Early Growth of Infantile Hemangiomas: What Parents’Photographs Tell Us
WHAT’S KNOWN ON THIS SUBJECT: Infantile hemangiomas havea period of rapid growth in early infancy. Most hemangiomagrowth is completed by 5 months of age, but the majority ofpatients are not seen by a specialist until after the growth phaseis complete.
WHAT THIS STUDY ADDS: The most rapid hemangioma growth isbetween 1 and 2 months of life, much earlier than previouslybelieved. Patients with high-risk hemangiomas should be followedclosely, and treatment initiation should be considered before orduring the most rapid growth phase.
abstractBACKGROUND AND OBJECTIVES: Infantile hemangiomas (IH) are rec-ognized as growing rapidly during the first months of life, but detailsof early growth before 3 months of age have not been well-characterized. Our goal was to study early IH growth by usingparental photographs of infant children with facial IHs to betterunderstand early hemangioma growth, with the aim of improvingguidance for physicians and parents of infants with high-risk IH.
METHODS: Serial images of 30 infants showing IH at intervals of 1 to 2weeks up to 6 months were analyzed for characteristics of color, thick-ness, and distortion of anatomic landmarks. The presence or absenceof an IH precursor at birth was noted. Mean scores per age intervalwere compiled. Results were analyzed by using signed rank test. Anassessment of “optimal time for referral” was made.
RESULTS: IH growth was nonlinear; most rapid growth occurred be-tween 5.5 and 7.5 weeks of age. The mean “optimal age for referral”was 4 weeks of age. Hemangioma precursors were present at birth in65% of patients.
CONCLUSIONS: The most rapid hemangioma growth occurs before 8weeks of age, much earlier than previously appreciated. Specialty eval-uation and initiation of treatment, however, typically occur after theage of most rapid growth. Our findings suggest a need for a paradigmshift in the timing of referral and initiation of treatment of high-risk IHso that therapy can be initiated before or early in the course of mostrapid growth, rather than after it is already completed. Pediatrics2012;130:e314–e320
AUTHORS: Megha M. Tollefson, MDa and Ilona J. Frieden,MDb
aDepartments of Dermatology and Pediatric and AdolescentMedicine, Mayo Clinic, Rochester, Minnesota; and bDivision ofPediatric Dermatology, University of California, San Francisco,California
KEY WORDSinfantile hemangioma, strawberry hemangioma, high-risk,referral practice
Drs Tollefson and Frieden made substantial contributions tostudy conception and design, acquisition of data, and analysisand interpretation of data; were involved in drafting andrevising the article for important intellectual content; and havegiven final approval of the version to be published.
This study was presented as a poster at the Society for PediatricDermatology Annual Meeting, Baltimore, MD, July 2011.
Dr Frieden is the Chair of the Data Safety ManagementCommittee of the HEMANGIOL study.
www.pediatrics.org/cgi/doi/10.1542/peds.2011-3683
doi:10.1542/peds.2011-3683
Accepted for publication Apr 16, 2012
Address correspondence to Megha M. Tollefson, MD, Mayo Clinic,200 First Street SW, Rochester, MN 55905. E-mail: [email protected]
Infantile hemangiomas (IH) are themostcommon tumor of infancy, estimated tooccur in ∼4% of white infants.1 Thenatural history of IH is typically of rapidproliferation followed by slower in-volution. Although most IH do not causeserious morbidities, a significant minor-ity can cause permanent disfigurementor functional compromise, particularlyif located on the face or involving vitalorgans.2 In addition, quality of life maybe significantly affected for both pa-rents and affected individuals, includingfeelings of loss of control, anxiety, guilt,grief, and concern for parents and lowself-esteem and bullying by peers forchildren with visible disfigurement.1 Forthose hemangiomas needing treatment,the ideal time to treat is before or assoon as evidence of permanent ana-tomic distortion or medical sequelaedevelop.
The general outlines of hemangiomagrowth have long been appreciated. IHgenerally proliferate during the firstyear of life, with most growth beingcompleted by age 6 to 9 months.3
A recent prospective cohort study ofmore than 1000 infants found growthoccurring even earlier: 80% of hem-angioma growth is completed by age3 months, and 80% of hemangiomashave completed growth by age 5months.4 The mean age of presentationto a pediatric dermatologist, however,was 5 months of age, a time that mostgrowth and many complications ofhemangiomas may have already oc-curred. These findings led to our desireto study hemangioma growth before3 months of age, both to better de-lineate growth characteristics and todetermine whether growth appeared tobe linear or nonlinear. Understandingearly hemangioma growth could help todetermine optimal timing of reevalua-tion in neonates and young infants withhemangiomas, as well as when referralor initiation of treatment in infants withhigh-risk hemangiomas (those deemed
to be at higher risk for scarring or othercomplications) should be considered. Tostudy early hemangioma growth, weused parents’ photographs from birththrough the first few months of life.
METHODS
Institutional reviewboardapprovalwasobtained for this study. Patients wererecruited through the University ofCalifornia at San Francisco pediatricdermatology clinics and the NationalOrganization of Vascular Anomalies,a patient advocacy group, betweenJanuary 2009 and March 2011. Parentswere asked to fill out a short parentalquestionnaire and submit photographsof their children that demonstratedtheir infantile hemangiomas over time.Photographs taken approximately ev-ery 2 weeks apart during the first 2.5to 6 months of life were requested.Seventy-two families expressed inter-est in the study. Of these, 36 parentsreturned materials including a con-sent form, a short parental question-naire, and photographs via compactdisc, secure E-mail, or hard copy. Six ofthese were excluded because of in-complete materials, inadequate pho-tograph spacing, or photographs ofpoor quality.
The remaining 30 patients met inclu-sion criteria. Hemangiomas, if not seenpersonally, were confirmed by the au-thors to be infantile hemangiomas andclassified as either segmental or lo-calized and as superficial, mixed, ordeep. Demographic data as supplied bythe parents on questionnaire werenoted. Medical records were not re-viewed. Photographs were arrangedsequentially in ∼2-week intervals (Figs1 and 2), with some intervals beingslightly longer or shorter depending onthe images available. Dates and ageswere removed from the arrangedphotographs. At least 2 months lapsedin each of the cases from the time ofarrangement of the photographs to
review by MMT and IJF. Both MMT andIJF reviewed photographs of patientsnot included in the study before re-viewing study cases. From this jointreview, consistency in review method-ology and interreviewer reliability wasestablished.
Each photograph was given a score foreach of 3 characteristics: color, thick-ness, and presence of local anatomicdistortion. Intensity of color was ratedfrom1 through 4 (1 = imperceptible, 2 =barely perceptible, 3 = red, 4 = brightred), thickness of tumorwas rated from1 through 4 (1 = flat/none, 2 = slightelevation, 3 = moderate elevation, 4 =marked thickness), and distortion oflocal anatomic landmarks was ratedfrom 1 through 3 (1 = no, 2 = yes,minimal, and 3 = yes,marked). For eachpatient, the 2 consecutive photographsthat demonstrated the greatest dif-ference in hemangioma volumetricgrowth were determined indepen-dently by each reviewer (MMT andIJF). A composite score consisting ofa tally of each of the 3 measuredcharacteristics was calculated foreach patient.
RESULTS
Demographic Data
Thirty patients met criteria for in-clusion in this study. Twenty-two (73%)were female and 8 (27%) were male.Nineteen (63%) had localized heman-giomas, and 11 (37%) had segmental IH.The majority of patients had primarilysuperficial hemangiomas (24 patients,80%), 1 (3%) had a primarily deephemangioma, and 5 (17%) patients hadmixed hemangiomas. Five (17%) of the30 patients were premature (,37weeks’ gestation); the remainder wereborn at term. All but 1 subject (a twin)were products of a single gestation.Each patient had 1 hemangioma thatwas studied. Of these, 28 (93%) werelocated on the face, with 2 located onthe scalp and neck.
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Hemangioma Precursors andGrowth Characteristics
Patient photographs were analyzed upto a mean of 19.1 weeks (median 20.8,range 9.4–24.9 weeks, 95% confidenceinterval [CI] 17.4–21.2). Only 2 patientshad their last photograph available atan age of ,12 weeks. Twenty-six (17localized, 9 segmental) of 30 patientshad photographs available from thefirst day of life, and of these, 17 (65%)had evidence of a cutaneous precursorlesion in their initial photograph shortlyafter birth including 10 of 17 (59%)patients with localized hemangiomasand 7 of 9 (78%) patients with seg-mental hemangiomas.
Differences in color, thickness, and an-atomicdistortionwereall demonstratedwhen comparing changes during thefirst 8 weeks of life versus age 8 weeksand older (P , .05) (Fig 3). The rate
of change in color was deemed to befaster than rates of change in thicknessand anatomic distortion, but this didnot reach statistical significance. Themost rapid rate of infantile hemangi-oma growth, as assessed by compos-ite score, was determined to be fromday 1 of life to 8 weeks of age (P, .001)versus 8 weeks and beyond (Figs 4and 5).
To determine whether growth was lin-ear or nonlinear, that is, if the rateof change in growth was the samethroughout the growth period or if therewas a critical period of nonlinear ac-celeratedgrowth,wecomparedchangesin interval photographs. The averageinterval length was 2.2 weeks (median2.1 weeks, 95% CI 2.0–2.7). The intervalswhen greatest change (ie, fastest rateof growth) appeared to be taking placewere determined. Twenty-nine of 30
patients (97%) were judged to havenonlinear growth, with the time periodof greatest growth being between 5.5weeks (95% CI 4.6–6.3) and 7.5 weeks(95% CI 6.7–8.4, median 4.3–6.8). Only 1patient (3%) was judged to have aneven rate of growth throughout. Wealso determined, via subjective assess-ment, the point in time when we wouldhave preferred to first see the patient inconsultation before the time of greatestproliferation such that if treatment wasneeded, it would have the greatest po-tential impact. The average age at whichreferral was desired using this “retro-spectoscope” was at a mean of 4.0weeks (median 3.6, 95% CI 2.7–4.9).
Treatment
Twenty (67%)of the 30patients receivedsome form of treatment. Eight (40%) ofthese received 2 modalities of treat-ment, and 12 (60%) received 1 type oftreatment. Treatment modalities usedincluded topical and/or intralesionalsteroids (9 patients), oral propranolol(6), oral steroids (5), surgery or pulseddye laser (5), and topical timolol (3).Treatment was initiated at a mean of11.4 weeks (median 10.7, 95% CI 8.8–13.6), and only 6 patients receivedtreatment before 9 weeks of life. Ofthese 6 patients, 2 were treated withtopical steroids, 2 with pulsed dye la-ser, 1 with oral steroids, and 1 with oralpropranolol. Four of these 6 patientswent on to receive a different modalityof treatment at a later age: 2 oral pro-pranolol, 1 topical timolol, and 1 surgi-cal debulking. Removing the 6 patientswho received early treatment (before 9weeks of life) resulted in the same re-sults of rate of infantile hemangiomagrowth as assessed by composite score,again determined to be from day 1 of lifeto 8 weeks of age (P , .005) versus8 weeks and beyond (Fig 6). The time ofgreatest growth for these 24 patientswas between 5.6 weeks (95% CI 3.2–8.0)and 8.1 weeks (95% CI 4.6–11.5). Sub-group analysis of the 10 patients who
FIGURE 1A, Evolution of an exophytic localized hemangioma frombirth to 3months. B, Same patient at 2.5 monthsandC,3 years .Despite initiationof systemic therapywith steroidsat2.5months, followedbypropranolol,residual telangiectasia and fibrofatty skin changes persisted, emphasizing that early growth, especiallyof superficial hemangiomas, can lead to irreversible skin changes.
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were not treated confirmed that thefastest rate of growth as measuredby composite score was during the first8 weeks of life (P , .05). The time ofgreatest growth for untreated patientswas between 6.4 (95%CI 4.7–8.0) and 8.5weeks (95% CI 6.4–10.7).
DISCUSSION
Growth is an essential, defining featureof infantile hemangiomas. Although thegeneral outlines of the natural historyof IH are understood, details of earlygrowthhavenotbeenwell characterized.
The primary goal of this study was tocharacterize the period of early growthas determined by color, thickness, andanatomic distortion. In this study, weused the unique method of examiningparents’ photographs of their childrento characterize hemangioma growth inearly infancy and to define a period ofmaximum growth velocity.
Our patients had photographs availableup to the mean age of 19.1 weeks, bywhich time, as recently discovered, IHgrowth is largely completed.4 We foundthat, at least in the case of superficialhemangiomas, the majority of thisgrowth occurs before 8 weeks of age.There also appears to be a period ofaccelerated growth velocity between5.5 to 7.5 weeks, suggesting that hem-angioma growth is nonlinear duringthat time period. When patients whowere treated before age 9 weeks wereexcluded, findings were found to benearly identical, likely reflecting therelatively small number of patientswho were treated that early and thevariety of treatment modalities used,which may have resulted in variableresponses. Additionally, when untreatedpatients were analyzed separately thefindings were quite similar.
A detailed description of early heman-gioma growth has not been previouslystudied. Our findings suggest the needfor a paradigm shift in management:early hemangiomas need to be recog-nized more promptly, and infants withhigh-risk hemangiomas (Table 1) shouldbe watched closely (eg, seen weekly orbiweekly), have treatment initiated, orbe referred to specialists promptly, ide-ally by 4 weeks of age, because a pe-riod of accelerated growth occursbetween 5.5 and 7.5 weeks of life. Theage of 4 weeks was also suggested inour determination of the ideal ageat which an infant might initially beseen for consultative care using aretrospectospcope. On the receiving end,specialists must have mechanisms in
FIGURE 2A, Evolution of a localized hemangioma frombirth to 4months of age. B, Same patient at 3months and C,1 year. Despite initiation of systemic therapy with propranolol at 3 months, residual telangiectasia andfibrofatty skin changes ultimately requiring surgical intervention had already occurred.
FIGURE 3Rate of growth for individual characteristics of color, thickness, and anatomic distortion.
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place for urgent evaluation of infantswith high-risk IH, or at least a triagesystem for reviewing clinical photo-graphs to determine optimal timing ofconsultation and management.
Several studies have shown that pa-tients with IH are generally not seen bya subspecialist until 3 to 5 months ofage.4–6 In our cohort, treatment wasfirst initiated at an average of 11.4weeks, with only 20% of patients re-ceiving treatment before 9 weeks. Thus,nearly all patients had initiation oftreatment after the period of maximalgrowth was over. Although there havenot been studies to date proving that
treatment initiated earlier is betterthan later, both the study by Changet al4 and our findings strongly supportthe idea that significant growth of hem-angiomas and resultant skin changesoccur early in the course of disease.Effective treatments to prevent the skinchanges that occur during this rapidgrowth phase are thus likely to helpprevent irrevocable skin changes.
Whichpatients requireactive treatmentis still a matter of controversy. Infantilehemangiomas do involute spontane-ously, but in addition to uncommon butwell-definedmedicalmorbidities,manyleave residual skin changes. Bauland
et al7 have recently reported on thelong-term follow-up of nearly 100 chil-dren with untreated infantile heman-giomas seen in a multidisciplinaryreferral center in the Netherlands. Theyfound residual skin changes in 69% ofcases, with superficial nodular heman-giomas being much more likely to leaveresidual skin changes (74%) than deephemangiomas (25%). Although residualskin changes in this cohort are un-doubtedly higher than in patients seenonly by primary care physicians be-cause of an ascertainment bias, suchoutcomes are not rare. A large cohortstudy found that 24% of patients withhemangiomas experienced $1 compli-cations, and 38% received some form oftreatment.8 In our much smaller study,we had an even higher rate of treatmentwith two-thirds of these infants re-ceiving $1 forms of treatment. Thisdifference is at least in part due to thefact that nearly all hemangiomas werelocated on the face, a site farmore likelyto be treated than hemangiomas lo-cated elsewhere on the body.8 In addi-tion, the use of b-blockers (both topicaland systemic) as a new modality oftreatment also likely contributed toa higher rate of treatment.
As newer, more effective treatmentsbecome available,9,10 earlier referral
and treatment of high-risk hemangio-
mas may have an even greater poten-
tial for preventing hemangioma-related
complications and permanent irre-
versible skin changes or complications.
Similarly, when designing clinical trials
studying the efficacy of such medica-tions, it is vital that infants be enrolledbefore the phase of greatest nonlineargrowth so that the efficacy and poten-tial impact of the medications can beappropriately evaluated. Although oralpropranolol can be efficacious beyondthe proliferative phase,11 irreversibleskin changesmay have already occurred(Figs 1C and 2C), again emphasizing theimportance of early treatment whenever
FIGURE 4Rapid rate of growth through week 8 for all 3 parameters.
FIGURE 5Composite score showing highest rate of growth until week 8.
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possible.12,13 It is also important to notethat many hemangiomas will displayrebound growth after discontinuation ofmedications such as propranolol. Thus,although early treatment before theperiod of greatest proliferation is vital,treatments may need to be continuedwell beyond the period of most rapidgrowth to prevent rebound growth.
Our cohort was relatively small, but itsdemographicfindings, including femalegender and rates of prematurity, weresimilar to those of previously describedlarge cohorts of patients with infantilehemangiomas.14–16 More had segmen-tal hemangiomas (37%) than are typi-cally seen,8,14 a difference that mostlikely reflects an ascertainment bias,
because parents willing to participatein the study were more likely to havechildren at the more severe end ofclinical spectrum. This disproportionatenumber of segmental hemangiomasmay actually have led to an underes-timation of early growth because seg-mental hemangiomas grow for a meanof 1 month longer than their localizedcounterparts.4 Although our samplesize was not large enough to separatethese 2 groups for this analysis, thefinding of accelerated early growth islikely to be generalizable to both local-ized and segmental hemangiomas.
A secondary goal of this study wasto determine the prevalence of heman-gioma precursors evident at birth.A classic teaching is that most heman-giomas are absent at birth and appearrapidly thereafter.3 Previous retrospec-tive reviews found hemangioma pre-cursors to be present at or near the timeof birth in 36% to 48% of patients.14,17
Our study, the first to examine parents’pictures from the first day of life ratherthan relying on parental memory, foundthat 65% of patients had a visiblehemangioma precursor noted on thefirst day of life, a rate far higher thanprevious reports but likely to be moreaccurate because of the objectivephotographic confirmation. Some pre-cursors, although clearly visible inretrospect, might not have been easilydistinguished from other marks inthe immediate newborn period, butnearly all became obvious within 1 or2 weeks as other postpartum changessubsided. An increased awarenessof hemangioma precursors would behelpful in identifying infants to beseen promptly, particularly in high-risk locations and for larger precursorlesions suggesting segmental distribu-tion (Table 1).
Our study has certain limitations. First,it is a fairly small study sample becauseparticipation did require some amountof effort on the part of busy parents.
FIGURE 6Composite score showing highest rate of growth until week 8 for all patients and for all patients nottreated before 9 weeks of life.
TABLE 1 High-risk Hemangiomas
Clinical Scenario Potential Sequelae
Potentially disfiguring sites Permanent distortion of anatomic landmarks,including fibrofatty residua, anetoderma,textural changes, and hyperpigmentation
Nasal tip Residual telangiectasiasPerioral High risk of ulceration, especially
perioral and neck fold hemangiomasGlabellaEarEyebrowCentral facial location, particularly
those medial to the outer canthi and.0.5 cm in size
Superficial thick or exophytic hemangiomas,in areas not easily covered by clothing
Periocular hemangiomas Astigmatism or visual axis obstructionpotentially resulting in permanent amblyopia
coarctation of aorta, ocular, and other anomalies)Ulceration, scarring, residual skin changes
Lumbosacral or perineal hemangiomas High risk of ulcerationTethered spinal cordLipomyelomeningoceleGenitourinary abnormalities
Airway hemangioma 6 “beard area”skin hemangiomas
Life-threatening airway obstruction, usuallybetween 4–6 wk of life
Multifocal ($5) infantile hemangiomas Hepatic hemangiomas: can be asymptomatic orresult in abdominal compartment syndrome,heart failure, and hypothyroidism
PHACE, Posterior fossa anomalies, Hemangioma, Arterial lesions, Cardiac abnormalities/coarctation of the aorta, Eyeabnormalities.
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Because of the limited of number ofparticipants, we were unable to ana-lyze subsets of patients per type andlocation of hemangioma or by treat-ment modality. Additionally, althoughhemangiomas at all sites were en-couraged, our patients had only headand neck hemangiomas because fre-quent photos of infants’ faces are farmore likely to be taken than of otherbody sites. Thus, using parental pho-tographs also limited our ability tostudy early growth characteristicsof hemangiomas at other body sites,particularly those involving the lowerhalf of the body, where less vigorousgrowth is often found.18 In addition wewere unable to collect precise volu-metric measurements of hemangio-mas, which might have given more
quantitative results regarding hem-angioma growth. Perhaps the mostimportant limitation is that the ma-jority of our patients had primarilysuperficial hemangiomas, and thegrowth characteristics found may beless generalizable to deeper heman-giomas, which can arise later in lifeand often grow for longer.5 Twentypercent of our cohort, however, didhave mixed type or primarily deephemangiomas, which could poten-tially have delayed the period ofmaximum growth calculated in ourstudy. Our sample size was not largeenough to separate the growth char-acteristics of superficial versus deephemangiomas, although clearly thefindings apply best to those with su-perficial skin involvement.
CONCLUSIONS
We have demonstrated via parentalphotographs that rapid, acceleratedgrowth of infantile hemangiomas mostoften occurs before 8weeksof age, oftenpeaking between 5.5 and 7.5 weeks. Thisfinding suggests that, at a minimum,frequent evaluation either in person orvia photographs, should be undertakenfor hemangiomas at high-risk sitesand that early initiation of treatment orspecialty referral should be stronglyconsidered in such cases with the goalof preventing permanent skin changesand growth-related complications.
ACKNOWLEDGMENTWe thank Karla Hall of the National Or-ganization of Vascular Anomalies.
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DOI: 10.1542/peds.2011-3683 originally published online July 23, 2012; 2012;130;e314Pediatrics
Megha M. Tollefson and Ilona J. FriedenEarly Growth of Infantile Hemangiomas: What Parents' Photographs Tell Us
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