Efficacy and safety of oral propranolol combined with intralesional injection of lauromacrogol for infantile hemangioma: a systematic review and meta-analysis

Introduction

Infantile hemangioma (IH) is recognized as the most common benign vascular tumor in infancy, with reported incidence ranging from approximately 3% to 10% of newborns worldwide (1). A recent systematic meta-analysis encompassing over 31 million infants estimated the pooled prevalence of around 2.8% [95% confidence interval (CI): 1.5–4.4%] (2). IH lesions predominantly occur on the head and neck region, with nearly 47.4% of cases localized there (95% CI: 39.5–55.4%) (2). These lesions typically are not evident at birth, but manifest within the first few weeks (often by 4–6 weeks), undergo a rapid proliferative phase, peak around 5 months of age, and gradually involute over years (1). Although most IHs involute spontaneously without harm, about 12–24% develop complications—such as ulceration (~16%), bleeding (~5.6%), visual impairment (~5.6%), infection (~2.8%), or airway obstruction (~1.5%)—necessitating intervention (1,2). Early treatment during the proliferative phase can mitigate these risks and reduce long-term sequelae.

The therapeutic landscape for IH includes systemic β-blocker treatment, local sclerosant injections, laser therapy, and surgery. Since its serendipitous discovery in 2008, oral propranolol (PRO)—a non-selective β-adrenergic receptor blocker—has become the first-line systemic treatment due to its proven efficacy and favorable safety profile (3). In a landmark multicenter, randomized, placebo-controlled trial, PRO at 3 mg/kg/day for 6 months achieved a 60% rate of complete or nearly complete resolution compared to 4% with placebo (P<0.001), with 88% of treated patients showing improvement as early as week 5 (1). Before PRO’s advent, systemic corticosteroids were used, but had inferior efficacy and more adverse effects (3,4).

On the other hand, intralesional lauromacrogol (LAU; polidocanol) injection, a form of sclerotherapy, has emerged as an effective local treatment—especially for superficial or localized IHs. A large retrospective study involving 368 infants showed that 61.4% achieved excellent regression, 29.4% good regression, and only 2.7% had poor outcomes. The incidence of adverse events was low (4.9%), with no serious complications reported (5). Given the complementary mechanisms—systemic action of PRO versus local sclerosis—some clinicians hypothesize that combining oral PRO with intralesional LAU injection may enhance therapeutic efficacy, shorten treatment duration, and maintain a favorable safety profile.

Accordingly, this study aims to conduct a meta-analysis to evaluate the efficacy and safety of PRO plus LAU combination therapy versus monotherapy (PRO or LAU alone) in treating IH, with the goal of determining whether combination therapy offers superior outcomes and may serve as a more effective clinical strategy. We present this article in accordance with the PRISMA reporting checklist (6) (available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0235/rc).

Methods

Literature retrieval

The PubMed, Web of Science, Chinese National Knowledge Infrastructure, and VIP databases were searched up to April 23, 2026 with the following terms: propranolol, Inderal, lauromacrogol, polidocanol, infant hemangioma and infantile hemangioma. Detailed search strategies in specific databases were presented in Appendix 1. References of included studies were also reviewed.

Criteria for inclusion

Studies met following criteria were included: (I) infants were diagnoses with hemangioma and treatment was needed; (II) patients received the combined treatment including the oral PRO and intralesional injection of LAU or monotherapy (PRO vs. LAU); (III) the efficacy or (and) safety between the groups were compared; (IV) randomized controlled trials (RCTs) or cohort studies; (V) full texts were available.

Criteria for exclusion

Studies met following criteria were excluded: (I) other medical interventions were involved; (II) duplicated, overlapped or insufficient data; (III) reviews, case reports or animal trials.

Data collection

The following information was collected from included studies: the first author, study design, country, year, overall sample size, sample size for experimental group, treatment of control group, location of hemangioma, endpoint, mean difference (MD) with standard deviation (SD) and odds ratio (OR) with 95% CI.

In our meta-analysis, endpoints of efficacy included the cure rate (reduction in size >75%), significant rate (reduction in size >50%), effective rate (reduction in size >25%) and treatment duration. The incidence rate of adverse reaction was applied to assess the safety of treatment.

Methodological quality assessment

The risk of bias in RCTs was assessed using the Cochrane Risk of Bias tool (RoB 1.0) implemented in Review Manager (RevMan) version 5.3. In addition, the Newcastle-Ottawa scale (NOS) was applied to evaluate the quality of retrospective cohort studies, and high-quality studies were defined as those with a NOS score ≥6 (7).

The study selection, data extraction, and risk of bias assessment were performed independently by two reviewers, and any disagreements were resolved through discussion.

Statistical analysis

All statistical analyses were conducted using RevMan version 5.3 software. Heterogeneity between studies was quantified by I² statistic and Q test. If significant heterogeneity was detected (I²>50% and/or P<0.10), the random effects model was used; or the fixed effects model was used (8,9). For continuous data, the MDs with SDs were combined to calculate the MDs with 95% CIs between the combined treatment group and control groups. Discontinuous data were compared and represented as ORs and 95% CIs. Sensitivity analysis was conducted to evaluate the stability of pooled results. Begg’s funnel plot and Egger’s test were performed to detect publication bias, and obvious publication bias was defined as P<0.05 (10,11). The P value <0.05 was considered to indicate statistical significance.

Protocol and registration

This meta-analysis was not prospectively registered in PROSPERO or other public platforms. The absence of prior registration should be considered a methodological limitation.

Results

Literature retrieval and selection

Figure 1 presents the literature retrieval and selection process. Fifty-seven records were searched from databases and 49 publications were excluded after reviewing titles, abstracts and full texts. Finally, eight available studies were included (12-19).

Figure 1 PRISMA flow diagram of this meta-analysis. *, PubMed (n=4), Web of Science (n=8), Chinese National Knowledge Infrastructure (n=34), VIP (n=11).

Basic characteristics of included studies

Among eight included studies, 668 patients were enrolled and 318, 250 and 100 patients received the combined therapy (PRO plus LAU), PRO monotherapy and LAU monotherapy, respectively. All studies were from China. Only one study by Han et al. (19) focused on periocular hemangioma. Four studies were RCTs and were of high quality (Figure 2). The other four studies were retrospective and also of high quality (Table 1).

Figure 2 Risk of bias summary (A) and bias graph (B) of randomized controlled trials.

Efficacy and safety of PRO combined with LAU by comparison with PRO monotherapy for IH

Seven studies explored the impact of PRO combined with LAU on the therapeutic effect and safety by comparison with PRO monotherapy (12-18). Pooled results demonstrated that the combined therapy manifested significant higher cure rate (OR =3.22, 95% CI: 1.40–7.41, P=0.006; I²=59%, P=0.02; Figure 3A), significant effective rate (OR =3.61, 95% CI: 1.94–6.74, P<0.0001; I²=0%, P=0.92; Figure 3B), shorter treatment time (MD =−72.81 days, 95% CI: −106.55 to −39.08, P<0.001; I²=97%, P<0.001) (Figure 3C) and lower incidence of adverse reaction (OR =0.55, 95% CI: 0.33–0.94, P=0.03; I²=47%, P=0.13; Figure 3D). Besides, the trend that combined therapy could improve the effective rate has also been observed although the differences were not statistically significant (OR =2.76, P=0.10; Figure 3E, Table 2).

Figure 3 The impact of propranolol combined with lauromacrogol on the cure rate (A), significant effective rate (B), treatment time (C), adverse reaction (D), effective rate (E) by comparison of propranolol monotherapy for infantile hemangioma. CI, confidence interval; SD, standard deviation.

Efficacy and safety of PRO combined with LAU by comparison with LAU monotherapy for IH

Four studies investigated the comparison of efficacy and safety between the combined therapy and LAU monotherapy for IH (12-14,19). Pooled results manifested that the cure rate of the combined group was significantly higher than that of LAU monotherapy group (OR =3.69, 95% CI: 1.05–12.93, P=0.04; I²=67%, P=0.03; Figure 4A). The combined therapy did not significantly improve the significant effective rate (OR =3.87, P=0.30; Figure 4B), effective rate (OR =5.05, P=0.30; Figure 4C), decrease treatment time (MD =−12.91 days, P=0.57; Figure 4D) or incidence of adverse reaction (OR =0.61, P=0.40; Figure 4E), but the tread was quite obvious (Table 2).

Figure 4 The impact of propranolol combined with lauromacrogol on the cure rate (A), significant effective rate (B), effective rate (C), treatment time (D), adverse reaction (E) by comparison of lauromacrogol monotherapy for infantile hemangioma. CI, confidence interval; SD, standard deviation.

Sensitivity analysis

Sensitivity analysis for the impact of PRO combined with LAU on the cure rate by comparison of PRO monotherapy for IH was performed, which indicated that the pooled results were stable and reliable (Figure 5A).

Figure 5 Sensitivity analysis (A) and Begg’s funnel plot (B) for the impact of propranolol combined with lauromacrogol on the cure rate by comparison of propranolol monotherapy for infantile hemangioma. CI, confidence interval; OR, odds ratio; SE, standard error.

Publication bias

Begg’s funnel plot (Figure 5B) and Egger’s test (P=0.16) revealed that there was no significant publication bias in this meta-analysis.

Discussion

It should be emphasized that intralesional LAU (polidocanol) is not currently recognized as a standard treatment for IH in major international guidelines. Its clinical application has been mainly reported in regional practice settings, particularly in China. Therefore, the conclusions of this meta-analysis should be interpreted within this specific clinical context rather than as a universally applicable treatment recommendation. Our meta-analysis manifested that oral PRO combined with intralesional LAU injection (PRO + LAU) provides superior therapeutic benefits compared with monotherapy in the management of IH. Specifically, combination therapy was associated with a significantly higher cure rate and significant response rate, a shorter treatment duration, and a lower incidence of adverse reactions compared with PRO alone. In addition, PRO + LAU achieved a higher cure rate than LAU monotherapy without increasing treatment-related toxicity. These findings suggest that combination therapy may enhance efficacy without a clear increase in adverse reactions, highlighting its potential to serve as a more effective clinical strategy for IH. From a practical perspective, this therapeutic regimen may accelerate lesion regression, reduce the risk of complications, and improve cosmetic and functional outcomes, which are of great importance in pediatric patients where early intervention is critical.

A plausible biological rationale explains why the PRO-LAU combination outperforms either monotherapy. Oral PRO acts systemically to blunt adrenergic signaling in hemangioma endothelial cells and perivascular cells, triggering vasoconstriction, apoptosis, and cell-cycle arrest while down-modulating pro-angiogenic pathways (VEGF/VEGFR-2, MAPK/ERK, PI3K/Akt and HIF-1α) and matrix-remodeling factors; these effects accelerate the transition from proliferation to involution but can be followed by regrowth in a subset of patients after drug withdrawal (5,20). In contrast, intralesional LAU (polidocanol) is a detergent sclerosant that causes direct endothelial injury with thrombosis and fibrosis of the abnormal vascular lumina, thereby collapsing residual or treatment-resistant channels within the lesion; contemporary pediatric series show high local response rates with low severe-complication rates and measurable reductions in circulating VEGF after treatment (5). Mechanistically, the two approaches are complementary: PRO suppresses neovascular drive and lesion perfusion globally, while LAU ablates the established microvasculature focally—particularly useful for bulky, mixed, or ulcerated IHs in which purely systemic therapy may leave residual vascular stroma. Clinical reports of combined regimens (e.g., parotid and lip IHs) support this synergy, noting satisfactory aesthetic outcomes without added safety signals and, in some cohorts, fewer total sclerotherapy sessions when started earlier (21). In aggregate, these data align with guideline realities: PRO remains the first-line systemic agent but carries dose-dependent adverse effects, so coupling it with a targeted sclerosant can plausibly shorten exposure, lower systemic dose requirements, and reduce rebound by permanently obliterating lesion vessels—consistent with the superior efficacy and safety signals observed in our meta-analysis (22,23).

Although our meta-analysis provides evidence supporting the superior efficacy and safety of PRO combined with LAU for IH, further investigations are warranted to strengthen the clinical evidence base. First, large-scale, multicenter, prospective RCTs are needed to validate these findings and to determine the optimal dosage, treatment duration, and administration intervals for combination therapy. Second, mechanistic studies should explore the molecular basis of synergy between PRO and LAU, particularly regarding their effects on angiogenic signaling pathways, hypoxia-related factors, and endothelial apoptosis. Third, future research should examine long-term outcomes, including recurrence rates, functional preservation, and cosmetic satisfaction, which are of critical importance for pediatric patients. In addition, comparative cost-effectiveness analyses and quality-of-life evaluations may help establish whether combination therapy should be prioritized as a standard of care in routine practice. Collectively, these avenues of research will contribute to refining therapeutic strategies and providing more individualized management for infants with hemangioma.

It is important to interpret our findings within the context of current international clinical practice guidelines. According to the 2019 American Academy of Pediatrics (AAP) clinical practice guideline for the management of IHs, oral PRO is recommended as the first-line therapy for IH, whereas intralesional sclerotherapy is not routinely endorsed as a standard treatment modality (22,23). Indeed, sclerotherapy with agents such as polidocanol has been more traditionally applied to slow-flow vascular malformations, including venous malformations, rather than IHs, which are characterized by a distinct biological behavior involving a proliferative phase followed by spontaneous involution (24). However, in certain clinical settings—particularly in parts of Asia—intralesional sclerosants, including LAU, have been used as an adjunctive or alternative therapy for selected IH cases, especially for localized, superficial, or treatment-resistant lesions. Emerging clinical evidence from these regions suggests that sclerotherapy may provide additional local control and enhance lesion regression when combined with systemic β-blocker therapy (5,18). Nevertheless, it must be emphasized that the evidence base remains geographically concentrated and largely absent from large-scale international randomized trials. Therefore, the results of this meta-analysis should be interpreted with caution, as they primarily reflect regional clinical practice patterns rather than globally established standards of care. The generalizability of our findings to broader international populations is limited, and further high-quality, multicenter studies conducted in diverse healthcare settings are required before this combined therapeutic approach can be widely recommended.

There are some limitations which should be carefully noted. First, all included studies were conducted in China, which not only limits the generalizability of our findings but also reflects region-specific clinical practice patterns. The absence of evidence from other countries raises uncertainty regarding the broader applicability, appropriateness, and safety of this therapeutic approach in different healthcare settings. Second, the therapeutic strategy involving intralesional LAU is not currently endorsed by major international guidelines, which may further limit the external validity and global applicability of our findings. Third, substantial heterogeneity was observed in several outcomes, particularly for treatment duration (I²>90%), which may limit the reliability and clinical interpretability of the pooled estimates. Although a random-effects model was applied and sensitivity analyses suggested relative stability of some primary outcomes, the presence of extreme heterogeneity indicates that the pooled results for these endpoints should be interpreted with caution. In such cases, the validity of quantitative synthesis may be limited. Fourth, due to the lack of detailed original data, we were unable to characterize adverse events in terms of specific type, severity, or causal relationship to treatment, including the occurrence of cutaneous necrosis. This limits the interpretation of safety outcomes, which is particularly important in a pediatric population, and future studies should report adverse events in a more detailed and standardized manner. Fifth, one included study was a master’s thesis without formal peer review, which may introduce potential bias and affect the overall quality of evidence. Sixth, we did not perform a formal assessment of the overall certainty of evidence [such as Grading of Recommendations, Assessment, Development and Evaluation (GRADE)], which limits the strength of conclusions and the ability to provide graded clinical recommendations. Seventh, we pooled RCTs and retrospective cohort studies in the primary meta-analysis. Although all included studies were of relatively high quality, this approach may limit causal interpretation. Sensitivity analysis excluding retrospective studies was not performed due to the limited number of included studies. In addition, this review was not prospectively registered, which may increase the risk of selective reporting bias.

Conclusions

In summary, oral PRO combined with intralesional injection of LAU shows superior efficacy, shorter treatment duration, and favorable safety compared with monotherapy, suggesting that this combined regimen may represent a potentially effective alternative strategy in selected clinical settings, although further high-quality international studies are required before broad clinical recommendations can be made. However, more RCTs are still needed to further validate our findings.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0235/rc

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0235/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0235/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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