Abstract
Numerous studies have shown that topical timolol is effective in treating infantile hemangioma (IH) with minimal adverse events. However, consensus is lacking on optimal timing, dosage, frequency, and safety parameters for this treatment. This study aims to explore the timing and safety of topical timolol treatment for superficial IH. A retrospective analysis included pediatric IH patients who underwent topical timolol treatment at the Department of Pediatric Surgery of Sichuan Provincial People’s Hospital between January 2019 and January 2023. Medical records were reviewed for patient information, lesion characteristics, outcomes, and complications. Topical timolol was administered to 666 IH patients. Median follow-up was 10 months. 480 cases had excellent or good outcomes, while 186 had fair or poor outcomes. Patients ≤ 3 months had better outcomes than those > 3 months (Z = 4.713, P < 0.001). Small IH had better outcomes than large IH (Z = 1.991, P = 0.046). Lesion locations did not significantly affect outcomes (H = 10.252, P = 0.114). Respiratory problems occurred in 58 (8.7%) cases, localized skin irritation occurred in 48 (7.2%) cases, sleep disturbance occurred in 30 (4.5%) cases, and residual skin lesions occurred in 26 (3.9%) cases. In 59 (8.8%) cases the IH had relapses.
Conclusions: Topical timolol is safe and effective for IH. Patients who are aged 1 < months ≤ 3 or have small (1.5 cm < max diameter ≤ 5 cm) IH are more likely to experience better outcomes. It also may reduce the incidence of residual skin lesions and relapse. Therefore it may be a useful alternative therapy option for superficial IH.
|
What is Known: • β-blockers are now considered to be first-line treatment of infantile hemangioma. • Topical timolol treatment is safe and effective for infantile hemangioma. |
|
What is New: • Patients who are aged ≤ 3 months or have a max diameter ≤ 5 cm infantile hemangioma are likely to experience better outcomes by topical timolol treatment. • Topical timolol treatment may reduce the incidence of residual skin lesions and infantile hemangioma relapses. |
Keywords: Topical timolol, Infantile Hemangioma, Adverse effects, Timing and safety, Retrospective analysis
Introduction
Infantile hemangioma (IH) is the most common benign tumor in infants. The incidence rate has been reported to be 4–5%, but it can be as high as 10% in caucasians, 20% in preterm infants and is more prevalent in females [1]. IH appears at birth or within the first 1 to 2 weeks of life [2]. IH experiences rapid proliferation, increasing in size between 2 and 6 months of age. After this stage, the growth of IH slows down, gradually plateaus and spontaneously resolves after 1 year of age. 90% of patients have IH resolve on their own completely around the age of 4 [3]. Although IH is benign and resolves spontaneously, about 69% are reported to be left with different degrees of sequelae such as fat accumulation, scar, hyperpigmentation, telangiectasia and skin redundancy. Meanwhile, 12% of patients may suffer from complications of different severity such as disfigurement, ulceration and hemorrhage [3]. However, IH growing in vital areas such as the ocular region, liver and respiratory tract may lead to functional limitations or even endanger life [4], making it a necessity to get diagnosed and treated in time.
Since Léauté-Labrèze et al. serendipitously found oral propranolol effective in reducing IH size, this new modality then became the first-line treatment for IH [5]. Not only has the treatment of IH been radically changed, but the timing, indications, and concept for treatment have also undergone great changes [6]. The existing body of knowledge has extensively demonstrated that a “wait and see” strategy is presently not advisable [6, 7]. Although oral propranolol has been proved to be more effective with fewer adverse effects than oral corticosteroids, there are still several serious side effects associated with its use, including hypotension [8], bradycardia, bronchospasm [9], hyperkalemia [10] and hypoglycemia [11]. Sometimes the side effects are so severe that even drug discontinuation is required [9].
In addition, propranolol suffers from a low oral bioavailability (≈30%) due to hepatic first-pass metabolism [12]. To enhance the effectiveness of treatment and mitigate the potential side effects of oral propranolol therapy from occurring, some researchers have tried to use topical β-blocker in treating IH [13]. Timolol is a β-blocker available for both topical and systemic administration [13]. While oral timolol's antihypertensive effects are about 4 times stronger than those of propranolol, its cardiac effects last approximately 10 times longer [13]. Numerous studies have shown that topical treatment with timolol has yielded good therapeutic effects for IH, with rare adverse events [14]. For instance, 13.7% of patients on oral propranolol experienced systemic adverse effects, compared to only 1 out of 554 patients experienced a systemic adverse effect, which was sleep disturbance after using topical timolol [14]. This is because the topical application of timolol can bypass first-pass liver metabolism and avoid the side effects of oral β-blockers. The favorable adverse effect profile and strong efficacy position topical timolol as an ideal first-line treatment.
However, currently there is no definitive agreement on the timing, dosage, frequency, size and safety of topical timolol treatment for IH. The main objective of this study was to report single-center experience to retrospectively analyze therapeutic outcomes and complications of topical timolol treatment among children of different ages afflicted with superficial IH, and to investigate the timing and safety of topical timolol treatment for IH.
Methods
This study was approved by the Institutional Review Board of Sichuan Provincial People’s Hospital (NO. 2024–48). Written informed consent for topical timolol treatment was obtained from the guardians of all pediatric patients. The authors affirm that human research participants provided informed consent for publication of the images in Figs. 1, 2, 3.
Fig. 1.
A female with a small superficial IH on the dorsum of the right foot. a The patient started receiving topical timolol treatment when she was 6 weeks old. The red colored lesions protruded from the skin surface. b 1 week, c 2 weeks, d 3 weeks, e 4 weeks, f 5 weeks and g 6 weeks after the initiation of timolol treatment, the lesions gradually became smaller, flatter and less red. h 4 months and i 5 months after the initiation of timolol treatment, although desquamation can be observed, the lesions shrinked and paled significantly. j 9 months after the initiation of timolol treatment, the IH lesions were almost invisible. In conclusion, excellent response with complete clinical resolution was obtained; therefore, the treatment was stopped. k 3 months and (l) 9 months after the timolol treatment stopped, no hyperpigmentation, scarring, residual fibrofatty tissue or recurrence was observed
Fig. 2.
A female with a large superficial IH on the right knee. a The patient started receiving topical timolol treatment when she was 6 weeks old. The red colored lesions protruded from the skin surface. b 1 week, c 2 weeks, d 3 weeks, e 4 weeks, f 5 weeks and g 6 weeks after the initiation of timolol treatment, the lesions gradually became smaller, flatter and less red. h 4 months, i 5 months, j 6 months, k 7 months, and (l) 8 months after the initiation of timolol treatment, although hyperpigmentation can be observed, the lesions shrinked and paled significantly. m 10 months after the initiation of timolol treatment, the IH lesions were almost invisible. In conclusion, excellent response with complete clinical resolution was obtained; therefore, the treatment was stopped. n 3 months and o 15 months after the timolol treatment stopped, no scarring, residual fibrofatty tissue or recurrence was observed
Fig. 3.
A female with a small superficial IH on the left periocular area. a The patient started receiving topical timolol treatment when she was 1 month old. The red colored lesions protruded from the skin surface. b 1 week, c 2 weeks, d 3 weeks, e 8 weeks, and f 11 weeks after the initiation of timolol treatment, the lesions gradually became smaller, flatter and color fading. g 12 weeks and h 14 weeks after the initiation of timolol treatment, erythema was observed. i 4 months, j 5 months, and k 11 months after the initiation of timolol treatment, although the color fading is not significant, the lesions slowly shrinked. (l) 12 months after the initiation of timolol treatment, although the treatment didn't achieve complete clinical resolution, significant shrinkage and color fading of the lesions were observed. In conclusion, good response was obtained; therefore, the treatment was stopped. m 8 months, n 9 months and o 10 months after the timolol treatment was completed, residual IH lesions were still observed
Patients
A retrospective analysis was performed of pediatric patients with superficial IH who underwent topical timolol treatment between January 2019 and January 2023 at the Department of Pediatric Surgery, Sichuan Provincial People's Hospital.
The diagnosis of IH was confirmed by clinical history, clinical evaluation and ultrasonography (US) according to the International Society for the Study of Vascular Anomalies (ISSVA) classification [15]. For the purpose of this study, all patients with superficial IH were grouped for analysis by three different factors, namely, IH location, the age receiving treatment and maximum diameter of IH. In order to look at the effect of IH location on outcomes, patients were divided into seven groups: head, neck, abdomen, chest, perineum, upper and lower extremities. For the age at which patients first received treatment, IH patients were divided into two groups, namely, ≤ 3 months and > 3 months. The final grouping divided IH into two groups according to the maximum diameter of IH: small (1.5 cm < max diameter ≤ 5 cm) and large (5 cm < max diameter ≤ 10 cm).
Patients who have undergone any previous treatment, or discontinued topical timolol treatment for more than 1 month for any reason, or had treatment initiated at younger than 1 month or older than 12 months, or were lost to follow-up (a minimum of six months after the treatment), were excluded from this study. All patients were evaluated with digital photographs, US or clinical evaluation before and after the treatment.
Topical timolol treatment procedure
Timolol maleate (0.5%) eye drops (Wuhan Wujing Pharmaceutical Co., Ltd., National Medicine Standard H42021078) was applied topically three times daily to the IH. The guardians were asked to apply 3–15 drops to a gauze pad and then cover the IH tissue with it for 30 min under a thin occlusive dressing.
Patients who remained in therapy for 12 months (even though the IH hasn't completely regression) and in whom the IH showed complete regression (even though the treatment is less than 12 months) were regarded as having the treatment completed. Patients were clinically followed-up for ≥ 6 months after the completion of therapy. Lesion color and volume changes, side effects, complications and recurrences were recorded during the treatment and follow-up.
The response to treatment was assessed only by lesion volume changes, which was assessed as excellent, good, fair or poor. Lesions with no remaining visible abnormality were considered to have excellent outcomes. Where lesions were visibly smaller than half their original size the outcome was considered to be good. For lesions that were visibly smaller but not less than half their original size the outcome was assessed as fair. Finally where lesions were visibly bigger than their original size or where there was no change in the size and volume the outcome was considered poor. IH volume (V) was calculated as V = π/6[(a × b)3/2] (a and b were the 2 largest diameters of IH lesions) [16]. The therapeutic effects were evaluated by 2 doctors experienced with IH.
In the study, we documented the incidence of topical adverse reactions, including localized skin irritation (itching, desquamation, erythema), erosions, ulcers, hyperpigmentation, hypopigmentation, residual fibrofatty tissue, and scars. Moreover, the incidence of systemic adverse reactions, such as bradycardia, shortness of breath, asthma, and sleep disorders, was also recorded.
Statistical analysis
Microsoft Office Excel 2007, R4.1.2 and SPSS 26.0 software were used for data organization and 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, %). Pearson chi-square test or exact probability method was employed to compare differences between groups. If the measurement data followed a normal distribution, they were expressed as mean ± standard deviation. Comparisons between two groups were conducted using the independent sample t-test, while one-way ANOVA was utilized for comparisons among three or more groups. For measurement data (or ordinal data) not following a normal distribution, the median (25th percentile-75th percentile) was used for representation. Comparisons between two groups were performed using the non-parametric Mann–Whitney U test, while the Kruskal–Wallis test was applied for comparisons among three or more groups. The results were considered statistically significant if P < 0.05.
Results
Topical timolol treatment was performed for 666 IH patients (male 241, female 425). The patients’ median age at the beginning of treatment was 104 (interquartile range (IQR), 65–166) days. The median treatment duration was 12 (IQR, 12–12) months. After the treatment, the median follow-up duration was 10 (IQR, 8–12) months (Table 1). 188 (28.2%) patients had excellent outcomes (Figs. 1j, 2m), which 127 patients showing this complete response before the 12-month treatment. 292 (43.8%) patients had good outcomes (Fig. 3l), 103 (15.5%) patients had fair outcomes, and 83 (12.5%) patients had poor outcomes. The treatment was started from ≤ 3 months in 285 (42.8%) cases (Figs. 1, 2, 3), and > 3 months in 381 (57.2%) cases. The locations of IH included head 276 (41.4%) cases (Fig. 3), neck 55 (8.3%) cases, abdomen 95 (14.3%) cases, chest 72 (10.8%) cases, perineum 59 (8.9%) cases, upper extremities 51 (7.7%) cases and lower extremities 58 (8.7%) cases (Figs. 1, 2). The small IH (1.5 cm < max diameter ≤ 5 cm) were 549 (82.4%) cases (Figs. 1, 3) and large IH (5 cm < max diameter ≤ 10 cm) were 117 (17.6%) cases (Fig. 2).
Table 1.
Characteristics of patients and infantile hemangioma (IH)
| Characteristics | Value (%) |
|---|---|
| Patients* | 666 (100%) |
| Gender* | |
| Male | 241 (36.19%) |
| Female | 425 (63.81%) |
| Location* | |
| Head | 276 (41.44%) |
| Neck | 55 (8.26%) |
| Chest | 72 (10.81%) |
| Perineum | 59 (8.86%) |
| Abdomen | 95 (14.26%) |
| Upper extremity | 51 (7.66%) |
| Lower extremity | 58 (8.71%) |
| Age* | |
| ≤ 3 months | 285 (42.79%) |
| > 3 months | 381 (57.21%) |
| Size of lesions | |
| Small: 1.5 cm < max diameter ≤ 5 cm | 549 (82.43%) |
| Large: 5 cm < max diameter ≤ 10 cm | 117 (17.57%) |
| Outcomes* | |
| Excellent | 188 (28.23%) |
| Good | 292 (43.84%) |
| Fair | 103 (15.47%) |
| Poor | 83 (12.46%) |
| Age at the beginning of treatment (days) ** | 104 (65–166) |
| Treatment duration (months) ** | 12 (12–12) |
| Follow-up duration (months) ** | 10 (8–12) |
*Values are presented as a number (percentage)
**Values are presented as a median (interquartile range)
After the Mann–Whitney U test, IH patients aged ≤ 3 months were more likely to have better outcomes than those > 3 months (Z = 4.713, P < 0.001). Small IH (1.5 cm < max diameter ≤ 5 cm) had better outcomes than large IH (5 cm < max diameter ≤ 10 cm) (Z = 1.991, P = 0.046) (Table 2). Kruskal–Wallis test was applied for the outcomes of age by re-grouping the patients into 2-month interval age groups. Only “1 < months ≤ 3” compare to “3 < months ≤ 5” (P = 0.005), “1 < months ≤ 3” compare to “7 < months ≤ 9” (P = 0.040) and “1 < months ≤ 3” compare to “9 < months ≤ 12” (P = 0.036) had the statistically significant difference (Table 3). The difference between other groups were no statistically significant. “1 < months ≤ 3” compare to “5 < months ≤ 7” (P = 0.080), “3 < months ≤ 5” compare to “5 < months ≤ 7” (P = 0.999), “3 < months ≤ 5” compare to “7 < months ≤ 9” (P = 0.981), “3 < months ≤ 5” compare to “9 < months ≤ 12” (P = 0.952), “5 < months ≤ 7” compare to “7 < months ≤ 9” (P = 0.951), “5 < months ≤ 7” compare to “9 < months ≤ 12” (P = 0.908), “7 < months ≤ 9” compare to “9 < months ≤ 12” (P = 1.000). After the Kruskal–Wallis test, lesion locations did not significantly affect outcomes (H = 10.252, P = 0.114) (Table 2, Fig. 4). During or after the treatment, respiratory problems occurred in 58 (8.7%) cases, localized skin irritation including desquamation (Fig. 1h, i), erythema (Fig. 3g, h) and itching occurred in 48 (7.2%) cases, sleep disturbance occurred in 30 (4.5%) cases, and residual skin lesions occurred in 26 (3.9%) cases (hyperpigmentation occurred in 6 cases and residual fibrofatty tissue occurred in 20 cases) (Fig. 2h-j, Table 4). In 59 (8.8%) cases the IH had relapses. No IH ulceration and scarring occurred during the treatment. Nor were adverse cardiovascular or systemic reactions noted (Table 4).
Table 2.
Infantile hemangioma (IH) patients’ outcomes from overall topical timolol treatment
| Variables | Excellent Outcomes (188, 100%) | Good Outcomes (292, 100%) | Fair Outcomes (103, 100%) | Poor Outcomes (83, 100%) | Statistics | P Value |
|---|---|---|---|---|---|---|
| Location (n, %)* | ||||||
| Head | 78 (41.5) | 130 (44.5) | 40 (38.8) | 28 (33.7) | H = 10.252 | 0.114 |
| Neck | 13 (6.9) | 23 (7.9) | 11 (10.7) | 8 (9.6) | ||
| Abdomen | 28 (14.9) | 42 (14.4) | 15 (14.6) | 10 (12.0) | ||
| Chest | 26 (13.8) | 33 (11.3) | 7 (6.8) | 6 (7.2) | ||
| Perineum | 14 (7.4) | 24 (8.2) | 7 (6.8) | 14 (16.9) | ||
| Lower extremity | 15 (8.0) | 23 (7.9) | 12 (11.7) | 8 (9.6) | ||
| Upper extremity | 14 (7.4) | 17 (5.8) | 11 (10.7) | 9 (10.8) | ||
| Age (n, %)* | ||||||
| ≤ 3 months | 89 (47.3) | 153 (52.4) | 25 (24.3) | 18 (21.7) | Z = 4.713 | < 0.001 |
| > 3 months | 99 (52.7) | 139 (47.6) | 78 (75.7) | 65 (78.3) | ||
| Size of lesions (n, %)* | ||||||
| Small: diameter ≤ 5 cm | 162 (86.2) | 241 (82.5) | 82 (79.6) | 64 (77.1) | Z = 1.991 | 0.046 |
| Large: diameter > 5 cm | 26 (13.8) | 51 (17.5) | 21 (20.4) | 19 (22.9) | ||
| Gender (n, %)* | ||||||
| Male | 64 (34.0) | 104 (35.6) | 43 (41.7) | 30 (36.1) | Z = 0.929 | 0.353 |
| Female | 124 (66.0) | 188 (64.4) | 60 (58.3) | 53 (63.9) | ||
*Values are presented as a number (percentage)
Table 3.
Infantile hemangioma (IH) patients’ outcomes from 2-month interval age groups
| Variables | Total (n = 666) | age_group | Statist-ics | P Value | ||||
|---|---|---|---|---|---|---|---|---|
| 1 < months ≤ 3 (n = 285) | 3 < months ≤ 5 (n = 179) | 5 < months ≤ 7 (n = 101) | 7 < months ≤ 9 (n = 54) | 9 < months ≤ 12 (n = 47) | ||||
| Outcome, n (%) | *P = 0.005 | *P = 0.040 | *P = 0.036 | χ2 = 23.422 | < 0.001 | |||
| Excellent | 188 (28.23) | 89 (31.23) | 45 (25.14) | 26 (25.74) | 16 (29.63) | 12 (25.53) | ||
| Good | 292 (43.84) | 153 (53.68) | 71 (39.66) | 42 (41.58) | 13 (24.07) | 13 (27.66) | ||
| Fair | 103 (15.47) | 25 (8.77) | 34 (18.99) | 17 (16.83) | 13 (24.07) | 14 (29.79) | ||
| Poor | 83 (12.46) | 18 (6.32) | 29 (16.20) | 16 (15.84) | 12 (22.22) | 8 (17.02) | ||
Kruskal–Wallis H test
*compare to “1–3 months” had the statistically significant difference
Fig. 4.
Topical timolol treatment outcomes. a Infantile hemangioma (IH) locations did not significantly affect topical timolol treatment outcomes (H = 10.252, P = 0.114). b Small IH had better outcomes than large IH (Z = 1.991, P = 0.046). c IH patients aged ≤ 3 months had better outcomes than those > 3 months (Z = 4.713, P < 0.001). Numbers of the ordinate represent rank variables for different outcomes: 1-Poor, 2-Fair, 3-Good, 4-Excellent
Table 4.
Adverse events with topical timolol treatment
| Adverse events | Value (%) |
|---|---|
| Topical adverse reactions | |
| Localized skin irritation (desquamation, erythema, itching) | 48 (7.2%) |
| Hyperpigmentation | 6 (0.9%) |
| Hypopigmentation | 0 |
| Residual fibrofatty tissue | 20 (3.0%) |
| Scarring | 0 |
| Erosions | 0 |
| Ulcers | 0 |
| Allergic contact dermatitis | 0 |
| Systemic adverse reactions | |
| Respiratory problems | 58 (8.7%) |
| Sleep disturbance | 30 (4.5%) |
| Bradycardia | 0 |
| Total | 162 (24.3%) |
| Recurrence | 59 (8.8%) |
Discussion
Timolol is a nonselective β-adrenergic receptor antagonist of moderate lipid solubility, widely used for glaucoma management. The exact mechanism of action of timolol on IH remains unclear. Timolol maleate relies on transcutaneous absorption, and has 10 times greater potency compared to propranolol [17, 18]. A lot of research suggests that timolol induces prompt vasoconstriction, which means the flow of blood through the lesion will be impacted immediately within the first 3 days of treatment. In the mid-term effect, angiogenic factors and low pH which promote the growth of the IH, will be blocked by timolol. In the long-term, timolol triggers the apoptosis of endothelial cells (ECs), leading to an increase in IH regression [19].
Timolol 0.5% drops, timolol 0.25% or 0.5% gel forming solution (GFS) and timolol 0.1% gel, among many, are the most commonly used preparations for IH topical treatment. They are applied in different frequencies from twice daily to five times daily ranging from 1 to 10 drops at each dose [18, 20, 21]. However, some research suggests that the concentration of a 0.25% or 0.1% dose of timolol may be too low [21] and that it is only effective for superficial, non-ulcerated IH [20]. Deep lesions have been treated successfully with ulcerated lesions healed after applying timolol 0.5% twice or three times a day [21]. To sum up, timolol 0.1% shows 100% success rate only with superficial lesions; timolol 0.5% solution has a success rate of over 98% in all studies, while timolol 0.5% GFS’s success rate varies between 60 and 100% [18]. Therefore, for patients with both superficial and deep lesions, many researchers advocate the use of topical timolol maleate 0.5% solution as the first-line treatment [12, 18]. In addition, according to Moehrle, the use of an occlusive dressing may facilitate the absorption of timolol and yield results superior to previously published data [22]. In this study, all the patients were treated with timolol maleate 0.5% solution three times daily using an occlusive dressing.
There has been no determined ideal age to start topical timolol treatment [21]. It was suggested that treatment be started in the proliferation phase to achieve excellent outcomes according to the natural history of IH [23]. Yu et al. noted patients treated before the age of 6 months had higher lesion regression rates than those who received treatment between 6 and 12 months (63.9% vs 56.4%) [24]. Semkova and Kazandjieva documented that topical timolol 0.1% gel was more effective in the proliferation than in the involution phase [25]. Similarly, the results of this study indicate that patients with IH who are aged ≤ 3 months are more likely to experience better outcomes than those aged > 3 months. In the analyze of 2-month interval age groups, the outcomes of aged ≤ 3 months were no difference between 5 < months ≤ 7. Due to the small sample size, we merged the remaining age groups into one group for individuals older than 3 months (3 < months ≤ 12) to reduce potential bias in the data. Some researchers found that IH has the fastest growth at 5–8 weeks of age [26] and grows to 80% of its maximum volume at 3 months of age [27]. It can be seen that early and effective control of IH growth is crucial for its prognosis. It may not only reduce its impact on surrounding structures, but also ultimately improve cosmesis of the lesion and sequelae [28].
The duration of topical timolol treatment varied across studies, with no specific timeframe consistently followed. However, it was noted that relapses might occur before the age of 11 months. Therefore, a recommendation was made for the treatment to continue at least through the proliferation phase, typically up to 8–12 months of age. In cases where treatment initiation was delayed, it was suggested to continue until maximal improvement [8]. Chan treated small, superficial lesions with timolol 0.5% maleate gel and compared the relative change in predicted volume of the IH with placebo. The results showed that a minimum of treatment going on for 16 weeks is required to see a statistically significant difference in size between treatment and placebo [29]. Chakkittakandiyil proposed that an extended duration of topical timolol treatment is linked to a more significant enhancement in the appearance of IH [21]. Therefore in this study, the topical timolol treatment duration was set to be 12 months (except for complete regressions). After the treatment, 59 (8.8%) patients had IH relapses, which obviously lower than oral propranolol therapy (18%) [30] ~ (67%) [7]. Those researches mentioned above did not specify the commencement or length of topical timolol treatment. The only thing that have been confirmed was that topical timolol treatment should start before 1 year of age, because timolol maleate uses transcutaneous absorption, and thus it’s effective against IH because the barrier function of the skin is not complete before 1 year of age [17]. Therefore, those who started treatment at an age older than 12 months were excluded from this study.
Timolol applied topically on its own demonstrated greater efficacy and safety compared to all the other controls, laser, placebo, or observation [31], and yielded excellent outcomes in patients with superficial IH, with only 3.4% of these patients experienced adverse effects [21]. A systematic review indicated that the response rate of IH to topical timolol can reach as high as 83%, with adverse events being infrequent [14]. These findings align with our study showing that 480 (72%) patients had excellent or good outcomes and small IH had better outcomes than large IH. In addition to good therapeutic effects of topical timolol treatment, numerous studies have shown that it has almost no side effects. Qiu et al. performed a paired comparison, comparing timolol 0.5% solution with imiquimod 5% cream. No adverse reactions or scarring were observed in the individuals who received timolol treatment, in contrast with a 65% incidence of crusting in lesions treated with imiquimod [32]. According to Ni et al.’s report on using timolol solution, no changes in heart rate were noted [33]. Xu et al. measured echocardiogram, blood pressure, heart rate and blood sugar prior to treatment, after one week and subsequently at intervals of 4 to 8 weeks thereafter. No side effects were noted [34]. Chan et al. measured blood pressure and heart rate prior to treatment and throughout the study period. No hypotension or bradycardia was observed in 19 patients [29].
However, topical timolol treatment does have several main side effects notably: sleep disturbance, localized skin irritation, and respiratory problems. Sleep disturbance was the sole systemic side-effect event with 0.5% timolol, which spontaneously resolved upon discontinuation of the drug [35]. Increased doses led to localized skin irritation, specifically pruritus, but this was alleviated with the use of topical antibiotics [18]. Lin et al. conducted a meta-analysis involving 2,098 patients, concluding that topical timolol is associated with a low incidence of adverse events, primarily categorizd as localized, such as desquamation and erythema [13]. Several cases of allergic contact dermatitis have been reported in literature after the application of topical timolol [36]. Tawfik and Alsharnoubi reported that 1 out of 60 children experienced insomnia and shortness of breath upon using topical timolol maleate 0.5% solution twice daily [37]. Furthermore, a recent large U.S. multi-center retrospective cohort study involving 731 children revealed only a 0.4% incidence of bronchospasm (3/731), no cardiovascular adverse reactions (0/731), or any other complications during topical treatment requiring timolol discontinuation [20], further supporting the superior safety profile of topical beta-blockers over oral propranolol treatment which has potentially serious cardiovascular side-effects include bradycardia, atrioventricular block, and hypoglycaemia [38]. This may because topical application of timolol can bypass first-pass liver metabolism and avoid side effects of oral β-blockers [12]. In this study, during or after the treatment, sleep problems occurred in 30 (4.5%) cases, desquamation, itching and erythema occurred in 48 (7.2%) cases. Respiratory problems occurred in 58 (8.7%) cases, a much higher incidence than in other researches. This may because the study was conducted in part during the COVID-19 pandemic, the guardians have payed more attention to the respiratory symptoms and reported even small or uncorrelated respiratory problems.
It have been reported that residual skin lesions (mostly fibrofatty) were observed in 45.8% to 66.7% of untreated IH, particularly those on the face [39]. After oral propranolol treatment, such lesions were observed in 34.9% of periocular IH [7]. While, in our study, residual skin lesions only occurred in 26 (3.9%) cases after the timolol treatment, which is much lower incidence than other researches. The possible explanation could be that: On the one hand, most of IH in this study were superficial and small (86.2%, max diameter ≤ 5 cm). Enjolras et al. have shown that the degree of damage to the skin and subcutaneous tissue is positively correlated with the final volume of IH and the extent to which the subcutaneous structure is affected [40]. On the other hand, topical application of timolol may improve the appearance of scars [41] by promoting keratinocyte migration and accelerating epithelialization [42]. The negative outcomes observed could stem from the prolonged time between the onset of the disease and the initiation of treatment or the considerable size of the IH. Nevertheless, irrespective of whether treatment was administered early or late, the occurrence of complications after treatment was notably lower compared to complications following spontaneous regression, which stood at 70% [43].
This study has several limitations. Firstly, the 12-month treatment duration may have excluded patients needing longer treatment for better outcomes. Secondly, the median follow-up duration was 10 (IQR, 8–12) months was too short to assess long-term efficacy, potentially overlooking chronic complications and disease recurrence. Future research should examine if early intervention can reduce long-term sequelae, such as residual fibrofatty tissue, scars, and hyperpigmentation. Thirdly, the study focused on patients exclusively treated with topical timolol for 12 months, excluding those who pursued alternatives such as laser, surgery, or injections. This approach likely omitted some patients who had poor timolol therapeutic effects. Lastly, side effects reported by family members might lack objectivity and accuracy. And they also inevitable submitted some unstandardized or blurred photos. Additionally, the study prompts further investigation into why topical timolol is more effective in infants under three month old, particularly regarding early intervention's role in preventing rapid IH growth; and why it may lower the incidence of residual skin lesions and IH relapses.
Conclusion
In this study, topical 0.5% timolol maleate treatment appears to be safe and effective for patients with superficial IH (max diameter ≤ 10 cm) at the age of 1–12 months. Patients with IH who are aged ≤ 3 months or have a max diameter ≤ 5 cm are especially more likely to experience better outcomes. In addition, topical timolol treatment may reduce the incidence of residual skin lesions and IH relapses. Therefore it may be a useful alternative therapy option for superficial IH.
Abbreviations
- ECs
Endothelial Cells
- GFS
Gel Forming Solution
- IH
Infantile Hemangioma
- IQR
Interquartile Range
- ISSVA
International Society for the Study of Vascular Anomalies
- US
Ultrasonography
- V
Volume
Authors’ contributions
All authors contributed to the study conception and design. M. X. drafted the manuscript. W. L. and Y. J. critical revised the manuscript for important intellectual content. Y. L. and K. D. collected and analyzed the data. Q. Z. validated the data. F. H. completed the final editing of the manuscript. All authors read and approved the final manuscript.
Funding
This work was supported by the National Natural Science Foundation of China (Grant No. 81300238), Key research Project of Sichuan Provincial Science and Technology Program (Grant No. 2021YFS0381), and Chengdu Science and Technology Program (Grant No. 2024YF0501871SN).
Data availability
Data is provided within the manuscript or supplementary information files.
Declarations
Ethics approval
This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China (NO. 2024–48).
Competing interests
The authors declare no competing interests.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
- 1.Munden A, Butschek R, Tom WL et al (2014) Prospective study of infantile haemangiomas: incidence, clinical characteristics and association with placental anomalies. Br J Dermatol 170:907–913. 10.1111/bjd.12804 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Hou F, Dai Y, Fan CY, Suen JY, Richter GT (2018) Estrogen is involved in hemagioma regression associated with mast cells. Orphanet J Rare Dis 13(1):181. 10.1186/s13023-018-0928-x [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Bauland CG, Lüning TH, Smit JM, Zeebregts CJ, Spauwen PHM (2011) Untreated hemagiomas: growth pattern and residual lesions. Plast Reconstr Surg 127(4):1643–1648. 10.1097/PRS.0b013e318208d2ac [DOI] [PubMed] [Google Scholar]
- 4.Léauté-Labrèze C, Harper JI, Hoeger PH (2017) Infantile haemangioma. Lancet 390(10089):85–94. 10.1016/S0140-6736(16)00645-0 [DOI] [PubMed] [Google Scholar]
- 5.Léauté-Labrèze C, Dumas de la Roque E, Hubiche T, Boralevi F, Thambo JB, Taïeb A (2008) Propranolol for severe hemangiomas of infancy. N Engl J Med 358:2649–2651. 10.1056/NEJMc0708819 [DOI] [PubMed] [Google Scholar]
- 6.Léauté-Labrèze C, Frieden I, Delarue A (2023) Early initiation of treatment with oral propranolol for infantile hemangioma improves success rate. Pediatr Dermatol 40(2):261–264. 10.1111/pde.15198 [DOI] [PubMed] [Google Scholar]
- 7.Ghahvehchian H, Kashkouli MB, Ghanbari S, Karimi N, Abdolalizadeh P, AbriAghdam K (2024) Long-term results of oral propranolol treatment protocol for periocular infantile hemangioma: should there be any contraindication? Ophthal Plast Reconstr Surg 40(1):61–69. 10.1097/IOP.0000000000002507 [DOI] [PubMed] [Google Scholar]
- 8.AI Dhaybi R, Superstein R, Milet A et al (2011) Treatment of periocular infantile hemangiomas with propranolol: case series of 18 children. Ophthalmology 118:1184–1188. 10.1016/j.ophtha.2010.10.031 [DOI] [PubMed]
- 9.Ginguerra MA, Saito O, Fernandes JBVD, Castro DS, Matayoshi S (2018) Clinical and radiological evaluation of periocular infantile hemangioma treated with oral propranolol: a case series. Am J Ophthalmol 185:48–55. 10.1016/j.ajo.2017.10.021 [DOI] [PubMed] [Google Scholar]
- 10.Pavlakovic H, Kietz S, Lauerer P, Zutt M, Lakomek M (2010) Hyperkalemia complicating propranolol treatment of an infantile hemangioma. Pediatrics 126:e1589–e1593. 10.1542/peds.2010-0077 [DOI] [PubMed] [Google Scholar]
- 11.Marey HM, Elmazar HF, Mandour SS, Khairy HA (2018) Combined oral and topical beta blockers for the treatment of early proliferative superficial periocular infantile capillary hemangioma. J Pediatr Ophthalmol Strabismus 55:37–42. 10.3928/01913913-20170703-12 [DOI] [PubMed] [Google Scholar]
- 12.Cheng CE, Friedlander SF (2016) Infantile hemangiomas, complications and treatments. Semin Cutan Med Surg 35(3):108–116. 10.12788/j.sder.2016.050 [DOI] [PubMed] [Google Scholar]
- 13.Lin Z, Zhang B, Yu Z, Li H (2020) The effectiveness and safety of topical b-receptor blocker in treating superficial infantile haemangiomas: a meta-analysis including 20 studies. Br J Clin Pharm 86:199–209. 10.1111/bcp.14196 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Ovadia SA, Landy DC, Cohen ER, Yang EY, Thaller SR (2015) Local administration of β-blockers for infantile hemangiomas: a systematic review and meta-analysis. Ann Plast Surg 74(2):256–262. 10.1097/sap.0000000000000390 [DOI] [PubMed] [Google Scholar]
- 15.International Society for the Study of Vascular Anomalies (2018) ISSVA classification of vascular anomalies. issva.org/classification. Accessed 24.10.22
- 16.Alexander MD, McTaggart RA, Choudhri OA, Pandit RP, Wu A, Ross M, Do HM (2016) Quantitative volumetric analysis of venous and lymphatic malformations of the head and neck to assess response to percutaneous sclerotherapy. Acta Radiol 57(2):205–209. 10.1177/0284185115575779 [DOI] [PubMed] [Google Scholar]
- 17.Xue K, Hildebrand GD (2012) Topical timolol maleate 0.5% for infantile capillary haemangioma of the eyelid. Br J Ophthalmol 96(12):1536–1537. 10.1136/bjophthalmol-2012-302396 [DOI] [PubMed]
- 18.Painter SL, Göran DH (2016) Review of topical beta blockers as treatment for infantile haemangiomas. Surv Ophthalmol 61(1):51–58. 10.1016/j.survophthal.2015.08.006 [DOI] [PubMed] [Google Scholar]
- 19.Calvo M, Garcia-Millán C, Villegas C, Fueyo-Casado A, Burón I (2013) Topical timolol for infantile hemangioma of the eyelid. Int J Dermatol 52(5):603–604. 10.1111/j.1365-4632.2011.05290.x [DOI] [PubMed] [Google Scholar]
- 20.Püttgen K, Lucky A, Adams D et al (2016) Topical timolol maleate treatment of infantile hemangiomas. Pediatrics 138(3). 10.1542/peds.2016-0355 [DOI] [PubMed]
- 21.Chakkittakandiyil A, Phillips R, Frieden IJ, Siegfried E, Lara-Corrales I, Lam J, Bergmann J, Bekhor P, Poorsattar S, Pope E (2012) Timolol maleate 0.5% or 0.1% gel-forming solution for infantile hemangiomas: a retrospective, multicenter, cohort study. Pediatr. Dermatology 29(1):28–31. 10.1111/j.1525-1470.2011.01664.x [DOI] [PubMed]
- 22.Moehrle M, Léauté-Labrèze C, Schmidt V, Röcken M, Poets CF, Goelz R (2013) Topical timolol for small hemangiomas of infancy. Pediatr Dermatol 30(2):245–249. 10.1111/j.1525-1470.2012.01723.x [DOI] [PubMed] [Google Scholar]
- 23.Han K, Wei J, Zheng H, Li X, Zhang A, Ma Y, Meng J, Hu Y (2024) Efficacy and safety of oral propranolol or topical timolol for the treatment of superficial infantile hemangiomas. J Craniofac Surg Published online February 12. 10.1097/SCS.0000000000010001 [DOI] [PubMed]
- 24.Yu L, Li S, Su B et al (2013) Treatment of superficial infantile hemangiomas with timolol: evaluation of short-term efficacy and safety in infants. Exp Ther Med 6(2):388–390. 10.3892/etm.2013.1176 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Semkova K, Kazandjieva J (2013) Topical timolol maleate for treatment of infantile haemangiomas: preliminary results of a prospective study. Clin Exp Dermatol 38(2):143–146. 10.1111/j.1365-2230.2012.04425.x [DOI] [PubMed] [Google Scholar]
- 26.Touefson MM, Frieden IJ (2012) Early growth of infantile hemagiomas: what parents’ photographs tell us. Pediatrics 130(2):e314–e320. 10.1542/Deds.2011-3683 [DOI] [PubMed] [Google Scholar]
- 27.Chang LC, Haggstrom AN, Drolet BA et al (2008) Growth characteristics of infantile hemangiomas: implications for management. Pediatrics 122(2):360–367. 10.1542/peds.2007-2767 [DOI] [PubMed] [Google Scholar]
- 28.Moyakine AV, Hermans DJ, Fuijkschot J, van der Vleuten CJ (2015) Propranolol treatment of infantile hemangiomas does not negatively affect psychomotor development. J Am Acad Dermatol 73(2):341–342. 10.1016/j.jaad.2015.04.053 [DOI] [PubMed] [Google Scholar]
- 29.Chan H, McKay C, Adams S, Wargon O (2013) RCT of timolol maleate gel for superficial infantile hemangiomas in 5 to 24-week-olds. Pediatrics 131(6):e1739–e1747. 10.1542/peds.2012-3828 [DOI] [PubMed] [Google Scholar]
- 30.Frongia G, Byeon JO, Mehrabi A, Günther P (2021) Recurrence rate of infantile hemangioma after oral propranolol therapy. Eur J Pediatr 180(2):585–590. 10.1007/s00431-020-03872-5 [DOI] [PubMed] [Google Scholar]
- 31.Zheng L, Li YL (2018) Effect of topical timolol on response rate and adverse events in infantile hemangioma: a meta-analysis. Arch Dermatol Res 310(4):261–269. 10.1007/s00403-018-1815-y [DOI] [PubMed] [Google Scholar]
- 32.Qiu Y, Ma G, Yang J, Hu X, Chen H, Jin Y, Lin X (2013) Imiquimod 5% cream versus timolol 0.5% ophthalmic solution for treating superficial proliferating infantile haemangiomas: a retrospective study. Clin Exp Dermatol 38(8):845–50. 10.1111/ced.12150 [DOI] [PubMed]
- 33.Ni N, Langer P, Wagner R, Guo S (2011) Topical timolol for periocular hemangioma: report of further study. Arch Ophthalmol 129(3):377–379. 10.1001/archophthalmol.2011.24 [DOI] [PubMed] [Google Scholar]
- 34.Xu G, Lv R, Zhao Z, Huo R (2012) Topical propranolol for treatment of superficial infantile hemangiomas. J Am Acad Dermatol 67(6):1210–1213. 10.1016/j.jaad.2012.03.009 [DOI] [PubMed] [Google Scholar]
- 35.Khan M, Boyce A, Prieto-Merino D, Svensson Å, Wedgeworth E, Flohr C (2017) The role of topical timolol in the treatment of infantile hemangiomas: a systematic review and meta-analysis. Acta Derm Venereol 97:1167–1171. 10.2340/00015555-2681 [DOI] [PubMed] [Google Scholar]
- 36.Sacchelli L, Vincenzi C, La Placa M, Piraccini BM, Neri I (2019) Allergic contact dermatitis caused by timolol eyedrop application for infantile haemangioma. Contact Dermatitis 80:255–256. 10.1111/cod.13190 [DOI] [PubMed] [Google Scholar]
- 37.Tawfik AA, Alsharnoubi J (2015) Topical timolol solution versus laser in treatment of infantile hemangioma: a comparative study. Pediatr Dermatol 32:369–376. 10.1111/pde.12542 [DOI] [PubMed] [Google Scholar]
- 38.Léaute-Labrèze C, Boccara O, Degrugillier-Chopinet C et al (2016) Safety of oral propranolol for the treatment of infantile hemangioma: a systematic review. Pediatrics 138(4):e20160353. 10.1542/peds.2016-0353 [DOI] [PubMed] [Google Scholar]
- 39.Chang SJ, Qiao C, Chang L, Gao W, Jin Y, Ma G, Qiu Y, Lin X (2019) A 7-year follow-up study on untreated deep or mixed facial infantile hemangioma in East-Asian patients: When propranolol was not yet an option. J Dermatol 46(11):962–966. 10.1111/1346-8138.15080 [DOI] [PubMed] [Google Scholar]
- 40.Enjolras O, Mulliken JB (1993) The current management of vascular birthmarks. Pediatr Dermatol 10(4):311–313. 10.1111/j.1525-1470.1993.tb00393.x [DOI] [PubMed] [Google Scholar]
- 41.Ghanbarzamani A, Salehifar E, Jafarirad A, Hesamirostami MH, Bagherzadehsaba A, Saeedi M, Ghazaeian M, Khorasani G, Moosazadeh M (2021) Efficacy and Safety of 0.25% Timolol Gel in Healing Split-Thickness Skin Graft Site. Iran J Pharm Res 20(3):178–186. 10.22037/ijpr.2020.114565.14915 [DOI] [PMC free article] [PubMed]
- 42.Braun LR, Lamel SA, Richmond NA, Kirsner RS (2013) Topical timolol for recalcitrant wounds. JAMA Dermatol 149(12):1400–1402. 10.1001/jamadermatol.2013.7135 [DOI] [PubMed] [Google Scholar]
- 43.Shi W, He H, Jiang J, Gao Y, Quan H (2021) Timing and efficacy of 595-nm pulsed-dye laser combined with 0.5% timolol maleate solution in the treatment of superficial infantile hemangiomas. Clin Cosmet Investig Dermatol 2:14:1593–1599. 10.2147/CCID.S337850 [DOI] [PMC free article] [PubMed]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data is provided within the manuscript or supplementary information files.