Propranolol or atenolol for the management of infantile hemangioma: implications for long-term health

To the Editor: Since 2008, beta-blockers have been the first-line treatment for infantile hemangioma (IH). Because side effects of treatment during infancy may become visible later in life, the aim of this study is to describe the physical health and development of children (aged ≥6 years) treated for IH during infancy with either propranolol or atenolol. This 2-center cross-sectional study was part of a larger long-term follow-up project.1Hermans M.M. Rietman A.B. Schappin R. et al.Long-term neurocognitive functioning of children treated with propranolol or atenolol for infantile hemangioma.Eur J Pediatr. 2023; 182: 757-767Crossref PubMed Scopus (1) Google Scholar Between August 2019 and March 2020, all eligible children (n = 158) were asked to participate. Eligible children had IH, were aged ≥6 years, and had been treated during infancy (aged ≤1 year) for at least 6 months with either propranolol ≥2 mg/kg/day or atenolol ≥1 mg/kg/day, as per clinical practice guidelines. Children born preterm (<37 weeks of gestation), children with low birth weight (<2.5 SD for gestational age), and children with suspected genetic syndromes (eg, PHACE syndrome) were excluded from the study. All parent(s)/legal guardian(s) provided written consent to participate in this study. Consent for the publication of photographs or other identifiable material is not applicable. In total, 103 eligible children were included (65% inclusion), of which 35% had been treated with propranolol, and consequently, 65% with atenolol (Table I). The systolic and diastolic blood pressure values were significantly higher than reference values, adjusted for age, sex, and height (0.88 SD [P < .001] and 0.30 SD [P = .005], respectively).2Neuhauser H.K. Thamm M. Ellert U. Hense H.W. Rosario A.S. Blood pressure percentiles by age and height from nonoverweight children and adolescents in Germany.Pediatrics. 2011; 127: e978-e988Crossref PubMed Scopus (209) Google Scholar All other physical measurements did not differ from reference values or between the 2 beta-blocker groups, when corrected for multiple comparisons (Dunn-Sidak corrected alpha = 0.005).3Fredriks A.M. van Buuren S. Burgmeijer R.J.F. et al.Continuing positive secular growth change in the Netherlands 1955-1997.Pediatr Res. 2000; 47: 316-323Crossref PubMed Scopus (924) Google Scholar Most parents (99%) rated their child’s health as “good” or “very good.” The following health problems were reported: atopic dermatitis (n = 33 [30%]), asthma (n = 9 [8%]), and respiratory tract infections (n = 9 [8%]). Incidences of all parent-reported health problems did not differ from the general population (Dutch public health registry; Supplementary Material S1, available via Mendeley at https://doi.org/10.17632/45s3dnp2vr.1). No differences were found between both beta-blocker groups in any of the parent-reported health outcomes. No additional health concerns or developmental problems were identified during the systematic clinical examination of the children by the pediatrician (assessed characteristics in Supplementary Material S2, available via Mendeley at https://doi.org/10.17632/45s3dnp2vr.1).Table ICharacteristics of children treated with propranolol or atenolol for infantile hemangiomaDemographicsTotal group (n = 103)P valueװP values represent the comparison of physical measurements with reference values (mean, 0.0; SD, 1.0).Propranolol (n = 36)Atenolol (n = 67)P value¶P values represent comparisons between children treated with propranolol and children treated with atenolol.Child age, yNA.001 Median (IQR)7.5 (6.9-8.6)8.1 (7.4-9.1)7.2 (6.7-8.3) Range6.0-11.96.5-11.96.0-9.8Sex, n (%)NA>.99 Female83 (81)29 (81)54 (81)Cumulative dose, mg/kg, median (IQR)581 (390-906)NA1123 (719-1282)419 (311-621)<.001Average dose, mg/kg, median (IQR)1.2 (1.0-1.8)NA1.9 (1.8-2.0)1.0 (1.0-1.0)<.001Treatment duration (months), median (IQR)13.7 (11.0-19.5)NA18.6 (12.5-22.7)13.0 (10.4-15.9).001Age at treatment initiation, mos, median (IQR)3.5 (2.1-5.1)NA3.6 (2.2-5.3)3.4 (2.1-5.0).57Infantile hemangioma pattern, n (%)∗One propranolol-treated patient and 1 atenolol-treated patient had missing data for infantile hemangioma morphology, n = 101 (propranolol n = 34, atenolol n = 67).NA.17 Focal71 (69)22 (61)49 (73) Segmental11 (11)7 (19)4 (6) Indeterminate18 (18)6 (17)12 (18) Multifocal1 (1)0 (0)1 (2)Physical measurements†Alpha corrected for multiple comparisons (Dunn-Sidak alpha = 0.005).Height cm, median (IQR)128 (123-133)132 (125-139)127 (121-132) SDS‡Two atenolol-treated patients had missing height, weight, and head circumference scores, n = 101 (propranolol n = 36, atenolol n = 65)., mean (SD)−0.22 (0.96).02−0.13 (0.83)−0.27 (1.02).47Weight kg, median (IQR)26 (23-30)28 (23-34)25 (23-29) SDS,‡Two atenolol-treated patients had missing height, weight, and head circumference scores, n = 101 (propranolol n = 36, atenolol n = 65). mean (SD)–0.20 (1.02).07−0.16 (0.96)−0.22 (1.06).80Head circumference cm, median (IQR)52 (51-53)52 (51-53)53 (51-53) SDS,‡Two atenolol-treated patients had missing height, weight, and head circumference scores, n = 101 (propranolol n = 36, atenolol n = 65). mean (SD)0.30 (1.09).0080.12 (0.96)0.39 (1.16).23Systolic blood pressure mm Hg, median (IQR)107 (101-115)106 (98-111)108 (102-116) SDS,§Three atenolol-treated patients had missing blood pressure scores, n = 100 (propranolol n = 36, atenolol n = 64). mean (SD)0.88 (1.28)<.0010.53 (0.98)1.08 (1.39).04Diastolic blood pressure mm Hg, median (IQR)64 (59-68)61 (56-69)64 (60-68) SDS,§Three atenolol-treated patients had missing blood pressure scores, n = 100 (propranolol n = 36, atenolol n = 64). mean (SD)0.30 (1.05).0050.00 (1.10)0.47 (1.00).03Heart rate bpm, median (IQR)86 (78-96)NA82 (76-96)87 (80-96).46Parent-reported healthGeneral impression, n (%)NA.11 Very good50 (49)13 (36)37 (55) Good52 (50)23 (64)29 (43) Could be better1 (1)0 (0)1 (2) Not good0 (0)0 (0)0 (0)bpm, beats per minute; NA, not applicable; SDS, standard deviation score.∗ One propranolol-treated patient and 1 atenolol-treated patient had missing data for infantile hemangioma morphology, n = 101 (propranolol n = 34, atenolol n = 67).† Alpha corrected for multiple comparisons (Dunn-Sidak alpha = 0.005).‡ Two atenolol-treated patients had missing height, weight, and head circumference scores, n = 101 (propranolol n = 36, atenolol n = 65).§ Three atenolol-treated patients had missing blood pressure scores, n = 100 (propranolol n = 36, atenolol n = 64).װ P values represent the comparison of physical measurements with reference values (mean, 0.0; SD, 1.0).¶ P values represent comparisons between children treated with propranolol and children treated with atenolol. Open table in a new tab bpm, beats per minute; NA, not applicable; SDS, standard deviation score. Overall, this extensive clinical assessment of children (aged 6-12 years) previously treated with propranolol or atenolol for IH revealed no long-term health or developmental problems. Although we observed statistically higher blood pressure values (systolic blood pressure P < .001; diastolic blood pressure P = .005), these were not clinically relevant at the assessment age of the children. We hypothesized that higher blood pressure could be due to white coat hypertension, since we used a single measurement of blood pressure and lacked a control group of untreated children with equally severe IH. However, a permanent rise in blood pressure may cause cardiovascular problems later in life. Therefore, a longitudinal study on blood pressure in children treated with beta-blockers for IH, with multiple measurements at each visit, is required to support our findings. International collaboration using a registry could be undertaken to support this design and clarify the association between the decrease in blood pressure during treatment of IH with beta-blocker and a possible permanent rise in blood pressure later in life.4Raphael M.F. Breugem C.C. Vlasveld F.A. et al.Is cardiovascular evaluation necessary prior to and during beta-blocker therapy for infantile hemangiomas? A cohort study.J Am Acad Dermatol. 2015; 72: 465-472Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar This may also elucidate the potential harmful effects and allow unraveling of pathophysiologic mechanisms. Further exploration of alternative agents that induce tumor reduction without cardiovascular sequelae may be of interest.5Sasaki M. North P.E. Elsey J. et al.Propranolol exhibits activity against hemangiomas independent of beta blockade.NPJ Precis Oncol. 2019; 3: 27Crossref PubMed Scopus (28) Google Scholar None disclosed. The authors would like to thank Beth Morrel for editorial assistance.