The impact of propranolol on the growth and development of children with proliferative infantile hemangioma during treatment

Abstract

Oral propranolol has not been shown to impact physical development, such as weight and height. The impact of children’s intellectual development has received relatively little attention from researchers. The effects of propranolol on the growth and development of children with proliferative infantile hemangiomas during treatment were analyzed retrospectively. The children with infantile hemangioma treated with oral propranolol in the Department of Burn and Plastic Surgery, Fuzhou Children’s Hospital of Fujian Province, from February 2017 to May 2022 were analyzed. A uniform therapeutic regimen was applied, including assessment, treatment, and follow-up. The assessment included physical development and intellectual development indices. The physical development indices were height and weight. Neuropsychological assessment uses developmental quotient (DQ) to assess intelligence development. The DQs on months 3, 6, and 9 posttreatment were compared to the pretreatment. Wilcoxon rank sum test of paired samples was used for height and weight. The developmental quotient was determined by paired t test. P < .05 indicated significant difference. A total of 51 patients were enrolled. All children completed the treatment successfully, without severe adverse drug reactions leading to treatment discontinuation. There was no significant difference in height and weight before and after treatment (P > .05). No significant difference was detected in DQ 3 months posttreatment and pretreatment (P = .19), while it decreased at 6 and 9 months posttreatment (P < .05). Oral propranolol does not have an impact on physical development (height and weight). No short-term effect was found on intellectual development, but a decrease was noted over 6 months, which needs to be investigated further.

1. Introduction

Infantile hemangioma is a common benign tumor type in the infantile period, formed by vascular tissue hyperplasia in the embryonic period, mainly manifested as vascular endothelial cell hyperplasia. It is self-limited and enters the regression stage around 1-year-old. Most hemangiomas can resolve completely.^[1] Reportedly, a specific proportion of untreated infantile hemangioma will have residual degenerative changes in the skin or subcutaneous tissue after regression, such as scar, telangiectasia, and skin relaxation.^[2] Thus, the early treatment of infantile hemangioma has become a consensus.^[3]

Reportedly, propranolol is a safe and effective drug treating infantile hemangioma and can control the proliferation of vascular endothelial cells at the proliferative stage.^[4,5] Currently, there are many reports on the adverse reactions of oral propranolol in the treatment of infantile hemangioma; however, the observation indices of such influence on children are not sufficient, mainly in the adverse reactions of the drug and physical development of children (for example, body weight and height), as well as intellectual development several years after discontinuation.

The 5 main areas of children’s intelligence development are gross motor, fine motor, adaptability, language, and social behavior, The development speed differs among children in all aspects during growth. This study retrospectively analyzed the development of 51 children with proliferative infantile hemangiomas while being treated with propranolol, and observed the effect of oral propranolol on physical development and intellectual development in children.

2. Methods

2.1. Study design and subjects

In this study, the children with infantile hemangioma treated with oral propranolol in the Department of Burn and Plastic Surgery, Fuzhou Children’s Hospital of Fujian Province from February 2017 to May 2022 were analyzed in this retrospective study. The inclusion criteria were as follows: Confirmed infantile hemangioma according to the guidelines for diagnosing and treating hemangioma and vascular malformation; Treated with β-receptor antagonist; Developmental evaluation was conducted both prior to and after treatment. The exclusion criteria were as follows: Contraindications to β-receptor antagonist therapy; Treatment not following medical advice and follow-up. This study was approved by the ethics committee, and the study was conducted with the informed consent of the child’s guardian.

A total of 51 patients were enrolled in this study. A unified therapeutic regimen was applied: Routine examination before medication, including routine hematuria fecal examination, biochemical examination, thyroid function, electrocardiogram, color echocardiography, and chest X-ray. Patients with bronchial asthma, lung infections, and serious heart disease were excluded. Physical and intellectual development was assessed. Adverse drug reactions and related risks were informed to the family members to obtain their consent for medication. After the assessment, the dosage was increased from 0.5 mg/kg/day to 1.5 to 2 mg/kg/day, 3 times/day. The drug was solubilized in warm water and administered orally or by mixing with milk. Then, adverse reactions, such as sleep disorder, hypoglycemia, and diarrhea, were observed. Review at least once a month, adjust the dose according to the change in body weight, and give physical development indicators and neuropsychological to evaluate the development level.

Physical development was assessed according to the standardized growth curve of height and weight of children and adolescents aged 0 to 18 years in China.^[6] The grade of 2 standard deviations (SD) below the mean is −3, −2 SD to −1 standard deviation is −2, −1 standard deviation to the mean is −1, the mean to 1 standard deviation is 1, 1 standard deviation to 2 SD is 2, and 2 SD above the mean is 3. On the other hand, intelligence development was assessed by neuropsychological assessment (0–6-year-old Children’s Neuropsychological Development Scale). Each item was evaluated by trained and qualified child health professional assessors. The Scale and the internationally adopted Denver Development Screening Tests also belong to the psychological assessment scales for children’s developmental behavior. It is a diagnostic scale independently developed by China that can objectively evaluate the degree of intellectual development of infants in this area. The scale is divided into 5 areas: gross motor, fine motor, adaptability, language, and social behavior. The child health professional evaluates each of the 5 fields on the scale and obtains a score for each field. They then determined the individual’s mental age = sum of the scores of the 5 areas/5, and then calculated the developmental quotient (DQ) = (mental age/actual month age) × 100.^[7]

By monitoring the data on physical and intellectual development after treatment. Paired and compared the statistical grade data on physical development and the developmental quotient values of intelligent development with pretreatment data to understand the changes in growth and development.

2.2. Statistical analysis

Data were analyzed using the SPSS software package, version 23.0 (IBM Corp). Compare the growth and development indicators at 3, 6, and 9 months after treatment with the self-reported data before treatment to evaluate any differences. For physical development indexes (height and weight), Wilcoxon rank sum test of paired samples was used, and P < .05 was considered a significant difference. Development quotient, an index of intelligence development, was tested by means of paired t test, and P < .05 was considered a significant difference. The participants were divided into 2 groups: the neonatal group and the non-neonatal group. An independent samples t-test was used to compare the difference in developmental quotient at 3, 6, and 9 months after treatment. A significant difference was considered when P < .05.

3. Results

A total of 51 patients, including 20 boys and 31 girls (ratio 1:1.5), were enrolled in this study. The cohort comprised 45 cases with facial hemangioma (including parotid gland), 4 cases with trunk and limb hemangioma, and 2 case with perineal hemangioma. The age of treatment initiation was 0.87 to 8.3 (average: 2.64 ± 1.74) months. Among them, 18 patients were 0 to 2-months-old, 15 patients were 2 to 3 months-old, 8 patients were 3 to 4-months-old, and 10 patients were > 4-months-old (Table 1).

Table 1.

Baseline characteristics at time of inclusion.

Characteristics	Observation group, n = 51
Sex, n (%)
Male	20 (39.2%)
Female	31 (60.8%)
Age at the time of first visit (mo)
≤2	18 (35.3%)
2–3	15 (29.4%)
3–4	8 (15.7%)
>4	10 (19.6%)
Location, n (%)
Head and face	45 (88.2%)
Trunk and limbs	4 (7.8%)
Perineal	2 (4%)

All 51 children completed the treatment successfully. Among the patients, 5 cases experienced adverse reactions, which were mostly mild and limited to annoyance and disturbed sleep during the early stages of treatment. No serious systemic adverse reactions such as abnormal heart rate, blood pressure and respiratory symptoms occurred and the treatment was stopped.

With regard to physical development, such as height and weight. Sixteen cases were examined for physical development followed up 3 months after treatment, 13 cases were followed up 6 months after treatment, and 7 cases were followed up 9 months after treatment. The height and weight grade indexes after treatment were compared with those before treatment, and the difference was not statistically significant (P > .05). (Fig. 1 and Fig. 2).

Figure 1.

Depicts the height grade data of subjects at 3, 6, and 9 months after treatment and before treatment.

Figure 2.

Depicts the weight grade data of subjects at 3, 6, and 9 months after treatment and before treatment.

Regarding the development of intelligence. There were 18 cases that had a follow-up visit 3 months after treatment. The DQ score was 98.54 ± 17.81 before the intervention, and 92.23 ± 8.50 after the intervention. There was no statistically significant difference in DQ before and after treatment (P = .19). There were 16 cases that had follow-up visits 6 months after treatment. The DQ score was 106.9 ± 14.79 before treatment, and decreased to 88.59 ± 10.11 after treatment. There was a significant decrease in the DQ after treatment (P < .05). There were 14 cases with a follow-up visit 9 months after treatment, dq100.8 ± 17.86 before treatment, dq89.09 ± 10.26 after treatment. There was a significant decrease in the DQ after treatment (P < .05). (Fig. 3).

Figure 3.

The measurement data of DQ was matched at 3, 6, and 9 months after treatment and before treatment. DQ = developmental quotient.

The groups were compared for the effects of different starting treatment times on intelligence development. There was no significant difference in the development quotient between the neonatal group and the non-neonatal group after treatment. (Fig. 4).

Figure 4.

The DQ of neonatal and non-neonatal groups was compared at 3, 6, and 9 months after treatment. DQ = developmental quotient.

4. Discussion

According to the International Society for the Study of Vascular Anomalies, based on the risk and severity of disfigurement, ulcer, and involvement of lumen and abnormal structure, infantile hemangioma is divided into high-risk, medium-risk, and low-risk levels. For high-risk and medium-risk infantile hemangioma with poor therapeutic effect, oral propranolol is the first-line treatment recommended by International Society for the Study of Vascular Anomalies.^[1]

Propranolol exerts anti-proliferation and cytotoxicity effects on hemangioma endothelial cells and stem cells and has an impact on the contraction ability of perivascular cells of infantile hemangioma, thus controlling the tumor growth. The mechanism may be related to the inhibition on the migration of hemangioma endothelial cells, network formation, VEGF-A production, activation of vascular endothelial growth factor receptor 2, and downregulation of the PI3K/Akt and mitogen-activated protein kinase signals.^[8–11]However, regarding whether changes in cytokines in the body affect children’s growth and development, there are currently literature reports on monitoring the physical development results of children taking medication, such as height and weight. Tang et al^[12] found that oral propranolol treatment for infantile hemangioma children had a certain impact on physical development indices in a study of 116 such children. Hu et al^[13] reported no impact on the growth through an investigation on 76 children with infantile hemangioma treated by oral propranolol. In the present study, the physical development of 51 children treated with the drug was monitored, and a similar result was obtained by comparing it with the standard of children’s growth and development in China.

During treatment, parents care about the impact on physical and intellectual development. Moyakine et al^[14] followed up with children with infantile hemangioma who were treated with oral propranolol for 4 and 7 years, respectively, and observed that there were no significant psychological effects.^[15] Wu et al^[16] assessed the effect of propranolol on the development of the nervous system in the treatment of infantile hemangioma and found no effect. The degree of children’s intellectual development is mainly reflected in the behavior, mental status, and psychology, but a professional and comprehensive assessment scale is essential. Thus, the scale used in this cross-sectional study was a longitudinal observation of children by the healthcare expert group throughout China. The scale is divided into 5 functional areas: gross motor, fine motor, adaptability, language, and social behavior, with a standardized assessment method.^[7]

This study first compared the impact of different medication times on intellectual development. There was no significant difference in the 3-month group before and after treatment, but the DQ of the 2 groups decreased after treatment at the 6 and 9 month groups. The possible reason for the decrease in DQ: Direct impact of the drug on humans. Propranolol is lipophilic and can pass through the blood-brain barrier^[17]; Adverse drug reactions, such as sleep disorders, diarrhea, and hypoglycemia, affect intelligence development^[18,19]; The influence of other people, family parenting, drug feeding, and anxiety of family members may impact the children. For example, adverse events affect children’s intellectual development; Data error: some parents in this study speculated that children had no abnormal development and were unwilling to participate in the assessment multiple times due to prolonged periods and multiple examinations, leading to a decreased sample size.

Infantile hemangioma often occurs at a younger age, typically in the neonatal period of 0 to 1 month, and has rapid tumor growth. In the treatment of these children, parents are concerned about imperfect organ development, the impact of drugs, and whether the drug metabolism affects intelligence development. Therefore, treatment initiation was grouped according to different ages in this study and compared again. The patients in whom the treatment was initiated in 0 to 1 months of age were classified as 1 group. The results did not show any significant difference between the 2 groups. Thus, propranolol is safe for the treatment of hemangioma in neonates.

The sample size of this study is small and continues to decrease during the follow-up. The family members of the lost cases speculated that the children had no abnormalities compared to their peers or gave up the growth and development assessment considering the cost. However, the family members who did not adhere to the intelligence assessment asked for subjective assessment during the follow-up and did not think that they had abnormal development. Thus, it is necessary to increase the sample size and conduct a multicenter study in the future to clarify whether long-term drug use has an impact on children’s intellectual development, which is affected by the small sample size.

5. Conclusion

This study evaluated the children with infantile hemangioma treated with oral propranolol and using the Chinese characteristic neuropsychological assessment. Oral propranolol has been indicated not to impact physical development, such as height and weight. No short-term effect was detected on the intellectual development, but a decrease was noted in the intellectual development over 6 months, which needs further investigation. For oral propranolol in the treatment of infantile hemangioma, multicenter intelligence developmental studies are necessary to determine the long-term safety of oral propranolol.

Author contributions

Conceptualization: Xiangshang Lin.

Data curation: Tao Wang, Changrong Liu, Licai Deng, Juhui Gao.

Formal analysis: Xiangshang Lin, Tao Wang, Changrong Liu.

Funding acquisition: Xiangshang Lin.

Investigation: Tao Wang, Licai Deng, Qian Wang, Xindi Chen, Shigong Chen.

Methodology: Xiangshang Lin, Linjuan Huang.

Project administration: Xiangshang Lin.

Writing – original draft: Xiangshang Lin, Tao Wang, Changrong Liu.

Writing – review & editing: Xiangshang Lin.