic together. During each follow-up period, children were requested to perform ECG, UCG and basic laboratory tests. The height, weight and head circumference of children was measured at the age of 6, 12, 18, 24 and 30 months.

Propranolol was considered to be discontinued gradually in 3 weeks, if IH fully involuted (no lesion was found by ultrasound) or severe side evens occurred. And all of side reactions (such as diarrhea, sleep disturbances, vomiting, agitation) told by parents was documented.

2.2 Statistical analysis

Quantitative data were displayed by means and standard deviation or median and interquartile range. And categorical data were described by number and percentage (N, %). Continuous data were analyzed by independent t test and categorical data were compared using Pearson’s chi-square test. SPSS v.22.0 statistical software (IBM Corporation, Armonk, NY, USA) was used for statistical analysis.

3. Results

3.1 Patient demographics and hemangioma characteristics

112 patients were included in the study and Table 1 shows the characteristics of patients. A total of 80 females and 32 males were included, and the ratio of female-to-male was 2.5:1. The median age and weight at the initiating treatment was, in general, 17 days of life (interquartile range, 13–22 days) and 4.2 kg (interquartile range 3.6– 5.0 kg), respectively. The patients’ median age at the beginning of propranolol treatment was 17 days (interquartile range, 13–22 days). There were fortyone (36.6%) premature infants among this study. The median weight at the start of propranolol administration was 4.2 kg (interquartile range 3.6– 5.0 kg). The most frequently location of IH was the head, face and neck area. 36 (32.1%) patients were diagnosed as segmental morphologic subtype in this study.

Seven patients among this cohort had abnormal ECG manifestations, 4 of them had nonspecific intraventricular conduction delay, and 3 had right bundle branch block. Eleven patients were confirmed to have congenital heart diseases via UCG, including atrial septal defect (5 patients), ventricular septal defect (3 patients), patent ductus arteriosus (1 patient), mild coarctation of the aortic (1 patient), mild pulmonary valve stenosis (1 patient). The defects found in UCG scans were considered not absolute contraindications for treatment with propranolol, after a consultation with a cardiologist.

3.2 Monitoring of patients during the hospitalization

3.2.1 BP and HR

Two patients did not add the oral dose in the 1st month, due to the drop in BP. Compared with 1st hour after propranolol initiation, systolic blood pressure (SBP) of infants was lower at 2nd hours after propranolol. Diastolic blood pressure (DBP) of infants was significantly lower compared with that prior to propranolol initiation. The change trends of SBP and DBP over time are shown in Figure.1, which were statistically significant (P = 0.015, P < 0.001, respectively) (table 2).

Four patients did not increase the oral dose on the second day because of the presence of bradycardia. The HR was slower than that before propranolol administration. Compared with 1st hour after propranolol initiation, the average HR was slower at 2nd hours after oral propranolol. As shown in Figure.1, the change trend of mean HR over time was statistically significant (P < 0.005) (Table 2).

3.2.2 BG

Before treatment, 4 infants were found to have hypoglycemia, but all of them were clinically asymptomatic; In addition, the fast glycemia maintained within normal range after a repeat fasting plasma glucose test. During the hospitalization period, 5 patients occurred asymptomatic hypoglycemia. There was no significant change in blood glucose level before and 2h after taking drug, as shown in Figure.1. 

3.3 Monitoring during follow-up

3.3.1 ECG and UCG

A higher incidence of bradycardia was identified with the longer duration of propranolol treatment, while the risk of prolonged PR interval did not increase with the prolongation of treatment (Table 3). No patients were detected abnormal UCG findings due to propranolol administration during treatment. 

3.3.2 BG

The incidence of asymptomatic hypoglycemia increased with the prolongation of propranolol treatment (Table 4). The prevalence of hypoglycemia was 4.5% (5/112), 2.6% (3/112), 3.5% (4/112), 8.0% (9/112), 8.9% (9/101), 11.1% (10/90), 11.9% (5/42), 13.0% (3/23) and 16.6% (2/12) after 1, 2, 3, 5, 7, 10, 13, 16 and 19 months of treatment. The changing trend in blood glucose with time was significant, as shown in Figure.2.

3.3.3 Liver enzymes, blood potassium, thyroid function

During the 19 months follow-up, alanine transaminase (ALT) increased twice as much as the normal value for 8 times, aspartate transaminase (AST) increased twice as much as the normal value for 6 times, especially in the first 5 months. The incidence of abnormal blood potassium reached the maximum at the 2 months of treatment, while the incidence of abnormal thyroid stimulating hormone (TSH) and free triiodothyronine (FT3) reached the maximum at the 3 months of treatment. The patients’ abnormal laboratory test values after initiation are summarized in Table 4. The changing trends in ALT, AST, TSH, FT3 and blood potassium over time are shown in Figure.2. 

3.3.4 Height, weight and head circumference monitoring 

In this study, the physical growth index for boys and girls in Zhu Futang Practical Pediatrics were considered to as the reference values for physical development of children [21].

At the age of 6 and 12 months, the average height of boys was significantly higher relative to normal reference value (P = 0.032 and P = 0.028, respectively), while the average height of girls was significantly higher at the age of 6, 12 and 18 months (P = 0.015, P = 0.035 and P = 0.026, respectively). In boys, there was no statistical difference between the mean height and normal parameters at the age of 18, 24 and 30 months (P = 0.678, P = 0.905 and P = 0.982, respectively) and that in girls at the age of 24 and 30 months (P = 0.658 and P = 0.865, respectively).

At the age of 6, 12 and 18 months, the average weight of boys was significantly heavier relative to normal reference value (P = 0.035, P = 0.016 and P < 0.001, respectively), while the average weight of girls was significantly higher at the age of 6 and 12 months (P = 0.043 and P = 0.012, respectively). In boys, there was no statistical difference between the mean weight and normal parameters at the age of 24 and 30 months (P = 0.783 and P = 0.942, respectively) and that in girls at the age of 18, 24 and 30 months (P = 863, P = 0.782 and P = 0.845, respectively).

At the age of 6 and 12 months, the average head circumference of boys was significantly larger relative to normal reference value (P = 0.023 and P = 0.015, respectively), while the average head circumference of girls was significantly larger at the age of 6, 12 and 18 months (P = 0.037, P = 0.035 and P < 0.001, respectively). In boys, there was no statistical difference between the mean head circumference and normal parameters at the age of 18, 24 and 30 months (P = 0.684, P = 0.745 and P = 0.326, respectively) and that in girls at the age of 24 and 30 months (P = 0.563 and P = 0.645, respectively). All of these results are shown in Table 5.

3.3.5 Adverse effects and tolerance

All of adverse events were documented during the medication. 33 (30.0%) patients had diarrhea, and 3 patients needed to rest for 7 days because of severe diarrhea before restarting treatment. 20 (17.9%) children occurred sleep disturbances and 20 (17.9%) children occurred bronchiolitis. Other common adverse effects, including vomiting, agitation and constipation, subsided spontaneously without stopping the drug (Table 6).

4. Discussion

It is now extremely explicit that most IHs could spontaneously regress, and accordingly, these patients will not require treatment. Thus, the current view is that the majority of IHs can be managed expectantly. The treatment method of ‘expectant management’ (or initial observation) was considered and is still frequently performed by pediatric clinicians. Nevertheless, approximately 10–15% IHs that have associated complications, such as obstruction, functional impairment, ulceration and disfigurement, require treatment [3]. Therefore, the initiation of management for IHs should be based on the risk-benefit analysis of any treatment, bearing in mind that ‘expectant management’ method may generally be considered, but early intervention is essential to minimize long-time sequelae in some patients.

Young infants are deemed to more likely than older children and adults to be intolerant of the drug of propranolol. Clinically, there is a controversy about applying propranolol to young infants. Majority of studies excluded infants whose corrected age was less than 5 weeks [22]. Previously, several studies provided that infants who were younger than 1 month and/or premature treated with oral propranolol were safe and efficacy, but they usually contained a short-term follow-up [16, 17, 23]. In addition, these studies did not fully contain the information on the laboratory tests, cardiovascular data, physical development and adverse events. At the present study, it successfully showed clinical evidence containing the above information to evaluate the safety of oral propranolol in young infants who younger than 30 days corrected age, especially with a long-term follow up.

4.1 Cardiovascular system

Propranolol is a beta-blocker drug, which has the potential to decrease HR and partly lower BP via the negative chronotropic and inotropic effects on the heart. One prospective research performed by Ji Y. and his colleagues concluded that the decreases in mean HR and SBP was statistically significant but not mean DBP, and all of the young infants presented clinically asymptomatic [17]. In our study, we found that all of infants appeared a decrease of BP, but remained no clinically symptoms, which is consistent with previous research. However, our results showed the long-term effect of propranolol on SBP was less than DBP that was significantly lower than before administration. Interestingly, SBP of infants was lower at 2nd hours after propranolol compared with 1st hour after propranolol initiation, but not DBP. When it comes to HR, compared to 1st hour after propranolol initiation, the average HR was slower at 2nd hours after oral propranolol. The peaked effects of oral propranolol on BP and HR in infants occurred approximately 2 h after every dose [17, 24]. Consistent with previous studies, SBP and HR demonstrated the same characteristics in the present study. Propranolol can slow down the conduction of atrium and atrioventricular node, which then could result in the prolongation of PR interval and certain abnormal ECG. GradeⅠatrioventricular block and T wave spikes were reported to be the common side effects on the heart of oral propranolol [25]. In our results, it demonstrated that the incidence of bradycardia was increased with prolong duration of propranolol treatment, but not the risk of prolonged PR interval, which result shares the same characteristics with infants older than 30 days [26].

4.2 Metabolism

Symptomatic hypoglycemia, although rare, can be considered as a severe side effect of oral propranolol. The exact mechanism of the effect of propranolol on BG remains incompletely understood so far, but it could block catecholamine-induced lipolysis, glycogenolysis and gluconeogenesis, which may lead to hypoglycemia in infants [27]. Young infants usually have a lower glycogen store compared to older infants, and they mainly rely on caregivers to provide food. In our study, all of patients were regularly feed by their parents during the treatment. Remarkably, our results confirmed that there was no statistically significant change in BG with oral propranolol during the first 3 days, but changing trend with time was significant during outpatient follow-up. This result suggested that the longer the duration of oral medication, the more prone to hypoglycemia. Thus, parental education on medication schedules and frequently feeding is vital to prevention of severe hypoglycemia during medication. When utility of beta-blocker drug including propranolol is not appropriate, patients may occur hyperkalemia. Propranolol is an inhibitor of epinephrine that is mediated via stimulation of the beta receptor to regulate blood potassium [28]. Our results showed that the risk of hyperkalemia did not increase with prolong duration of oral propranolol.

4.3 Liver function

With the prolongation of propranolol administration, the incidence of abnormal AST and ALT decreased. The reason for abnormal liver function caused by oral propranolol may be that it eliminated by liver and thus formed to other several metabolites [29]. Further, young infants seem more likely to have abnormal liver function, one of the reasons may be that the metabolic rate of propranolol is slower than that of adults.

4.4 Thyroid function

Propranolol is an effective drug in the treatment of hyperthyroidism through the mechanism of inhibiting the conversion of peripheral T4 to T3 [30, 31]. Not surprisingly, and in accordance with it as an antithyroid drugs, some children may occur abnormal thyroid function, mainly hypothyroidism, during propranolol treatment. In our study, the incidence of abnormal TSH and FT3 reached the maximum at the 3 months of treatment and then decreased.

4.5 Physical development

Currently, it is unclear whether propranolol administration affects the growth and development of children. A study conducted by Moyakine et al. confirmed that oral propranolol could not associate with the developmental risk [32]. Hu et al. implied that during the treatment, the growth curve of patients dropped by more than 20%, but nearly 50% of children backed to normal level after drug discontinued [33]. Huo et al. indicated that oral propranolol could be considered to be safety and efficacy, and that did not harm the physical development of children who younger than 2 years and below [34]. Recently, a large retrospective study of propranolol for IH in an Asian population concluded that propranolol did not affect the growth and development of children [26].  In our results, the height, weight and head circumference of male and female infants at 6, 12, 18, 24 and 30 months were more than the normal range. The reason for this phenomenon may be that the standard reference range exists a certain discrepancy with the actual situation, particularly owing to the improvement of China's nutrition level in the past ten years. Remarkably, this study assessed these physical developmental indicators of children only to the age of 30 months. Therefore, larger prospective and confirmatory studies are need to provide sufficient evidence to evaluate the long-time influence of propranolol on the physical and central nervous system development of children.

4.6 Adverse effects and tolerance

Our results indicated that oral propranolol was fairly good tolerance for the treatment of IHs in young infants. When combined with two other large studies, the most frequently adverse effects of propranolol were considered to be sleep disturbances/insomnia (~15%), coolness of the hands and/or feet (~8%), agitation/ irritability (~8%), diarrhea (~5%), sleepiness (~5%), and decreased appetite (~3%) [22, 35, 36]. In our study, however, the most common adverse effects were diarrhea (30.0%), sleep disturbance (17.9%), bronchiolitis (17.9%), vomiting (9.8%), agitation (8.0%), which is not similar to older patients. In addition, no severe side events reported when initiating and maintaining propranolol administration, and the side effects at the present study were transient and controllable. Nevertheless, we should realize that the satisfactory result demonstrated in our research was associated with the strict inclusion and exclusion criteria. All of young infants in this study had neither diseases or conditions that could be unable to import food normally nor contraindications for the treatment with propranolol. Based on these strict inclusion and exclusion criteria, the risk of certain side effects in young infants is more likely to be decreased.

4.7 Limitations

Limitations of this study include its retrospective nature, and small sample size. Thus, the clinical sample size in future studies needs to be increased. 

5. Conclusion

In brief, our results provided a reliable basis for the evaluate of the effects of propranolol on hemodynamics, blood glucose, liver function, blood potassium, thyroid function and physical development in young infants. In addition, our study showed that oral propranolol was safe and well-tolerated for treatment of IH in properly selected young infants.

Abbreviations

IH Infantile hemangioma

UCG Ultrasound echocardiography

ECG Electrocardiography

BP Blood pressure 

HR Heart rate

BG Blood glucose

FDA The US Food and Drug Administration

SBP Systolic blood pressure 

DBP Diastolic blood pressure

ALT Alanine transaminase 

AST Aspartate transaminase 

TSH Thyroid stimulating hormone  

FT3 Free triiodothyronine 

T4 Tetraiodothyronine

T3 Triiodothyronine 

Declarations

Acknowledgment 
The authors thank all the infantile hemangioma patients who participated in this study.

Funding 
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Conflict of interest 
All authors declare that they have no conflict of interest.

Authors’ contributions 
Conceptualization: Ronghua Fu; methodology: Yun Zou and Hua Yuan; validation: Pingliang Jin; formal analysis: Zhiping Wu; investigation: Ronghua Fu; data curation: Jun Cheng; writing – original draft preparation: Hanxiang Bai and Yun Zou; writing–review and editing: Mengyu Huang and Xiangquan Huan, supervision: Zhiping Wu and Hua Yuan; project administration:Hua yuan. All authors have read and agreed to the published version of the manuscript.

Ethical approval 

All procedures performed were in accordance with the ethical standards of the institutional research committee (Radboudumc Committee on Research Involving Human Subjects, reference number 2017-3850) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This research was granted by the Institutional Review Committee of ethics Committee of Jiangxi Provincial Children's Hospital, and all guardians signed informed consents. 

Informed consent This research was granted by the Institutional Review Committee of ethics Committee of Jiangxi Provincial Children's Hospital, and all guardians signed informed consents. 

Availability of data and materials

The datasets used or analyzed during the current study are available from the corresponding author on reasonable request.

References

1. Rodríguez Bandera AI, Sebaratnam DF, Wargon O, Wong LF. Infantile hemangioma. Part 1: Epidemiology, pathogenesis, clinical presentation and assessment. J Am Acad Dermatol. 2021;85(6):1379-92. https://doi.org/10.1016/j.jaad.2021.08.019.
2. Bauland CG, Lüning TH, Smit JM, Zeebregts CJ, Spauwen PHM. Untreated hemangiomas: growth pattern and residual lesions. Plast Reconstr Surg. 2011;127(4):1643-48. https://doi.org/10.1097/PRS.0b013e318208d2ac.
3. Léauté-Labrèze C, Harper JI, Hoeger PH. Infantile haemangioma. Lancet. 2017;390(10089):85-94. https://doi.org/10.1016/s0140-6736(16)00645-0.
4. Darrow DH, Greene AK, Mancini AJ, Nopper AJ. Diagnosis and Management of Infantile Hemangioma. Pediatrics. 2015;136(4):e1060-104. https://doi.org/10.1542/peds.2015-2485.
5. Léauté-Labrèze C, Dumas de la Roque E, Hubiche T, Boralevi F, Thambo JB, Taïeb A. Propranolol for severe hemangiomas of infancy. N Engl J Med. 2008;358(24):2649-51. https://doi.org/10.1056/NEJMc0708819.
6. Léauté-Labrèze C, Hoeger P, Mazereeuw-Hautier J, Guibaud L, Baselga E, Posiunas G, Phillips RJ, Caceres H, Lopez Gutierrez JC, Ballona R, Friedlander SF, Powell J, Perek D, Metz B, Barbarot S, Maruani A, Szalai ZZ, Krol A, Boccara O, Foelster-Holst R, Febrer Bosch MI, Su J, Buckova H, Torrelo A, Cambazard F, Grantzow R, Wargon O, Wyrzykowski D, Roessler J, Bernabeu-Wittel J, Valencia AM, Przewratil P, Glick S, Pope E, Birchall N, Benjamin L, Mancini AJ, Vabres P, Souteyrand P, Frieden IJ, Berul CI, Mehta CR, Prey S, Boralevi F, Morgan CC, Heritier S, Delarue A, Voisard JJ. A randomized, controlled trial of oral propranolol in infantile hemangioma. N Engl J Med. 2015;372(8):735-46. https://doi.org/10.1056/NEJMoa1404710.
7. Polites SF, Watanabe M, Crafton T, Jenkins TM, Alvarez-Allende CR, Hammill AM, Dasgupta R. Surgical resection of infantile hemangiomas following medical treatment with propranolol versus corticosteroids. J Pediatr Surg. 2019;54(4):740-3. https://doi.org/10.1016/j.jpedsurg.2018.08.001.
8. Chinnadurai S, Fonnesbeck C, Snyder KM, Sathe NA, Morad A, Likis FE, McPheeters ML. Pharmacologic Interventions for Infantile Hemangioma: A Meta-analysis. Pediatrics. 2016;137(2):e20153896. https://doi.org/10.1542/peds.2015-3896.
9. Malik MA, Menon P, Rao KL, Samujh R. Effect of propranolol vs prednisolone vs propranolol with prednisolone in the management of infantile hemangioma: a randomized controlled study. J Pediatr Surg. 2013;48(12):2453-9. https://doi.org/10.1016/j.jpedsurg.2013.08.020.
10. You Y, Li Y, Xiao Y, Zhang J. Propranolol vs. steroids in the treatment of infantile hemangiomas: A meta-analysis. Mol Clin Oncol. 2021;15(2):156. https://doi.org/10.3892/mco.2021.2318.
11. Krowchuk DP, Frieden IJ, Mancini AJ, Darrow DH, Blei F, Greene AK, Annam A, Baker CN, Frommelt PC, Hodak A, Pate BM, Pelletier JL, Sandrock D, Weinberg ST, Whelan MA. Clinical Practice Guideline for the Management of Infantile Hemangiomas. Pediatrics. 2019;143(1): e20183475. https://doi.org/10.1542/peds.2018-3475. 
12. Tollefson MM, Frieden IJ. Early growth of infantile hemangiomas: what parents' photographs tell us. Pediatrics. 2012;130(2):e314-20. https://doi.org/10.1542/peds.2011-3683.
13. Xu MN, Zhang M, Xu Y, Wang M, Yuan SM. Individualized Treatment for Infantile Hemangioma. J Craniofac Surg. 2018;29(7):1876-9. https://doi.org/10.1097/scs.0000000000004745.
14. Pam N, Kridin K, Khamaysi Z. Propranolol for infantile hemangioma: Evaluating efficacy and predictors of response and rebound growth. Dermatol Ther. 2021;34(3):e14936. https://doi.org/10.1111/dth.14936.
15. Yang H, Hu DL, Shu Q, Guo XD. Efficacy and adverse effects of oral propranolol in infantile hemangioma: a meta-analysis of comparative studies. World J Pediatr. 2019;15(6):546-58. https://doi.org/10.1007/s12519-019-00285-9.
16. Gatts JE, Rush MC, Check JF, Samelak DM, McLean TW. Safety of propranolol for infantile hemangioma in infants less than five weeks corrected age. Pediatr Dermatol. 2022;39(3):389-93. https://doi.org/10.1111/pde.14966.
17. Ji Y, Chen S, Xiang B, Yang Y, Qiu L. Safety and tolerance of propranolol in neonates with severe infantile hemangiomas: a prospective study. Sci Rep. 2017;7(1):1503. https://doi.org/10.1038/s41598-017-01321-2.
18. Hoeger PH, Harper JI, Baselga E, Bonnet D, Boon LM, Ciofi Degli Atti M, El Hachem M, Oranje AP, Rubin AT, Weibel L, Léauté-Labrèze C. Treatment of infantile haemangiomas: recommendations of a European expert group. Eur J Pediatr. 2015;174(7):855-65. https://doi.org/10.1007/s00431-015-2570-0.
19. Hengst M, Oelert M, Hoeger PH. Blood Pressure Monitoring During the Induction and Maintenance Period of Propranolol Therapy for Complicated Infantile Hemangiomas: A Prospective Study of 109 Infants. Pediatr Dermatol. 2015;32(6):802-7. https://doi.org/10.1111/pde.12681.
20. Koh TH, Eyre JA, Aynsley-Green A. Neonatal hypoglycaemia--the controversy regarding definition. Arch Dis Child. 1988;63(11):1386-8. https://doi.org/10.1136/adc.63.11.1386.
21. Jiang Z, Shen Y. Zhu Futang practice of pediatrics. 8th. China: People’s Medical Publishing House; 2015. p. 17–21. Chapter 2, Growth and development.
22. Léaute-Labrèze C, Boccara O, Degrugillier-Chopinet C, Mazereeuw-Hautier J, Prey S, Lebbé G, Gautier S, Ortis V, Lafon M, Montagne A, Delarue A, Voisard JJ. Safety of Oral Propranolol for the Treatment of Infantile Hemangioma: A Systematic Review. Pediatrics. 2016;138(4): e20160353. https://doi.org/10.1542/peds.2016-0353.
23. Kado M, Shimizu A, Matsumura T, Mochizuki M, Mizuno H, Hayashi A. Successful Treatment of Infantile Hemangiomas With Propranolol in Low-Birth-Weight Infants. J Craniofac Surg. 2017;28(3):789-93. https://doi.org/10.1097/scs.0000000000003542.
24. Song H, Shi H, Zhang X, Wang J, Yu Y, Chen W, Zhou H. Safety profile of a divided dose of propranolol for heart rate in children with infantile haemangioma during 16 weeks of treatment. Br J Dermatol. 2015;172(2):444-9. https://doi.org/10.1111/bjd.13250.
25. Gwinup GR. Propranolol toxicity presenting with early repolarization, ST segment elevation, and peaked T waves on the ECG. Ann Emerg Med. 1988;17(2):171-4. https://doi.org/10.1016/s0196-0644(88)80308-1.
26. Yu L, Wei L, Xu Z, Zhang B, Han X, Sun Y, Liu Y, Wang C, Qiu L, Xiu B, He R, Li L, Ma L. Safety assessment of propranolol for infantile hemangioma: a study in an Asian population. Expert Rev Clin Pharmacol. 2022;15(2):237-242. https://doi.org/10.1080/17512433.2022.2020638.
27. Ji Y, Chen S, Xu C, Li L, Xiang B. The use of propranolol in the treatment of infantile haemangiomas: an update on potential mechanisms of action. Br J Dermatol. 2015;172(1):24-32. https://doi.org/10.1111/bjd.13388.
28. DeFronzo RA, Bia M, Birkhead G. Epinephrine and potassium homeostasis. Kidney Int. 1981;20(1):83-91. https://doi.org/10.1038/ki.1981.108.
29. Gow PJ, Treepongkaruna S, Ghabrial H, Shulkes A, Smallwood RA, Morgan DJ, Ching MS. Neonatal hepatic propranolol elimination: studies in the isolated perfused neonatal sheep liver. J Pharm Sci. 2000;89(5):586-93. https://doi.org/10.1002/(sici)1520-6017(200005)89:5<586::Aid-jps4>3.0.Co;2-6.
30. Feely J. Clinical pharmacokinetics of beta-adrenoceptor blocking drugs in thyroid disease. Clin Pharmacokinet. 1983;8(1):1-16. https://doi.org/10.2165/00003088-198308010-00001.
31. Sharma A, Stan MN. Thyrotoxicosis: Diagnosis and Management. Mayo Clin Proc. 2019;94(6):1048-64. https://doi.org/10.1016/j.mayocp.2018.10.011.
32. Moyakine AV, Kerstjens JM, Spillekom-van Koulil S, van der Vleuten CJ. Propranolol treatment of infantile hemangioma (IH) is not associated with developmental risk or growth impairment at age 4 years. J Am Acad Dermatol. 2016;75(1):59-63.e1. https://doi.org/10.1016/j.jaad.2016.02.1218.
33. Hu L, Zhou B, Huang H, Chang L, Qiu Y, Ma G, Chen H, Jin Y, Xu X, Lin X, Li W. Effects of systemic propranolol treatment on physical growth of patients with infantile hemangiomas. J Dermatol. 2016;43(10):1160-6. https://doi.org/10.1111/1346-8138.13324.
34. Li X, Yang K, Li H, Huo R. Propranolol Treatment for Infantile Hemangiomas: Short-Term Adverse Effects and Follow-Up to Age Two. Biomed Res Int. 2019;2019:2728952. https://doi.org/10.1155/2019/2728952.
35. Droitcourt C, Kerbrat S, Rault C, Botrel MA, Happe A, Garlantezec R, Guillot B, Schleich JM, Oger E, Dupuy A. Safety of Oral Propranolol for Infantile Hemangioma. Pediatrics. 2018;141(6): e20173783. https://doi.org/10.1542/peds.2017-3783.
36. Prey S, Voisard JJ, Delarue A, Lebbe G, Taïeb A, Leaute-Labreze C, Ezzedine K. Safety of Propranolol Therapy for Severe Infantile Hemangioma. Jama. 2016;315(4):413-5. https://doi.org/10.1001/jama.2015.13969.

Tables

Table 1. Baseline characteristics of patients and IH. ECG, electrocardiogram; IH, infantile hemangioma.

* Values are presented as a number (percentage). ** Values are presented as a median (interquartile range).

Table 2. Changes of mean systolic blood pressure (SBP) and mean diastolic blood pressure (DBP) during propranolol treatment. Values are presented as a mean ± SD.

 Table 3. Incidence of bradycardia and PR interval prolongation.

Table 4. Abnormal laboratory test values in children during follow-up.

Bold values indicate the month with the highest incidence of abnormal values. 

ALT: alanine transaminase; AST: aspartate aminotransferase; FT3: free triiodothyronine; TSH: thyroid stimulating hormone.

 Table 5. Height, weight and head circumference comparison in patient

*P＜0.05; The reference value of physical growth index for boys and girls came from Zhu Futang Practical Pediatrics.

 Table 6. Adverse events with oral propranolol treatment during follow-up (n = 112).