doi: 10.1111/j.1365-3016.2008.00983.x
125
The epidemiology of neuroblastoma: a review
Julia E. Hecka, Beate Ritza,b, Rayjean J. Hunga,c, Mia Hashibea and Paolo Boffettaa
a
International Agency for Research on Cancer, Lyon, France, bDepartments of Epidemiology, Environmental Health Sciences, and Neurology,
University of California, Los Angeles, CA, and cSamuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada
Summary
Correspondence:
Dr Paolo Boffetta,
International Agency for
Research on Cancer, 150
cours Albert Thomas, 69008
Lyon, France.
E-mail: boffetta@iarc.fr
Heck JE, Ritz B, Hung RJ, Hashibe M, Boffetta P. The epidemiology of neuroblastoma:
a review. Paediatric and Perinatal Epidemiology 2009; 23: 125–143.
Neuroblastoma is the most common tumour in children less than 1 year of age. The
goal of this review was to summarise the existing epidemiological research on risk
factors for neuroblastoma.
A comprehensive search of the literature was undertaken using PubMed for epidemiological studies on neuroblastoma risk factors. We ascertained 47 articles which
examined the risk factors. Ten studies employed population-based case-control
designs; six were hospital-based case-control studies; two were cohort studies; and five
employed ecological designs. Studies ranged in size from 42 to 538 cases. Three studies
showed evidence of an increased risk of disease with use of alcohol during pregnancy
(OR range 1.1, 12.0). Protective effects were seen with maternal vitamin intake during
pregnancy (OR range 0.5, 0.7) in two studies, while risk of disease increased with
maternal intake of diuretics (OR range 1.2, 5.8) in three studies. Three studies reported
a decrease in risk for children with a history of allergic disease prior to neuroblastoma
diagnosis (OR range 0.2, 0.4). The rarity of neuroblastoma makes this disease particularly challenging to study epidemiologically. We review the methodological limitations
of prior research and make suggestions for further areas of study.
Keywords: neuroblastoma, risk factors, maternal alcohol consumption, maternal prenatal
medication, diuretics, maternal prenatal vitamins, childhood allergies, paternal occupation,
breast feeding.
Introduction
Neuroblastoma, a malignant embryonal tumour of the
neural crest cells, is the most common tumour among
children less than 1 year of age worldwide. Each year,
approximately 1500 cases occur in Europe and 700 in
the USA and Canada,1–3 accounting for about 28% of
all cancers diagnosed in European and US infants.3,4
Although it may be diagnosed in either childhood or
adulthood, its incidence peaks in infancy and then
drops by half in the second year of life, with most cases
occurring in early childhood. In contrast to many adult
cancers, relatively few causative factors have been
identified for childhood tumours. The sporadic occurrence has made this disease particularly challenging to
study, with the result that the aetiology of neuroblastoma remains poorly understood.
Neuroblastoma is a malignancy of the cells of the
neural crest. The neural crest forms in the third to
fourth week of embryonal development and some of
these cells differentiate and migrate to create the sympathetic nervous system.5 Tumours may arise anywhere along the sympathetic nervous system, but are
found most frequently in the adrenal glands (approximately 40% of tumours) or elsewhere in the abdomen,
chest, or pelvis.2 Disease classification is based on the
International Neuroblastoma Pathology Classification
system, which uses age, grade, mitotic rate, mitosiskaryorrhexis index and the presence of calcification to
predict prognosis.6
In recent years, screening programmes have been
implemented in parts of several countries, including Japan, Germany and Canada. Although these
Paediatric and Perinatal Epidemiology, 23, 125–143. © 2008 The Authors, Journal Compilation © 2008 Blackwell Publishing Ltd.
126
J. E. Heck et al.
programmes were associated with a vast increase in
the incidence of stage 1 disease, there is little evidence
of a decrease in the incidence of late-stage disease.
Evaluations of these programmes found little or
no association with decrease in mortality, leading
researchers to conclude screening for neuroblastoma
has little merit.7–10
Importantly, it has been suggested that the incidence
of neuroblastoma has increased in recent years. It is of
interest to determine whether this is in part the result
of increased surveillance and screening or is rather due
to increases or changes in potential risk factor distributions.11,12 Little is known about the causes of neuroblastoma, and currently no recommendations exist
for disease prevention. The goal of this review is to
evaluate the existing literature on the aetiology of neuroblastoma and make recommendations for future epidemiological studies. As neuroblastoma is extremely
rare in adulthood, the majority of epidemiological
research of neuroblastoma has focused on children
(age < 15 years).
Descriptive epidemiology
As stated above, the majority of neuroblastoma cases
occur in infancy and early childhood. In one North
American review of 3059 cases, 40% of patients were
diagnosed in infancy, 89% by age 5 and 98% by age 10.13
In most countries, boys are diagnosed at rates equivalent to or slightly higher than girls.1,3,11,14–16
There is no strong evidence for differences in
disease occurrence across ethnic groups. Even though
in the USA the rate for whites (12.8 per million) has
been reported as being higher than for blacks (9.6) or
Hispanics (9.9), it is possible this is due to a greater
medical surveillance for neuroblastoma in white populations.11 No evidence has been found that incidence
varies between Asians and whites in the UK, a country
where the incidence of neuroblastoma is reported to be
lower than in other European nations.17 Internationally,
neuroblastoma appears to have the highest incidence
among populations with greater medical surveillance,
including Western Europe (12.0 per million), the USA
(9.1), Canada (11.4), Japan (12.5), Hong Kong (8.2),
Australia (9.9), New Zealand (11.9 among the nonMaori population), Cuba (8.9) and Israeli Jews (15.1).3,11
Rates reported for children in low and medium
resource countries of Eastern Europe, Asia (with the
exception of Japan), Africa and Central and South
America are generally lower.11,15 For example, the rate
in Egypt is 5.4 per million; Zimbabwe, 4.0; Costa Rica,
4.5; Uruguay, 2.9; Thailand, 2.7; Bulgaria, 5.0; and
Poland, 5.3 per million.11
Survival
Due to its general variability in outcome, neuroblastoma has long been considered one of the most enigmatic of cancers. Clinical behaviour has three distinct
patterns: rapid progression to life-threatening illness,
maturation to benign ganglioneuroma and spontaneous regression. The likelihood of survival is dependant
on the age of the patient, the stage and biological characteristics of the disease. The poorest prognosis is seen
in children diagnosed at older age (>15 months), those
diagnosed at later stages of disease, and those positive
for certain molecular biological markers such as
myelocytomatosis viral related oncogene, neuroblastoma derived (MYCN) amplification, which occurs in
5–10% of cases in infants up to 1 year and in 20–30% of
childhood and adolescent cases.18–21
Treatment protocols depend on risk stratification of
the tumour, which involves tumour stage, the age of
the child, histology and tumour biology. In general,
survival has improved only modestly in recent years,
with 5-year overall survival rates reported as 58% in
the USA and Europe, and lower survival in Eastern
European countries.3,22,23 On the other hand, the disease
has the highest rate of spontaneous regression of any
cancer. This phenomenon was first noted in case
reports and autopsy reviews of children who had died
from other causes.24 In stage 4 patients without MYCN
amplification, survival rates have been estimated to be
over 90%.25 Variation in survival rates worldwide may
partially reflect treatment success but is additionally
dependent on the rate of diagnosing asymptomatic
cases in infants that would spontaneously regress; this
rate may have increased in some countries.26
Methods
Our goal was to identify all published articles on neuroblastoma epidemiology. We undertook a Medline
search to ascertain articles on neuroblastoma aetiology,
using the search term neuroblastoma AND (risk factors
OR epidemiology OR case-control studies OR aetiology); this identified 319 articles. We used a similar
strategy in Dissertation Abstracts to find unpublished
dissertations. We additionally looked for articles which
reported results for multiple types of childhood cancer,
Paediatric and Perinatal Epidemiology, 23, 125–143. © 2008 The Authors, Journal Compilation © 2008 Blackwell Publishing Ltd.
Epidemiology of neuroblastoma
using the search terms (neoplasms AND child) AND
(risk factors OR epidemiology OR case-control studies
OR aetiology), which yielded 1477 papers. In order to
ensure the search was thorough, we reviewed the
citations of recent articles and used the PubMed
‘all related articles’ feature to ascertain any additional
papers; for older articles, we additionally examined the
references of a 1999 book on childhood cancer epidemiology.27 Included papers were required to report
results specific to neuroblastoma rather than broader
classes of childhood cancer, and to have a comparison
group. This yielded 47 articles including case-control,
cohort and ecological studies (Table 1). The following
review includes the major aetiological factors reported
to date. When a range of odds ratios (OR) is shown, we
additionally provide the median to give an idea of the
distribution.
Results
Genetic predisposition and familial risk
Although rare, familial clustering of neuroblastoma has
been reported and has been estimated to account for
<5% of all neuroblastomas.28–30 This may be an underestimate if genetic types are more prone to spontaneous
regression of the undiagnosed tumour or are more
likely to coincide with lethal birth defects. Genetic predisposition seems to follow an autosomal-dominant
pattern of inheritance with incomplete penetrance.
Although early reports suggested familial neuroblastoma may be more likely to exhibit certain clinical
and prognostic patterns that differ from sporadic
disease, more recent papers have not supported that
assertion.31 In a recent comprehensive review of 2863
European patients, Claviez and colleagues did not find
familial neuroblastoma to have distinct clinical patterns that allow their differentiation from cases of
sporadic disease, including lack of differences in age
at diagnosis, multiple primary tumours, or variation in
MYCN amplification status.30
Congenital anomalies co-occur in 5% of neuroblastoma cases.32 A recent review in Britain of 1208 neuroblastoma cases reported that the most common sites
for malformations are the head and neck, gastrointestinal and musculoskeletal systems.32 Co-occurring
congenital conditions include Beckwith-Wiedemann
syndrome, von Recklinghausen syndrome, Hirschsprung’s disease, Rubenstein-Taybi syndrome and
several congenital heart conditions.33–37
127
Several inherited genetic alterations have been identified as likely to predispose to the development of
neuroblastoma. Deletions in the short arm of chromosome 1 (1p36) are a common characteristic of neuroblastoma tumours, and this region was previously
hypothesised as a likely candidate for tumour suppressor genes.38,39 However, studies have found evidence
for other candidate genes at 16p, 4p, 2p and 12p.40–42
Given that several regions have been identified, it is
plausible that more than one gene may be involved in
the development of the disease. Several researchers
have postulated that Knudson’s two-hit hypothesis,
in which two successive mutations are required for
tumour development, is the model that best explains
the genetic complexity of this disease.28,43,44
Low-penetrance genetic sequence variations have
been implicated in childhood cancer aetiology.
However, the current literature on neuroblastoma is
still very sparse. Only one published study examined
GSTM1 and GSTT1 polymorphisms and deletions on
neuroblastoma risk but did not find any association.45
Parental demographics
Parental age
No pattern emerges between parental age and the risk
of neuroblastoma. Younger maternal age at childbirth
(<18 or <20 years in differing studies) has not been
found to be clearly associated with the risk of neuroblastoma of the child (OR range 0.7, 1.4, median
OR = 1.0).46–51 No study has found an association with
older maternal age, which has been defined as either
>35 or >40 years at the time of child’s birth.47–52
Paternal age has been less studied, but a moderately
sized population-based study suggested associations
with older (>40 years) paternal age. The New York
study reported a crude OR of 1.5 [95% confidence
interval (CI) 1.0, 2.3].48 In contrast, the California
(crude OR = 1.7, 95% CI 0.8, 3.6), Washington (crude
OR = 1.3, 95% CI 0.8, 1.9) and Minnesota (crude
RR = 0.8, 95% CI 0.4, 1.5) studies, in which older age
was defined as greater than 35 years, showed no clear
pattern.49–51
Socio-economic measures
No clear pattern emerges between maternal educational attainment and neuroblastoma. A large North
American hospital-based case-control study described
Paediatric and Perinatal Epidemiology, 23, 125–143. © 2008 The Authors, Journal Compilation © 2008 Blackwell Publishing Ltd.
104
104
Pennsylvania, USA 1970–197956,66
North Carolina, USA 1972–198147
97
164
Northern England 1968–200059,92
Minnesota, USA 1968–?49
157
Texas, USA 1964–197855,103
93
101
Case-control studies
Ohio, USA 1942–196757
UK 1977–198168
435
n cases
Cohort studies
Swedenb 1958–200258,99,114
Location and years of recruitment
Table 1. Neuroblastoma study descriptionsa
All children admitted with
histologically confirmed NB
in 11 regional NC hospitals,
100% ascertainment among
eligible cases
Cases in the Greater Delaware
Valley Pediatric Tumor
Registry, 57% ascertainment
Patients seen at participating
hospitals in Minnesota.
Linkage to birth certificates
possible for 39% of patients.
Cases from the Northern
Region Young Persons
Malignant Disease Registry
All Texas children who died
from neuroblastoma who
were born in the state, 95%
ascertainment
Cases in the Oxford Survey of
Childhood Cancers, 61%
response rate
Histologically confirmed cases
from Columbus Children’s
Hospital Tumor Registry,
77% ascertainment
Cases from Swedish cancer
registry.
Case description
208 (1), 86 (2),
184 (3)
101
388
14 400
314
93
404
N/A
n controls
3 control groups: (1)
Hospitalised children
without cancer matched by
age, race, sex, hospital,
hospital service (medical or
surgical) and year of
admission, (2) All children
diagnosed in study
hospitals with Wilms’
tumour in the study period,
(3) chronologically closest
liveborn children of same
race, sex, and county of
birth in NC Center for
Health Statistics birth
registry
Population controls matched
by area code + first 5 digits,
race, year of birth (⫾ 3
years), 57% response rate
Controls matched by year of
birth from all children born
in Minnesota
Controls matched by year of
birth and sex
Children born in Texas during
the same birth year
distribution as the cases
Controls chosen from birth
registers, matched by sex
and date of birth
Children from Ohio birth
certificate lists, matched by
year of birth, sex, race and
county of residence
Controls taken from census
lists
Control description
Birth certificate and medical
record review
Telephone interview
Birth certificate review
Birth certificate review
Death certificate review, birth
certificate review
Parental interview
Birth certificate review
Linkage of cancer registry to
census and death registers
Data collection methods
Review of hospital discharge
rosters, NC tumour registry
review, birth certificate
registry review
Random digit dialling
Random selection of children
from Minnesota birth
certificate rolls
Random selection from the
Cumbrian Births database
Random selection from all
children born in Texas
Selected from birth register in
local area where case was
living at the time of
diagnosis
Selection of birth certificates
closest in age to the cases
N/A
Control recruitment
128
J. E. Heck et al.
Paediatric and Perinatal Epidemiology, 23, 125–143. © 2008 The Authors, Journal Compilation © 2008 Blackwell Publishing Ltd.
240
360
508
192
538
180
Washington State, USA 1980–200451
New York, USA 1985–200148,60,67,84
California, USA 1988–199750
Germany 1992–199452,70,87,105
Multicentre, USA and Canada
1992–199646,53,61–65,72,83,85,86,95,107,111
UK 1991–199669,90
All children diagnosed with
neuroblastoma in Family
Health Services Authority
records, 87% participation in
cohort of all childhood
cancers
Newly diagnosed cases at 139
hospitals in the US and
Canada, 73% participation
German Childhood Cancer
Registry cases, 85%
participation
Cases from the California
Cancer Registry who were
born in the state. Linked to
birth certificate files, record
linkage of 86%
All children in the NY State
cancer registry, excluding
NY City. 85% participation
in the study with
interviews; record linkage
of 75% in study of birth
certificates
Patients from the Cancer
Surveillance System of
Western Washington, 100%
ascertainment
Newly diagnosed patients
<age 9 receiving treatment
at St. Jude Children’s
Hospital, 64% ascertainment
Case description
Not provided
504
2 537
1 015
12 664
2 400
690
n controls
Randomly selected children
from Family Health Services
Authority registers and
health boards, matched by
sex, date of birth and
geographical area. 64%
participation
Population controls
ascertained by random digit
dialling, matched by first 8
digits of telephone number
and age, 72% participation
Population controls selected
from local files of residents.
Some controls were
matched by community of
residence, others were
selected at random.
Matched by sex,
community, and age, 71%
participation
Population controls selected
from California birth
certificate files, matched by
sex and date of birth
Randomly selected children
born in NYS (not NYC),
frequency matched to cases
by year of birth, 83%
participation in study with
interviews
Randomly selected birth
certificates frequency
matched by the year of
birth of cases, 100%
ascertainment
Patients with other childhood
cancers. 68% ascertainment
Control description
Approached GPs for
permission, then contacted
parents
Random digit dialling
Telephone interview
Parental interview
Random selection of children
from registry rolls
Random selection of children
from registry rolls
Random selection of birth
certificates
Random selection of birth
certificates
Mothers of other childhood
cancer patients treated in
the same hospital
Control recruitment
Self-administered
questionnaire and telephone
interview; both parents
interviewed
Birth certificate review and US
Census data
Cancer registry data and birth
certificate review. One
project involved parental
interview
Birth certificate review and
hospital discharge data
Maternal interview
Data collection methods
One of the papers from this cohort was a nested case-control study.
b
differing in the total number of cases. When that occurs, the description shown in the table is from the most recent paper published.
a
Cohort and case-control studies only. Studies shown in this table had >50 cases and studied more than one exposure. Papers from the same data source did not always use the same time periods, frequently
101
n cases
Tennessee, USA 1979–198671
Location and years of recruitment
Table 1. Continued
Epidemiology of neuroblastoma
129
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130
J. E. Heck et al.
an imprecisely estimated twofold increase for neuroblastoma and attainment of less than a high school
degree (crude OR = 2.2, 95% CI 0.8, 6.3).53 In contrast,
more recent population-based American studies have
found generally lower odds of disease among progeny
of women with less than a high school degree.48
A recent California study reported a doubling of rates
of disease among children of women with more than
16 years of education (crude OR = 2.1, 95% CI 1.5,
3.0).50
Two older population-based studies conducted in
the USA and Denmark saw an inverse relationship
between socio-economic status (SES, measured as
family income or employment category) and neuroblastoma incidence.28,54 Because of non-universal
health care coverage in Denmark during much of the
time period covered by the Danish study and those
conducted in the USA, there may have been differential rates of diagnosis of neuroblastoma by SES, i.e.
family income and maternal education. Three other
studies found no association between disease and
education or SES.48,49,52
mates were based on a combination of self-reports and
literature review-based job title ratings.
The largest multi-centre case-control study of neuroblastoma to date included 538 cases61 and reported
both job title and agent-specific risk increases for
parental exposures. Consistent with previous reports
they found increased risks for parental occupations
with electromagnetic field and pesticide exposure
potential (electrical power line installers and plant
operators, broadcast, telephone and dispatch operators, farmers and farm workers, landscaper and
groundskeeper, flower and garden store workers)
but also reported risk increases for jobs with
potential exposure to hydrocarbons (painters and
hairdressers).62–65 Based on the job exposure matrix,
this group identified the following agents as potential
risk factors when fathers were exposed: non-volatile
and volatile hydrocarbons (OR = 1.5, 95% CI 1.0, 2.2;
OR = 1.5, 95% CI 1.0, 2.1), specifically diesel fuels,
lacquer thinner and turpentine, and also wood dusts
and solders. Exposure of the mother to any of these
chemicals, however, was quite rare and not found to be
associated with neuroblastoma risk in this study.
Parental occupational exposures
The case-control studies that investigated potential
links between parental occupational pre-conceptional
and prenatal exposures and neuroblastoma risk in
offspring relied on exposures being self-reported in
interviews or inferred exposures from job title information. Early studies of relatively small size suggested
increases in risk for dozens of broad industrial and
occupational groupings. Most consistently they implicated parental farming and work in electronics assembly and repair and in electricians,55–57 giving rise to
speculations about the influence of electromagnetic
fields and pesticides. The former hypothesis was
further addressed by Feychting in a large cohort study
of children born in Sweden that assessed parental
exposures to electromagnetic fields with a validated
job exposure matrix instrument.58 However, due to the
rarity of disease in this cohort (25 cases), risk estimates
for parental exposure prior to conception were highly
unstable or showed no clear pattern with increasing
dose. Three retrospective case-control studies reported
risk increases with self-reported occupational exposures to pesticides.52,59,60 Kerr et al. 60 furthermore identified two- to threefold risk increases for parental jobs
with likely exposure to insecticides, some metals
(lead), coal tar and soot, and petroleum; exposure esti-
Tobacco, alcohol and recreational drug use
Maternal or paternal tobacco exposure
There is little evidence to support a causal association
between maternal tobacco use in pregnancy and neuroblastoma (OR range 0.6, 1.6, median OR = 1.0).48,66–70
The most in-depth studies, examining tobacco use by
trimester of pregnancy or by cigarettes smoked per day
show no clear pattern.51,52,71,72 There also has been no
evidence of an association for smoking in the preconception period.69,70 Tobacco use in pregnancy is by
its nature a sensitive subject, and differential reporting
leading to bias is an issue that retrospective studies
cannot address. Notably, the studies with prospective
exposure assessment, in which smoking status during
pregnancy was abstracted from birth certificates, also
did not find any evidence for an association with
maternal smoking, although smoking may be underreported in this data source.48,51,67
Paternal smoking history has been less frequently
assessed. Two investigations reported no association
for paternal smoking either prior to or during pregnancy,68,72 while one found a weak positive association
(crude OR = 1.4, 95% CI 1.0, 1.9) with smoking prior to
conception.69
Paediatric and Perinatal Epidemiology, 23, 125–143. © 2008 The Authors, Journal Compilation © 2008 Blackwell Publishing Ltd.
Epidemiology of neuroblastoma
Location
Pennsylvania66,a
Pennsylvaniaa
Pennsylvaniaa
Germany52,b
Tennessee71,c
US and Canada72,d
US and Canadad
US and Canadad
US and Canadad
Exposure
OR [95% CI]
ⱖ1 drink/day
ⱖ3 drinks/occasion
Either ⱖ1 drink/day or ⱖ3 drinks/occasion
>7 glasses/week
Any use in pregnancy
Around the pregnancy (any/none)
1st trimester (any/none)
2nd trimester (any/none)
3rd trimester (any/none)
9.00 [2.16, 37.56]
6.00 [1.26, 28.54]
12.00 [3.14, 45.82]
3.04 [0.75, 12.20]
0.7 [0.4, 1.1]
1.1 [0.8, 1.4]
1.2 [0.9, 1.7]
1.6 [1.0, 2.4]
1.40 [0.9, 2.1]
131
Table 2. Alcohol use in pregnancy and
neuroblastoma
a
Unadjusted estimate.
Matched by sex, age, and birth year, and adjusted for socio-economic status and
urbanisation.
c
Control group was other cancer cases.
d
Adjusted for child’s sex, mother’s race and education, and household income.
b
Maternal alcohol consumption
It is well established that fetal exposure to alcohol
causes disruption of normal neuronal development.
Early ethanol exposure interferes with neuronal cell
migration and proliferation and can cause neuronal cell
loss.73 It has also been shown to induce apoptosis in
neural crest cells.74,75 The possibility of a link between
alcohol intake and neuroblastoma was raised by case
reports that described the tumour as co-occurring with
fetal alcohol syndrome.76–78
Nonetheless, there have been few epidemiological
investigations of alcohol consumption and neuroblastoma. Two population-based studies, in Pennsylvania
and in Germany, reported a strong association with
disease and daily or binge drinking in pregnancy
(Table 2).52,66 In Germany, low to moderate drinking
in pregnancy is not a social taboo. The Pennsylvania
study collected data for patients diagnosed between
1970 and 1979, i.e. prior to the first US Surgeon General’s report on alcohol drinking in pregnancy.79 Thus,
these findings for alcohol drinking are strengthened
by the fact that both studies investigated cultures in
which moderate drinking in pregnancy was more
widespread, potentially lessening the concern that
mothers of cases and controls may modify their
answers in a socially acceptable manner even when
asked about binge or daily drinking.
In addition, a large, more recent case-control study
of North American patients found an elevated risk for
ever drinking in the second trimester (adjusted
OR = 1.6, 95% CI 1.0, 2.4), while ever drinking in the
first and third trimesters were associated with weaker
risks (ORs = 1.2, 1.4, respectively), and no doseresponse trend was seen with consumption.72 As
alcohol consumption in pregnancy is frowned upon in
modern US society, the validity of self-reporting of this
behaviour in general population samples is a concern.80
The only study that did not find any association with
alcohol consumption used other childhood cancer
cases as controls.71
Maternal recreational drug use
Use of recreational drugs has been implicated in the
aetiologies of several childhood cancers, including
acute non-lymphoblastic leukaemia, brain tumours,
and rhabdomyosarcoma.27,81,82 There have only been
three published reports examining recreational drug
use and neuroblastoma. The New York study found a
doubling of risk of neuroblastoma among drug users
(crude OR = 2.2, 95% CI 0.9, 5.1).48 However, drug use
recorded on New York birth certificates is defined
broadly and includes any use of heroin, cocaine
or crack, marijuana, methadone, amphetamines,
sedatives/tranquilisers/anticonvulsants and, importantly, also prescription drugs other than vitamins.
The second and very large North American hospitalbased case-control study was able to stratify by type of
drug used.83 Positive but imprecisely estimated associations were reported for use of marijuana, cocaine or
crack, hallucinogens and stimulants controlling for
household income and age at diagnosis. Further analyses identified marijuana use in the first trimester as
having the strongest association with neuroblastoma
(crude OR = 4.8, 95% CI 1.6, 16.5).
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132
J. E. Heck et al.
The third study compared children with neuroblastoma with children with other childhood cancers and
found no association with self-reported recreational
drug use in the year prior to pregnancy.71
Maternal medication use, chronic illnesses and
interventions in pregnancy
Oral contraceptives or other sex hormones
including fertility hormones
A German study reported a fourfold risk increase for
oral contraceptives or other sex hormones used in early
pregnancy and risk of neuroblastoma among children
diagnosed at stage 1 or 2 (adjusted OR = 4.5, 95% CI
1.2, 16.5).52 In the same study no such association
existed for children diagnosed at a later stage of
disease. One study reported a strong association
between fertility hormones and neuroblastoma (crude
OR = 10.4, 95% CI 1.2, 90), although the number of
subjects who reported using these drugs was very
small (n = 6).84 Other studies have not found any clear
association with sex hormone use71 including studies
that examined specific hormone preparations and the
gestational periods in which they were taken.85,86
Diuretics
Three studies have examined use of diuretics or other
pills to treat water retention in pregnancy. An early,
small population-based Pennsylvania study reported
a strong association (crude OR = 5.8, 95% CI 2.6, 12.6).66
Two other studies of small to moderate size, one
hospital-based and one population-based, reported
imprecisely estimated but elevated associations of
lower magnitude (ORs 1.2, 2.5).71,84 In addition, one
study which did not distinguish between diuretics and
other types of hypertensive medications reported a
strong association (adjusted OR = 3.2, 95% CI 1.0, 9.7).87
Other prescription and non-prescription
drugs
There are few other drugs which have been studied
extensively, and the studies that exist have generally
examined broad classes of drugs. The Pennsylvania
study found a positive association between disease
and intake of prescription pain medications during
pregnancy (crude OR = 6.0, 95% CI 2.0, 18.1) in which
the type of medication was not specified.66 The Tennes-
see study found a positive association with use of
prescription analgesics (adjusted OR = 3.2, 95% CI 1.4,
7.5),71 while a New York state study found no association with ‘drugs taken for fever in pregnancy’ (crude
OR = 1.4, 95% CI 0.6, 3.4).84 No association was found
in a German study (adjusted OR = 1.1) for intake of any
type of pain medication.87
The one large study able to examine classes of drugs
more specifically found a positive association between
disease and intake of codeine during pregnancy or
lactation (adjusted OR = 3.4, 95% CI 1.4, 8.4) and also
for intake of any opioid agonist, a result that the
authors stated was mostly driven by the findings for
codeine use (adjusted OR = 2.4, 95% CI 0.8, 1.8).86
Hypertension or diabetes in pregnancy
No convincing association has been established
between maternal hypertension in pregnancy and neuroblastoma. A population-based study in New York
reported a positive association with hypertension in
pregnancy (crude OR = 1.7, 95% CI 1.1, 2.7).48 In contrast, two hospital-based studies found no association.47,53 It is not known if the association found may be
due to any medications the mother took to treat the
condition.
Only two studies examined maternal diabetes and
neither differentiated between chronic and gestational
diabetes; no association was found in either study.48,53
Radiation or ultrasound exposure
The three studies that examined an association
between maternal exposure to X-rays in pregnancy and
neuroblastoma did not find an association47,71 including a study which conducted detailed analyses of the
time period of exposures.46 Similarly, the one study that
examined the child’s X-ray history did not find any
association.52
A population-based study in New York State found
an elevated risk for neuroblastoma when mothers
had undergone an ultrasound examination during
pregnancy (adjusted OR = 2.5, 95% CI 2.0, 3.2).48
This association may be due to the fact that some neuroblastomas are diagnosed during fetal ultrasound
examinations.
Method of delivery
Having a caesarean section has been weakly positively
associated with neuroblastoma (OR range 1.4, 1.5,
Paediatric and Perinatal Epidemiology, 23, 125–143. © 2008 The Authors, Journal Compilation © 2008 Blackwell Publishing Ltd.
Epidemiology of neuroblastoma
median OR = 1.4).48,50,53 However, this method of
delivery may be a marker for intrauterine health problems of the infant that may also be related to disease
status.
Infections and immunity
Infectious agents
Malignancies with an infectious aetiology may also be
expected to exhibit varied incidence in geography or
time, such as seasonality or greater incidence in areas
with higher population density.88 An early examination
of neuroblastoma death patterns in England and Wales
for the period 1958–1964 reported higher neuroblastoma mortality in the summertime.89 However, in three
later studies there was no evidence of space time clustering.47,90,91 An ecological investigation conducted in
the North of England compared the yearly incidence of
neuroblastoma among children younger than 15 years
with annual rates of community infectious diseases
including influenza, measles, whooping cough, scarlet
fever, infective jaundice and acute meningitis, but
found no association.92
Maternal infections in pregnancy
There have been few reports specifically examining
neuroblastoma and maternal infections. One paper
described an association between sexually transmitted
diseases (STD) and neuroblastoma (adjusted OR = 3.1,
95% CI 1.4, 7.0).53 Another study found vaginal infections to be positively associated with neuroblastoma
(crude OR = 2.2, 95% CI 1.2, 4.0)84 while in a separate
investigation no association was found for vaginitis
(adjusted OR = 1.0).53 Given the association of STD
infection with a wide spectrum of behavioural risk
factors for disease, including alcohol and recreational
drug use,93,94 confounding may have existed in these
studies.
No association with neuroblastoma has been shown
with a maternal history of influenza, urinary tract
infection and its treatment, fever, general maternal
viral infections, or a history of taking anti-infective
drugs in pregnancy.48,53,67,84,86
Childhood infectious exposures
No clear pattern has been established between common
childhood infectious diseases and neuroblastoma.
133
Among older (age > 1 year) children, one study
reported a dose-response protective association with
a history of specific childhood infections, including
chickenpox, mumps, measles and German measles
(crude OR = 0.1, 95% CI 0.0, 0.7 for a history of
two or more infections).95 There was also no clear association between day care attendance and neuroblastoma.95 Several studies that investigated a possible role
for human polyomavirus BK and neuroblastoma were
inconclusive.96–98
Birth order and family size
Studies have had mixed results when investigating the
association between family size or birth order with
disease. The studies of family size show no clear
pattern, while those of birth order mostly suggest that
later birth is protective (Table 3).47–50,52,66,67,71,84,99 Because
average family size has changed in recent decades, we
examined the data for evidence of a temporal trend
in findings but none could be seen. However, as an
alternative to exposure to infectious diseases in larger
sibships, differences in prenatal exposures have
been proposed as explanations for such findings. For
example, lower oestrogen levels commonly observed
in later pregnancies might reduce the tumour risk in
later born children.100
Allergies or asthma
Atopic conditions have been negatively associated with
other cancers.101 Three studies observed inverse associations between childhood allergies and the later
development of neuroblastoma (Table 4).47,52,95 Family
history of asthma was also found to be inversely associated with neuroblastoma status (crude OR = 0.4, 95%
CI 0.2, 0.8).47 However, maternal history of allergies
was not associated with neuroblastoma in another
study (adjusted OR = 0.9, 95% CI 0.6, 1.3).52
Gestational age, birthweight and growth
in early childhood
Birthweight and gestational age
A majority of studies found an increased risk of neuroblastoma among both low (<2500 g) and high (>3800 g)
birthweight babies (Table 5).47,48,50,52,53,102–104 Two papers
that reported no association dichotomised birthweight
(⫾3805 and ⫾4000 g, respectively) which would not
allow the observation of a U-shaped relationship.49,71
Paediatric and Perinatal Epidemiology, 23, 125–143. © 2008 The Authors, Journal Compilation © 2008 Blackwell Publishing Ltd.
134
J. E. Heck et al.
Table 3. Results of studies which
examined the association between
neuroblastoma (NB) and birth order or
family size
Location
Exposure
Birth order
Risk of disease among firstborn, in
comparison to later-born children
Minnesota49,a
North Carolina47,ab
North Carolinaac
Germany52,d
New York State48,a
Risk of disease among laterborn in
comparison to firstborn, or first
and second-born
Pennsylvania66,a
Tennessee71,ae
Larger family size in comparison
to smaller
Sweden99,f
New York State84,a
New York State67,a
California50,g
Washington State51,h
OR [95% CI]
Firstborn
Firstborn
Firstborn
Firstborn
Firstborn
1.19
1.31
2.26
1.14
1.15
[0.74,
[0.66,
[1.00,
[0.82,
[0.93,
2.06]
2.62]
5.11]
1.59]
1.42]
3rd or later child
2nd or later child
1.30 [0.73, 2.33]
0.93 [0.61, 1.42]
4 or more siblings (birth order
of NB child unspecified)
3 or more children (birth order
of NB child unspecified)
3 or more children (birth order
of NB child unspecified)
3 or more prior pregnancies
2 or more prior births
1.44 [0.86, 2.43]
0.87 [0.58, 1.30]
0.70 [0.40, 1.10]
0.63 [0.44, 0.91]
1.12 [0.80, 1.58]
a
Unadjusted estimate.
Hospital non-cancer controls.
c
Birth certificate controls.
d
Matched by sex, age and birth year, and adjusted for socio-economic status and
urbanisation.
e
Other cancer controls.
f
Adjusted for age, sex, socio-economic status, birth cohort and residential area.
g
Adjusted for race, gestational age, birthweight, socio-economic status, initiation of
prenatal care, type of delivery.
h
Adjusted for birth year.
b
Table 4. Associations between
neuroblastoma and child and familial
history of allergic diseases
Location
Prior diagnosis in the child
North Carolina47,ab
North Carolinaab
Germany52,c
USA and Canada95,d
USA and Canadad
USA and Canadad
USA and Canadad
Familial diseases
North Carolina47,ab
North Carolinaab
Germany52,c
Exposure
OR [95% CI]
Allergies
Asthma
Allergy
Asthma
Hay fever
Eczema
Asthma, hay fever, or eczema
0.22
1.66
0.20
0.69
0.43
0.82
0.68
[0.06,
[0.22,
[0.06,
[0.36,
[0.18,
[0.41,
[0.44,
0.82]
12.34]
0.65]
1.34]
1.04]
1.62]
1.07]
Asthma
Allergies
Allergy in the mother
0.35 [0.15, 0.78]
0.66 [0.27, 1.65]
0.88 [0.60, 1.30]
a
Unadjusted estimate.
Hospital noncancer controls.
c
Matched by sex, age and birth year, and adjusted for socio-economic status and
urbanisation.
d
Adjusted for age at diagnosis, mother’s race, mother’s education and household income.
b
Paediatric and Perinatal Epidemiology, 23, 125–143. © 2008 The Authors, Journal Compilation © 2008 Blackwell Publishing Ltd.
Epidemiology of neuroblastoma
Location
High birthweight
Minnesota49,a
Tennesseea
North Carolina47,ab
North Carolinaac
Washington State51,d
Germany52,e
USA and Canada53,f
USA and Canadaf
Adjusted for gestational age
Germany105,g
New York State48,h
Singapore106,i
Term births only
Texas103,a
California50,j
Low birthweight
USA and Canada53,f
USA and Canadaf
North Carolina47,ab
North Carolinaac
Washington State51,d
Germany52,e
Adjusted for gestational age
Germany105,g
New York State48,h
Term births only
Texas103,a
California50,j
Exposure
Reference group
OR [95% CI]
High (>4000 g)
High (>3805 g)
High (>3500 g)
High (>3500 g)
High (>4000 g)
High (>4000 g)
High (4000–4499 g)
Very high (>4500 g)
<4000 g
<3805 g
2500–3499 g
2500–3499 g
2500–3999 g
2500–4000 g
2501–4000 g
2501–4000 g
0.96
0.87
1.14
1.38
1.25
1.35
1.10
1.40
>90th percentile
High (>3500 g)
High (>3501 g)
10–90th percentile
2500–3500 g
2500–3500 g
1.57 [0.90, 2.71]
1.34 [1.05, 1.71]
3.30 [1.10, 10.10]
High (>3850 g)
High (>4000 g)
2500–3850 g
2500–4000 g
0.61 [0.32, 1.15]
1.24 [0.85, 1.81]
Very low (<1500 g)
Low (1500–2500 g)
Low (<2500 g)
Low (<2500 g)
Low (<2500 g)
Low (<2500 g)
2501–4000 g
2501–4000 g
2500–3500 g
2500–3500 g
2500–3999 g
2500–4000 g
2.60
1.10
1.30
0.55
0.75
2.41
<10th percentile
Low (<2500 g)
10–90th percentile
2500–3500 g
1.23 [0.70, 2.15]
1.43 [0.87, 2.28]
Low (<2500 g)
Low (<2500 g)
2500–3850 g
2500–4000 g
1.95 [0.81, 4.72]
1.16 [0.49, 2.74]
135
Table 5. Associations
between neuroblastoma and
birthweight
[0.47, 1.73]
[0.52, 1.44]
[0.65, 1.98]
[0.74, 2.59]
[0.87, 1.79]
[0.83, 2.19]
[0.70, 1.70]
[0.60, 3.20]
[0.68, 9.97]
[0.60, 2.01]
[0.48, 3.56]
[0.24, 1.24]
[0.38, 1.51]
[1.24, 4.69]
a
Unadjusted estimate.
Hospital noncancer controls.
c
Birth certificate controls.
d
Adjusted for birth year.
e
Matched by sex, age and birth year, and adjusted for socio-economic status and urbanisation.
f
Adjusted for child’s sex, mother’s race and education and household income.
g
Frequency matched by sex and age at diagnosis; adjusted for degree of urbanisation and socioeconomic status; outcome is percentile of birthweight adjusted for gestation.
h
Adjusted for birth year, Hispanic ethnicity, non-white race, sex, and gestational age.
i
Adjusted for sex, gestational age, birth order and maternal age.
j
Adjusted for race, time of initiation into prenatal care, caesarean delivery, parity and census block
population percentage with a college degree.
b
However, given the close correlation of birthweight
and gestational age, it is important to examine associations between birthweight and neuroblastoma after
stratification for gestational age to distinguish the
effects of growth retardation from those of immaturity.
One study focusing on term babies (37–41 weeks gestation) reported no elevated risk (adjusted OR = 1.2,
95% CI 0.5, 2.7) for low weight, while two others suggested a modest increase (OR = 1.2, 95% CI 0.7, 2.2;
OR = 1.4, 95% CI 0.9, 2.3) in small-for-gestational-age
birth; a third found a twofold risk increase (crude
OR = 2.0, 95% CI 0.8, 4.7).48,50,103,105 High birthweight in
term babies did not show a clear relationship with
disease.50,103,105,106
One recent study suggested that the association
between neuroblastoma and high birthweight may be
stronger in children diagnosed with neuroblastoma in
infancy than after age 1 year. An analysis from New
York State supported a slightly higher risk (adjusted
OR = 1.7, 95% CI 1.1, 2.8) for higher-birthweight
Paediatric and Perinatal Epidemiology, 23, 125–143. © 2008 The Authors, Journal Compilation © 2008 Blackwell Publishing Ltd.
136
J. E. Heck et al.
Table 6. Associations between
neuroblastoma and gestational age
Location
Exposure
Preterm birth
Very preterm
USA and Canada53,a
New York State48,b
Preterm
Texas103,c
Minnesota49,b
USA and Canada53,a
North Carolina47,bd
North Carolinabe
Germany52,f
California50,g
New York State48,h
Post-term birth
North Carolina47,bd
North Carolinabe
New York State67,i
New York State48,h
Washington State51,j
USA and Canada53,e
California50,g
Reference group
OR [95% CI]
ⱕ32 weeks
ⱕ35 weeks
37–42 weeks
37–42 weeks
1.90 [0.70, 4.80]
1.64 [1.01, 2.68]
ⱕ36 weeks
ⱕ37 weeks
33–36 weeks
ⱕ36 weeks
ⱕ36 weeks
ⱕ36 weeks
ⱕ36 weeks
ⱕ37 weeks
37 weeks+
38 weeks+
39–41 weeks
37–40 weeks
37–40 weeks
37–42 weeks
37–41 weeks
38–41 weeks
0.29
1.29
0.50
0.85
0.61
2.46
0.75
1.07
[0.10,
[0.24,
[0.30,
[0.39,
[0.25,
[1.30,
[0.46,
[0.75,
0.86]
6.43]
1.00]
1.84]
1.50]
4.64]
1.23]
1.49]
41 weeks+
41 weeks+
42 weeks+
42 weeks+
42.1 weeks+
43 weeks+
42 weeks+
37–40 weeks
37–40 weeks
37–41 weeks
38–41 weeks
37–42 weeks
37–42 weeks
37–41 weeks
1.10
0.97
0.30
0.70
1.40
0.90
1.13
[0.39,
[0.55,
[0.10,
[0.46,
[0.74,
[0.30,
[0.74,
3.13]
1.71]
0.70]
1.03]
2.64]
3.00]
1.72]
a
Adjusted for child’s sex, mother’s race and education and household income.
Unadjusted estimate.
c
Adjusted for birth order, birthweight, duration of prenatal care, parity, prior fetal death
and presence of congenital malformations.
d
Hospital non-cancer controls.
e
Birth certificate controls.
f
Matched by sex, age and birth year, and adjusted for socio-economic status and
urbanisation.
g
Adjusted for child’s race, birthweight, presence of congenital abnormalities, time of
initiation into prenatal care, caesarean delivery, parity and census block population percentage with a college degree.
h
Adjusted for birth year, Hispanic ethnicity, non-white race, sex of the child and
birthweight.
i
Adjusted for gravidity, mother’s age, plurality of birth, smoking and alcohol use in
pregnancy, birthweight, birth injury, abnormal bleeding, placenta praevia, contracted
pelvis, repeat caesarean delivery, pre-eclampsia and 1-min Apgar score.
j
Adjusted for birth year.
b
(>3500 g) children diagnosed before age 1 than for
children diagnosed after age 1 (adjusted OR = 1.2, 95%
CI 0.9, 1.6).48 In contrast, among high-birthweight
(>4000 g) children born at term in California, the risk of
neuroblastoma was very similar for children diagnosed in infancy (adjusted OR = 1.4, 95% CI 0.7, 2.6)
to that of children diagnosed after age 1 (adjusted
OR = 1.3, 95% CI 0.8, 2.1).50
Concerning gestational age, there is no clear relationship established between neuroblastoma and length of
gestation, including either preterm (typically ⱕ36 or
ⱕ37 weeks) or post-term birth (typically longer than 41
or 42 weeks) (Table 6).47,49,51,52,103 In addition, the studies
that either controlled for birthweight or reported
results only among the normal-birthweight babies also
showed no clear association.48,50,67
However, babies born very early (<35 weeks) may
be at increased risk of neuroblastoma. The New York
study reported a risk increase (crude OR = 1.64, 95% CI
1.01, 2.68) for very preterm babies (<35 weeks gestation).48 Similarly, another large study also reported an
elevated risk (OR = 1.9, 95% CI 0.7, 4.8, adjusted for
birthweight) only among children born before 33
weeks gestation.53
Paediatric and Perinatal Epidemiology, 23, 125–143. © 2008 The Authors, Journal Compilation © 2008 Blackwell Publishing Ltd.
Epidemiology of neuroblastoma
Early childhood growth
An ecological investigation in Japan reported children
who had been diagnosed with neuroblastoma before
age 1, in comparison with the general Japanese population, experienced greater increases in weight in the
time period between birth and diagnosis.102
Nutrition
Vitamin supplementation in pregnancy
Two studies observed a protective association between
vitamin intake during pregnancy and neuroblastoma.
The New York study estimated a halving of disease risk
(OR = 0.5, 95% CI 0.3, 0.7) while the North American
study considered time periods of exposure and found
vitamin use in the first trimester to be associated with
the greatest reduction in risk (OR = 0.7, 95% CI 0.5, 1.0
for daily use).84,107 As vitamin intake in pregnancy is
associated with maternal educational attainment,108
it is notable that the finding persisted after control for
this factor.107 In contrast, an investigation which did
not distinguish between multivitamin, folate or iron
supplements found a positive association between
intake and disease (adjusted OR = 1.50, 95% CI 1.06,
2.13).87 A separate investigation using other childhood
cancer cases as controls found no association.71
Interestingly, an ecological investigation reported a
decline in rates of neuroblastoma in Ontario after the
1997 implementation of a folic acid fortification programme for Canadian cereal grains. Rates of neuroblastoma dropped from 1.57 per 10 000 births in
1985–1997 to 0.62 per 10 000 births in 1998–2000, the
first 2 years after fortification began.109 A concurrent
drop in the incidence of neural tube defects suggests
that the results might not be solely attributable to ecological bias. This finding is intriguing given the established relationship between folate intake and neuronal
cell development in utero.
Breast feeding
Breast feeding is known to be protective against many
childhood diseases because of its nutritional, growthpromoting and immune-modulating benefits. On the
other hand, the possibility has been raised that
breast-fed children may incur a greater disease risk if
maternal milk were contaminated with environmental
137
pollutants or with medications or recreational drugs
that the mother consumed during this time.110
Studies of breast feeding have mostly reported protective associations for neuroblastoma. A large casecontrol study conducted in the USA and Canada
found that infants breast fed the longest, 13 months
or more, exhibited half the risk of neuroblastoma
(OR = 0.5, 95% CI 0.3, 0.9).111 Although this analysis
controlled for family income, this study was later
criticised for unequal participation by SES that
resulted in greater numbers of control families having
both higher educational levels and higher rates of
breast feeding.112 However, two small studies provided some corroborating evidence. A Russian study
of 42 cases reported an elevated odds of disease
among those who breast fed less than 1 month, in
comparison with those breast feeding longer than 12
months (crude OR = 7.5, 95% CI 0.7, 97.3).113 Similarly,
a Swedish study (n cases = 34) found breast feeding
to halve neuroblastoma risk (crude OR = 0.5, 95% CI
0.1, 2.6 for breast feeding >6 months),114 but the effect
estimates were imprecisely estimated due to small
sample sizes in both studies. Strengthening the validity of this later finding was that breast feeding was
assessed by medical record review rather than by
parental recall. However, the authors noted that
breast feeding is so common in Sweden that women
who breast fed their children only shortly or not at all
may have had unique circumstances such as having
had difficulty breast feeding or children who were
too ill to be able to breast feed.114
In contrast, a population-based case-control study
conducted in Germany did not find breast feeding
protective against neuroblastoma (adjusted OR = 1.1,
95% CI 0.7, 1.8 for breast feeding >6 months), and no
exposure-response pattern emerged with length of
breast feeding.52
Discussion
The above studies have examined a range of familial,
lifestyle and environmental risk factors for neuroblastoma. Although the number of studies has not been
large, relatively consistent patterns have been seen thus
far with several risk factors (Table 7). Prior diagnosis
of atopic conditions in the child as well as maternal
or familial history of atopic diseases have generally
been inversely associated with neuroblastoma. Use of
alcohol in pregnancy also appears to be linked with
neuroblastoma diagnosis. Although the number of
Paediatric and Perinatal Epidemiology, 23, 125–143. © 2008 The Authors, Journal Compilation © 2008 Blackwell Publishing Ltd.
138
J. E. Heck et al.
Table 7. Summary of findings
Suggestive evidence of
positive association
Maternal alcohol
consumption
Paternal exposure to
nonvolatile and volatile
hydrocarbons, wood
dusts and solders
Use of diuretics
Suggestive evidence of
inverse association
No evidence of
association
Lack of evidence to
draw conclusions
Vitamin supplementation
Maternal age
Socio-economic status
Folic acid supplementation
Maternal smoking
Paternal age
History of asthma or allergies
Maternal infections in
pregnancy
Maternal recreational
drug use
Use of pain medications
or codeine
X-ray exposure
Pregnancy-related
hypertension or diabetes
Low birthweight
Common childhood
infectious diseases
Gestational age > 41 weeks
Ethnicity
Use of sex hormones
studies controlling for gestational age is small, there is
a suggestion of a relationship with low birthweight.
When reviewing the literature on the aetiology of
neuroblastoma it is necessary to consider the methodological challenges associated with such research.
Due to the rarity of this childhood tumour the majority of investigations have utilised a retrospective
case-control design, and as such, data are more likely
to be subject to erroneous parental memory and possibly also differential and intentional misreporting,
especially of socially unaccepted behaviours such
as illegal drug use and alcohol drinking during
pregnancy.
Some studies utilised birth certificates for the collection of medical information prior to diagnosis, a
data source with varied accuracy, depending on the
risk factor under study. A validation study of New
York State birth certificates found that, when compared with medical records, birth certificates had
high sensitivity and specificity for reporting use of
tobacco and illicit drugs but poorer sensitivity for the
use of prescription medications.115 Other studies have
also reported poorer sensitivity, although typically
high specificity, for maternal lifestyle factors and use
of prenatal care. In general, factors associated with
labour and delivery, such as birthweight and vaginal
or caesarean delivery, have been found to be recorded
fairly accurately.116
High birthweight
Gestational age < 35 weeks
Breast feeding
Growth in early childhood
Birth order
Paternal smoking
Differences may also be related to the choice of a
control group. One of the studies in this review used
three control groups: population controls, hospital
non-cancer controls and hospital controls diagnosed
with other cancers; the differences in findings reported
for each group across a variety of outcomes demonstrated the degree to which control group selection
influences results.47 Because of overmatching on shared
risk factors such as alcohol consumption,117,118 studies
utilising other cancer cases as controls may have biased
estimates of effect towards the null.
Given these limitations it is not surprising that the
literature has not always been consistent in its results.
With this in mind, we suggest the following considerations be taken into account in future epidemiological
research on neuroblastoma:
1 Investigate common sequence variants and the risk
of neuroblastoma
Molecular epidemiological studies of neuroblastoma have focused on molecular markers that influence disease prognosis, such as DNA methylation and
MYCN amplifications; only limited studies have been
conducted on the association between genetic factors
such as common sequence variants and the risk of
neuroblastoma.
2 Examine age-stratified risk factors
The differing molecular biological markers and prognosis of children diagnosed before 12–15 months in
Paediatric and Perinatal Epidemiology, 23, 125–143. © 2008 The Authors, Journal Compilation © 2008 Blackwell Publishing Ltd.
Epidemiology of neuroblastoma
comparison with children diagnosed at an older age
has led some researchers to speculate that neuroblastoma may represent two distinct entities.119 Several
studies have presented findings stratified by age at
diagnosis and have found that some exposures in
pregnancy do appear to be more strongly related to
earlier than to later diagnoses.48,50 It may help to shed
light on this complex disease if future studies with
adequate sample size reported both age-stratified and
combined estimates.
3 Conduct a large-scale collaborative study or pool
data
Many investigations of neuroblastoma and other
childhood cancers are limited to fewer than 300 cases
of disease, which does not allow for consideration of
rarer exposures. Studies of a potential effect resulting
from specific pharmaceutical or recreational drug use
in pregnancy necessitate either analyses of doseresponse effects or large sample sizes in order to
examine different drugs by themselves and also to
allow examining hypotheses regarding the trimester
of exposure. Such rare exposures may be best
examined in the setting of large-scale collaborative
studies or within populations in which certain exposures are more common. Alternatively, researchers in
the field should consider standardising or at least
sharing data collection methods to facilitate future
pooled analyses.
4 Other areas for further research
Several studies have identified potential risk or protective factors that, in our view, merit further investigation, including fetal growth, diet, breast feeding,
asthma or allergies and certain drugs, including recreational drugs, codeine and diuretics. Due to the
uneven medical surveillance across and within countries, it has not been well established whether there is
differential incidence by SES. The variation in incidence by SES seen in Germany could be a result of
certain exposures being more common among lower
SES subjects.
Studies examining associations with breast feeding
face challenges related to potential bias due to the
selection of healthier children for breast feeding. If
neuroblastoma is associated with congenital abnormalities, these sicker children may not be able to breast
feed successfully. Thus, in future studies it may be
useful to examine only children without concurrent
congenital malformations, or investigate the reasons
why women stopped breast feeding (normal weaning
vs. illness of the child).
139
There have been no studies that have investigated a
possible relationship between maternal diet and neuroblastoma. Other studies have found an influence of
pregnancy diet on the development of other childhood
cancers.120–122 The potential protective effect seen with
folic acid supplementation and intake of vitamin
supplements merits further investigation, especially in
the light of the established relationship between nutrient intake and neuronal development. More studies
that differentiate between types of vitamin supplements are needed.
Other areas meriting further research are alcohol
and recreational drug use and intake of codeine in
pregnancy. These areas are subject to potential bias
because data collection almost always depends on
accuracy of parental recall. These topics might be best
studied in settings where use of medication or alcohol
in pregnancy is more widely accepted. In addition,
researchers may consider utilising study methodologies shown to prompt memory and accuracy such as
asking specifically about certain drugs. In addition,
the data collection method, whether it is by selfadministered questionnaire or an interviewer, may
influence disclosure.123
When observing associations between drug use and
neuroblastoma, it is important to distinguish risks
from use of medication from risks owing to the underlying medical condition, a bias generally referred to as
confounding by indication. None of the studies investigating medication use were able to compare treated
and untreated mothers with the same underlying condition, which would allow estimating risk conferred
by the use of the medications from the risk owing to
the medical condition. Codeine is typically taken as a
cough suppressant or for pain relief, while diuretics are
used for cardiovascular, hepatic, renal or pulmonary
conditions. Until bias by indication can be addressed
properly in future studies, findings for risks owing
to certain medications should be interpreted with
caution.
In conclusion, although the aetiology of neuroblastoma remains largely unknown, a body of literature
has begun to emerge that suggests that certain exposures are more common among neuroblastoma
patients. These findings necessitate replication and the
field would be advanced by studies designed to precisely elicit the exposures and the time frames in which
they occur. The rarity of this disease is a challenge
for epidemiological research, and there is a need for
larger-scale studies to build on the knowledge base.
Paediatric and Perinatal Epidemiology, 23, 125–143. © 2008 The Authors, Journal Compilation © 2008 Blackwell Publishing Ltd.
140
J. E. Heck et al.
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