Prospective Study of Infantile Hemangiomas: Demographic, Prenatal, and

Perinatal Characteristics
THE HEMANGIOMA INVESTIGATOR GROUP: ANITA N. HAGGSTROM, MD, BETH A. DROLET, MD, EULALIA BASELGA, MD,
SARAH L. CHAMLIN, MD, MARIA C. GARZON, MD, KIMBERLY A. HORII, MD, ANNE W. LUCKY, MD, ANTHONY J. MANCINI, MD,
DENISE W. METRY, MD, BRANDON NEWELL, MD, AMY J. NOPPER, MD, AND ILONA J. FRIEDEN, MD

Objectives To characterize demographic, prenatal, and perinatal features of patients with infantile hemangiomas and to
determine the importance of these factors in predicting rates of complication and treatment.
Study design We conducted a prospective study at 7 U.S. pediatric dermatology clinics. A consecutive sample of 1058
children, aged 12 years and younger, with infantile hemangiomas was enrolled between September 2002 and October 2003.
A standardized questionnaire was used to collect demographic, prenatal, perinatal, and hemangioma-specific data. National
Vital Statistic System Data (NVSS) was used to compare demographic variables and relevant rates of prenatal events.
Results In comparison with the 2002 United States National Vital Statistics System birth data, we found that infants with
hemangiomas were more likely to be female, white non-Hispanic, premature (P < .0001) and the product of a multiple
gestation (10.6% versus 3.1%; P < .001). Maternal age was significantly higher (P < .0001), and placenta previa (3.1%) and
pre-eclampsia (11.8%) were more common.
Conclusions Infants with hemangiomas are more likely to be female, white non-Hispanic, premature, and products of
multiple gestations. Prenatal associations include older maternal age, placenta previa, and pre-eclampsia. No demographic,
prenatal, and perinatal factors predicted higher rates of complications or need for
treatment. (J Pediatr 2007;150:291-4)

nfantile hemangiomas are the most common tumors of childhood, estimated to occur

I
From University Dermatology Associates,
in 3% to 10% of Caucasian infants.1 Previous case series and retrospective studies have Washington, DC; Department of Derma-
tology, Indiana University, Indianapolis, IN
suggested that female sex, prematurity, fair skin and history of chorionic villus (A.H.); Department of Dermatology, Med-
sampling may all be risk factors for the development of infantile hemangiomas.1-3 ical College of Wisconsin, Milwaukee, WI
(B.A.D.); Department of Dermatology,
Demographic, prenatal, and perinatal factors in patients with hemangiomas may provide Hospital de la Santa Creu I Sant Pau, Bar-
clues to pathogenesis. For example, the increased incidence of hemangiomas in premature celona, Spain (E.B.); Departments of Pedi-
atrics and Dermatology, Northwestern
infants has been hypothesized to be related to an early withdrawal of placental antian- University Feinberg School of Medicine,
giogenic factors.4 Other prenatal and perinatal risk factors, such as alcohol, tobacco, or Chicago, IL (S.C., A.J.M.); Department of
other drug use, have not been investigated previously, in part because hemangiomas are Dermatology, Columbia University; New
York, NY (M.C.G.); Section of Dermatol-
not present at birth and thus do not lend themselves to conventional birth defect registries. ogy, Childrens Mercy Hospital, Kansas City,
Our study was undertaken to better characterize these factors in patients with infantile KS (K.A.H., B.N., A.J.N.); Department of
Dermatology, Cincinnati Childrens Hospi-
hemangiomas and to determine whether specific patient characteristics predisposed pa- tal, University of Cincinnati, Cincinnati, OH
tients to complications, the need for treatment, or both. (A.W.L.); Department of Dermatology,
Baylor College of Medicine, Houston, TX
(D.W.M); and Department of Dermatol-
METHODS ogy, University of California, San Francisco,
CA (I.J.F.).
Study Design Supported by the Dermatology Foundation
and American Skin Association.
A prospective study of patients with infantile hemangiomas was initiated in Sep-
Submitted for publication Mar 15, 2006;
tember 2002 by members of the Hemangioma Investigator Group (HIG) at 7 U.S. last revision received Oct 4, 2006; accepted
academic pediatric dermatology clinics. One additional site in Spain enrolled patients, but Dec 4, 2006.
data from that site was not used in the analysis of demographic features because U.S. Reprint requests: Anita N. Haggstrom, MD,
Department of Dermatology, 550 N. Uni-
National Vital Statistics System (NVSS) birth data was used for comparison. The versity Blvd, Indianapolis, IN 46202. E-mail:
anitahaggstrom@yahoo.com.
0022-3476/$ - see front matter
Copyright 2007 Mosby Inc. All rights
HIG Hemangioma Investigator Group P1GF Platelet growth factor
reserved.
NVSS U.S. National Vital Statistics System
10.1016/j.jpeds.2006.12.003

291
institutional review board at each participating institution
approved the study protocol. Patients/guardians provided
signed informed consent at the time of enrollment.
Investigator Training
A manual outlining study procedures was distributed to
all study investigators before patient enrollment commenced.
The investigators attended 2 training sessions (in New Or-
leans, LA, in March 2002, and in Annapolis, MD, in May
2002), where study procedures and data collection forms were
reviewed and terminology and hemangioma subtype classifi-
cation criteria were defined.
Patients
Study investigators offered participation in the study to
eligible patients in their pediatric dermatology clinics. To be
eligible, patients had to be 12 years or younger at the time of
enrollment and have had 1 infantile hemangiomas in any
stage of evolution. Patients with other vascular malformations
in the absence of infantile hemangiomas were excluded. A
consecutive sample was enrolled by each investigator. A total
of 1096 patients, of whom 1058 were U.S. patients, were
enrolled in a 13-month period from September 2002 to
October 2003. Clinical follow-up continued until June 2004.
Main Outcome Measures
Using standardized computer-scannable forms, investi-
gators collected information about patient sex, ethnicity, pre-
maturity, birth weight, maternal/paternal age, prenatal testing
procedures and infertility treatments, placental abnormalities,
maternal smoking and drug use, and family history. Clinical
features of each hemangioma were recorded, and treatment
and complications incurred before and during the study pe-
riod were noted. The study period extended for a minimum of
8 months and as long as 23 months after enrollment to
maximally capture morbidities during hemangioma prolifer-
ation. In addition, a digital photograph of each patient was
obtained at the time of enrollment. Each patients intake
forms and digital images were identified with study code
number and stored securely to protect patient confidentiality.
Follow-up visits were scheduled according to clinical need.
Statistical Analysis
Data was sent to the National Outcomes Center, an
independent data management and statistical group, where
forms were scanned into a computer database. Information
was manually verified. The database was managed in Mi-
crosoft Access and SAS software programs. Digital images
were coded and sent to the University of California, San
Francisco, for storage. Data analysis was performed in con-
junction with the National Outcomes Center and the Uni-
versity of California, San Francisco biostatistics department.
The demographic data were compared to the NVSS birth
data for the year 2002.
292 Haggstrom et al
RESULTS
Group Characteristics
A total of 1058 U.S. patients were enrolled in a 1-year
period. Most (68%) of our patients were younger than 1 year.
Ninety percent of patients were 2 years or younger. A total of
750 patients (71%) were female, and 308 patients (29%) were
male. White, non-Hispanic patients comprised 68.9% of pa-
tients. African-American and Hispanic patients comprised
2.8% and 14.4% of patients, respectively. Data on gestational
age were available on 1047 patients, 214 (20.4%) of whom
were born prematurely (defined as younger than 37 weeks
gestational age), and 60 (5.7%) of whom were born very
prematurely (defined as younger than 32 weeks of age). The
mean birth weight was 3.1 kg (SD 0.8), and the median
birth weight was 3.2 kg. Of the 1058 patients in the group, 55
(5.2%) were very low birth weight (defined as 1500 g), 141
(13.3%) were low birth weight (defined as 1500-2499 g), and
862 (81.5%) were normal birth weight (defined as to
2500 g).
One hundred twelve infants (10.6%) were products of
multiple gestations. Most of these patients (99/112) were
twins; 13 were products of triplet gestation. Sixty-two infants
(54.8%) of multiple gestation were dizygotic, 23 infants
(20.4%) were monozygotic, 5 (4.4%) were mixed, and 22
(19.6%) were of unknown zygosity. A positive family history
of vascular anomalies in first-degree relatives (parents or sib-
lings) was reported in 348 patients (32.9%). These anomalies
included hemangiomas, port wine stains, medial telangiectatic
nevi, venous malformations, cutis marmorata telangiectatica
congenita, and arterial-venous malformations. Hemangiomas
were present in first-degree relatives of 130 patients (12.3%).
The maternal age of patients ranged from 14 to 49
years, with a mean maternal age of 29.9 years (SD 6.1) and
a median age of 30.0 years. The average maternal age for
infants who were the first-born was 28.2 years (95% CI,
27.7-28.8; SD, 6.3). Prenatal and perinatal data revealed a
higher than expected incidence of placenta previa and pre-
eclampia. Placenta previa was reported in 35 patients (3.3%),
and pre-eclampsia was reported in 122 patients (11.8%).
Chorionic villus sampling was performed in 37 patients
(3.5%) with normal results in all patients except 1. A history
of amniocentesis was obtained in 129 patients (12.4%), all
who had normal results.
No maternal chronic or prenatal illness was over-rep-
resented in our study population. Alcohol and tobacco use
were not increased compared with NVSS data. There was no
increased usage of other drugs, including prescription drugs
and illicit drugs.
Complications were noted in 299 patients (28.3%) be-
fore enrollment; 255 patients (24.1%) experienced complica-
tions during the study period. During the study period, ul-
ceration was the most common complication, noted in 168
patients (16.0%); threat to vision (59, 5.6%), airway obstruc-
tion (15, 1.4%), auditory canal obstruction (6, 0.6%), and
cardiac compromise (4, 0.4%) were seen less commonly.
The Journal of Pediatrics March 2007
 Treatment was administered in 269 patients (25%) be-
fore enrollment, and 402 (38%) during the study period.
During the study period, patients received systemic steroids
(130, 12.3%), intralesional steroids (43, 4.1%), topical steroids
(103, 9.8%), wound care for ulceration (145, 13.7%), oral
antibiotics (21, 2.0%), pulsed dye laser (84, 8.0%), and exci-
sional surgery (60, 5.7%). Rarely, interferon (1 patient) and
vincristine (3 patients) were used. Some patients received 1
mode of therapy.
National Vital Statistic Comparison
Sex, ethnicity, gestational age, birth weight, maternal
age, twinning, and rate of placenta previa were compared with
NVSS data from 2002. These data, which are taken from
birth certificates, are a comprehensive data base that captures
vital statistics on virtually all births in the United States each
year and are reported by the National Center for Health
Statistics (http://www.cdc.gov/nchs/nvss.htm).
Seven hundred fifty patients (71%) were female and 308
(29%) were male, which was significantly different than
NVSS population data (P .0001). Distribution among
ethnic groups differed significantly from NVSS population
data (P .0001); there was a higher proportion of white,
non-Hispanic patients and a lower proportion of African-
American and Hispanic patients in our group. Study patients
were more likely to be preterm (37 weeks) and very preterm
(32 weeks; P .0001). They were also more likely to be of
low birth weight or very low birth weight (P .0001) The
mean maternal age for first-born infants in the study group
(28.2 years) was significantly higher than the mean maternal
age for first-born children in the NVSS data (25.1 years; P
.0001). Similarly, overall maternal age differed significantly
from the general population, with a higher proportion of
mothers who were 30 years and older; 55.1% of our group had
mothers who were 30 years old or older, compared with
37.5% of the general population (P .0001). One hundred
twelve infants (10.6%) were products of multiple gestations,
compared with 3.1% in the NVSS report (P .001). Placenta
previa was reported in 35 patients (3.1%) in the study group,
compared with 0.41% in the NVSS population data.
The role of demographic, prenatal, and perinatal
factors in predicting complications and the need for treat-
ment was examined by using regression analysis. Neither
sex nor ethnicity predisposed patients to experience com-
plications or receive treatment. Fifty percent of Hispanic
patients received some form of treatment, compared with
46.9% of white non-Hispanic patients and 41.4% of Afri-
can-American patients, reflecting a marginally significant
difference (P .05). Subanalysis by type of treatment
revealed that 32.3% and 31.1% of Hispanic and white
non-Hispanic patients, respectively, received systemic
therapy, compared with only 24.1% of African-American
patients, but the small number of African-American in-
fants precludes robust analysis of this trend. No correlation
between patient birthweight and the presence of compli-
cations or need for treatment was seen. Premature gesta-
Prospective Study of Infantile Hemangiomas: Demographic, Prenatal, and Perinatal Characteristics
tional age, multiple gestation, placenta previa, and pre-
eclampsia were not predictive of a higher likelihood of
experiencing complications or receiving treatment.
DISCUSSION
Identifying patient characteristics associated with the
development of a birth defect or birthmark has traditionally
been performed by using formal birth defect registries. Birth
defect registries are tools used to identify demographic, pre-
natal, and perinatal characteristics and potential risk factors
that can have both clinical and scientific implications. Unfor-
tunately, hemangiomas, though considered a type of birth-
mark have not been included in such registries because their
presence at birth is subtle at best, with diagnostic clinical
characteristics usually appearing within the first few days to
weeks of life. In this large group, we systematically collected
demographic, prenatal, perinatal, and clinical data on infants
with hemangiomas to identify important trends.
Demographic Factors
Previously recognized risk factors for the development
of infantile hemangiomas, including female sex and fair skin,
were confirmed in our study. The female-to-male ratio was
2.4:1.0, which is similar to previously published ratios that
ranged from 1.4:1.0 to 3:1.4,5 The reason for female predom-
inance is unclear. Kindred studies have suggested a subset of
hemangiomas may be heritable and linked to genes on chro-
mosome 56; no genetic mutations on the X chromosome have
been reported. Historically, some have argued that parents
perceive hemangiomas to pose a greater cosmetic concern
when females are affected, and therefore they are over-repre-
sented in dermatology clinics.
The racial/ethnic distribution is significantly different
in our study group compared with the general population
data. There was a higher proportion of white non-Hispanic
patients and a lower proportion of black and Hispanic pa-
tients. We recognize a limitation of our study is that our
patients were enrolled from pediatric dermatology centers
(referral bias); patients enrolled from a general pediatric prac-
tice would have more been more generalizable. Future studies
with a control group are certainly warranted to confirm these
observations.
Prenatal and Perinatal Factors
Prematurity and low birth weight were significantly
more common in our study group compared with NVSS data.
Our data was obtained through parental recall, introducing
the potential for some recall bias. Twenty percent of infants
were premature (defined as younger than 37 weeks gestational
age) and 6% of patients were very premature (defined as
younger than 32 weeks of age). It is unclear whether the
presence of hemangioma places infants at risk for prematurity
or vice versa. It is possible that an imbalance of angiogenic
control mechanisms may result from prematurely removing a
developing fetus from maternal and placental influences.
293
 Chorionic villus sampling during pregnancy has also
been suggested to result in a higher risk of hemangioma
development.2,7 A history of chorionic villus sampling was
found in only a small minority (3.5%) of our patients. On the
basis of our study, chorionic villus sampling does not appear
to play a significant role in the formation of most hemangi-
omas.
Advanced maternal age was found more frequently in
our group compared with the general population data. The
rate of pre-eclampsia (11.6%) was surprisingly high as well.
Because advanced maternal age and multiple gestation are
associated with a higher incidence of pregnancy complications
including preterm birth, low birth weight, and pre-eclampsia,
we recognize these as possible confounding factors. The
pathogenesis of pre-eclampsia is incompletely understood,
but certain placental growth factors may play a role in its
development. Alterations in platelet growth factor (PlGF)
and soluble fms-like tyrosine kinase 1 are more pronounced in
patients with pre-eclampsia.8 PlGF is significantly lower at 13
to 16 weeks gestational age in patients in whom pre-eclampsia
later develops.8 PlGF was recently shown by means of im-
munohistochemical staining to be expressed in involuting
hemangiomas, giving further support to the notion that hem-
angiomas and placenta are under similar angiogenic control
mechanisms.9 Levels of placental proteins, such as human
placental lactogen, differ in multiple gestation pregnancies
compared to singleton pregnancies.10 Our group had a dis-
proportionate number of infants of multiple gestation
(10.6%). Placental abnormalities were not diagnosed in most
of our patients. Further studies are needed to understand the
role of angiogenic growth factors in relation to hemangioma
and placental vessels.
Family History
Rigorous studies of family histories in patients with
hemangiomas have not been previously reported. One third of
the patients in our group had a first-degree relative with a
vascular anomaly, and 12% had a first-degree relative with a
hemangioma. The percent of patients with a family history of
hemangiomas is only slightly higher than the cited incidence
in the general population (3%-12%), but some of the studies
used to cite the incidence of hemangiomas include other
vascular birthmarks such as vascular malformations and nevus
simplex in their reports of hemangiomas. Other studies have
relied on parental recall and primary care physicians for di-
agnosis, which may have contributed to inaccuracies. A study
294 Haggstrom et al
of 3 kindreds with familial hemangioma revealed linkage to
chromosome 5q31-33,11 with various vascular growth factors
suspected to be responsible. Although this likely represents
only a small percentage of patients with hemangiomas, the
role of genetics as a co-factor increasing the expression of
hemangiomas deserves further study.
On the basis of the results of this study, a profile for
patients with infantile hemangiomas can be constructed.
Hemangiomas more commonly occur in fair-skinned, prema-
ture, female infants who are more likely to be born as a
product of multiple gestation. Compared with the general
population, their mothers are of higher maternal age, have a
higher incidence of pre-eclampsia and placenta previa, and are
more likely to have had multiple gestation pregnancies. Ad-
ditional controlled studies are needed to further define risk
factors for hemangiomas and to understand the relationship
between potentially confounding factors.
The authors gratefully acknowledge our colleagues and staff in the
Vascular Anomalies Centers at each institution for their hard
work and caring for our patients, and Alan Bostrom, Charles
McCulloch, and the National Outcomes Center for their database
and statistical expertise. We would like to acknowledge Dr Nancy
Esterly for all her support and guidance.
REFERENCES
1. Jacobs AH, Walton RG. The incidence of birthmarks in the neonate. Pediatrics
1976;58:218-22.
2. Burton BK, Schulz CJ, Angle B, Burd LI. An increased incidence of haemangio-
mas in infants born following chorionic villus sampling (CVS). Prenat Diagn
1995;15:209-14.
3. Amir J, Metzker A, Krikler R, Reisner SH. Strawberry hemangioma in preterm
infants. Pediatr Dermatol 1986;3:331-2.
4. Bree AF, Siegfried E, Sotelo-Avila C, Nahass G. Infantile hemangiomas: specu-
lation on placental trophoblastic origin. Arch Dermatol 2001;137:573-7.
5. Finn MC, Glowacki J, Mulliken JB. Congenital vascular lesions: clinical applica-
tion of a new classification. J Pediatr Surg 1983;18:894-900.
6. Berg JN, Walter JW, Thisanagayam U, Evans M, Blei F, Waner M. et al.
Evidence for loss of heterozygosity of 5q in sporadic haemangiomas: are somatic
mutations involved in haemangioma formation? J Clin Pathol 2001;54:249-52.
7. Kaplan P, Normandin J Jr, Wilson GN, Plauchu H, Lippman A, Vekemans M.
Malformations and minor anomalies in children whose mothers had prenatal diagnosis:
comparison between CVS and amniocentesis. Am J Med Genet 1990;37:366-70.
8. Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF, et al. Circulating
angiogenic factors and the risk of preeclampsia. N Engl J Med 2004;12;350:672-83.
9. Frischer JS, Huang J, Serur A, Kadenhe A, Yamashiro DJ, Kandel JJ. Biomolec-
ular markers and involution of hemangiomas. J Pediatr Surg 2004;39:400-4.
10. Westergaard JG, Teisner B, Hau J, Grudzinkas JG. Placental protein and hor-
mone measurements in twin pregnancy. Br J Obstet Gynaecol 1985;92:72-6.
11. Walter JW, Blei F, Anderson JL, Orlow SJ, Speer MC, Marchuk DA. Genetic
mapping of a novel familial form of infantile hemangioma. Am J Med Genet
1999;82:77-83.
The Journal of Pediatrics March 2007