Cancer Epidemiology Biomarkers & Prevention Vol. 9, 967-972, September 2000
© 2000 American Association for Cancer Research
Parental Smoking and Alcohol Consumption and Risk of Neuroblastoma1
Qinghong Yang,
Andrew F. Olshan2,
Melissa L. Bondy,
Narayan R. Shah,
Brad H. Pollock,
Robert C. Seeger,
A. Thomas Look and
Susan L. Cohn
Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, North Carolina 27599 [Q. Y., A. F. O.]; Department of Epidemiology, The University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030 [M. L. B.]; Department of Pediatric Hematology-Oncology, Geisinger Medical Center, Danville, Pennsylvania 17822 [N. R. S.]; University of Florida, Pediatric Oncology Group Statistical Office and Department of Health Policy and Epidemiology, Gainesville, Florida 32610 [B. H. P.]; Children’s Hospital of Los Angeles, Children’s Cancer Group Neuroblastoma Resource Laboratory, Los Angeles, California 90027 [R. C. S.]; Dana Farber Cancer Institute, Boston, MA 02115 [A. T. L.]; and Children’s Memorial Hospital and Department of Pediatrics, Northwestern University, Chicago, Illinois 60614 [S. L. C.]
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Abstract
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Previous studies and animal evidence have suggested a relationship
between parental tobacco or alcohol use and the risk of some childhood
cancers, including neuroblastoma. A case-control study was conducted to
investigate the relationship between parental tobacco smoking, alcohol
consumption, and risk of neuroblastoma. Cases were children diagnosed
with neuroblastoma over the period 1992–1994 at Children’s Cancer
Group and Pediatric Oncology Group institutions throughout the United
States and Canada. One matched control was selected using random-digit
dialing. Information on parental smoking and drinking history was
obtained from 504 case and 504 control parents by telephone interview.
Overall, there was no consistent pattern of association with parental
smoking and alcohol consumption. For example, both maternal smoking and
drinking during the period from 1 month before pregnancy through
breastfeeding had adjusted odds ratios (ORs) of 1.1 [95% confidence
interval (CI), 0.8–1.4]. There was no association with paternal
smoking (OR, 1.2; 95% CI, 0.8–1.6) or paternal drinking 1 month
before conception (OR, 1.0; 95% CI, 0.7–1.4). There was no consistent
increase in risk by the amount of smoking or drinking during any time
period relative to pregnancy. There was no suggestion of an increased
risk when only one parent smoked. Smoking or drinking among both
parents did not jointly increase the risk of neuroblastoma in their
offspring. The child’s age at diagnosis, stage, or
MYCN oncogene amplification status did not
materially alter the OR estimates. It is concluded that the results
from this study do not indicate any evidence for a relationship between
neuroblastoma and parental tobacco or alcohol use.
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Introduction
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Neuroblastoma is an embryonic tumor of the sympathetic nervous
system. It is the third most common neoplasm of children under 15 years
of age and the most common tumor in infants (1, 2)
, but
little is known about the etiology of neuroblastoma. This early age at
diagnosis suggests that prenatal exposures might play an important
role. Previous epidemiological studies have reported that an increased
risk of neuroblastoma was associated with maternal use of certain
medications during pregnancy, parental occupational exposures, and
birth characteristics (3)
.
Tobacco smoke is of interest as a potential risk factor for
childhood cancers because it contains a number of mutagenic and
carcinogenic compounds that can cross the placenta (4, 5, 6)
.
Of particular interest are N-nitroso compounds (NNOs), which
have been shown to induce nervous system tumors in animals
(7, 8)
. Compounds in tobacco smoke, including
N-nitroso compounds, can also induce male germ cell
mutations (9)
. Alcohol and its metabolites have been shown
to be teratogenic, mutagenic, and carcinogenic (10, 11, 12)
.
Additionally, there have been case reports of fetal alcohol syndrome
and neuroblastoma (13)
. However, parental smoking and
alcohol consumption were not consistently associated with an increased
risk in previous epidemiological studies (14
, 15) . This
inconsistency may have resulted from the relatively small study sizes,
failure to consider specific time windows of exposure, and limited
information on confounding factors. We report the results of a large
case-control study that evaluated potential risk factors for
neuroblastoma, including parental smoking exposure and alcohol
consumption during time periods before conception and pregnancy and
after birth.
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Subjects and Methods
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Cases.
Cases were children under age 19 years, newly diagnosed with
neuroblastoma during the study period (1992–1994) at member
institutions of two North American collaborative clinical trial groups:
the Children’s Cancer Group (CCG) and the Pediatric Oncology Group
(POG). All of the neuroblastoma cases were pathologically confirmed.
Case eligibility criteria included: physician consent; the availability
of the biological mother for interview; the ability on the part of the
parents to speak either English or Spanish; and the presence of a
telephone in the household. Among the 741 potentially eligible
cases, a total of 538 (73% of eligible) case mothers were successfully
interviewed. A total of 405 case fathers were independently
interviewed, and proxy interviews were conducted with case mothers when
fathers were unavailable (n = 67; 12%). Reasons for
nonparticipation of mothers included physician refusal
(n = 90; 12%), mother’s refusal
(n = 57; 8%), not traceable (n = 44;
6%), and other reasons (n = 12; 2%).
Controls.
One control was selected for each case using a random-digit
dialing method based on the first eight digits of the case’s telephone
number (16)
. Each randomly selected control number was
contacted up to 6 times. Controls were individually matched to cases on
date of birth (±6 months for cases 
3 years of age and ±1 year for
cases >3 years of age). The response proportion for the random-digit
dialing screening phase was 74%. Eligibility criteria for controls
were the same as for the cases. Among the 703 eligible controls, 504
(72%) control mothers were successfully interviewed, and 304 control
fathers were directly interviewed. Proxy interview for fathers was
obtained for 142 (28%) controls. The reasons for mothers’
nonparticipation were refusal (n = 143; 20%) or not
traceable (n = 57; 8%).
Interview.
Trained interviewers administered a structured telephone interview
to parents. Parents of cases and controls were asked for information
about occupational history, medication use, pregnancy history,
pregnancy and birth complications, and other factors. Parental smoking
history included smoking status (never, past, and current), timing of
smoking (month before the index pregnancy; first, second, and third
trimesters separately; after birth; and during breastfeeding),
intensity of smoking (number of cigarettes or packs per day), and
duration of smoking (years). Ever-smoking was defined as a history of
smoking at least one cigarette per day for 6 months or longer. In
addition, information on tobacco type (cigarette, cigar, pipe, chewing,
snuff) was also requested from fathers. Mothers of cases and controls
were asked about alcohol consumption with respect to timing (month
before, during pregnancy, and during breastfeeding), types of alcohol
(wine, beer, and hard liquor), frequency and quantity of consumption
(glass/cans of beer or shots of liquor or glasses of wine per day,
week, or month). For paternal alcohol consumption, the timing of
exposure was restricted to 2–12 months and 1 month before pregnancy.
Data Analysis.
We estimated the risk of neuroblastoma associated with parental
cigarette smoking and alcohol consumption using conditional logistic
regression. Cigarette smoking was analyzed as dichotomous (no, yes) and
quantitative (cigarettes per day and pack-years) variables. Paternal
smoking was also evaluated according to type of tobacco consumed. The
total amount of alcohol consumption was calculated by summing the
number of grams of alcohol for all of the three types of alcoholic
beverages. It was assumed that a 12-ounce bottle or can of beer
contained 12.8 g of alcohol; a 4-ounce glass of wine contained
10.8 g of alcohol; and a 1.5-ounce shot of liquor contained
15.1 g of alcohol (United States Department of Agriculture
Nutrient Database for Standard Reference, Release 12, March 1998).
Alcohol consumption was examined in different forms: a dichotomous
variable (none, yes), a quantitative variable (grams per day), and by
type (beer, wine, and liquor). The exposure variables were further
evaluated based on the timing of exposure such as before pregnancy; in
first, second, and third trimesters; during breastfeeding; and after
birth. In the analyses of the fathers’ data, results from the entire
dataset (direct and proxy interview combined) were compared with the
analysis of data from direct paternal interview.
Maternal education, household income in the birth year, child’s
gender, and mother’s race were included as potential confounders in
the logistic regression analysis. The joint effects (interaction) of
maternal and paternal smoking as well as parental drinking were also
evaluated. Child’s age at diagnosis was investigated as a potential
effect modifier. Because stage and tumor MYCN oncogene
amplification status may represent a clinically and genetically
distinct subgroup of neuroblastoma cases (17)
, additional
analyses were conducted among the subgroups defined by these factors.
The International Neuroblastoma Staging System was used.
MYCN copy number was determined by Southern blot
(18)
or fluorescence in situ hybridization
(19)
.
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Results
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In total, 504 matched pairs were used for the analysis of
maternal smoking and alcohol consumption. Of the 409 cases with staging
data, 16% were stage 1, 6% stage 2a, 6% stage 2b, 18% stage 3, 46%
stage 4, and 7% stage 4S. A total of 381 cases had MYCNdata, with 67 case tumors having detectable amplification.
Complete information about paternal exposure was available for 390
matched pairs. Table 1
presents the distribution of cases and controls according to selected
sociodemographic factors. Slight case-control differences were found
for gender and maternal race. More case mothers than control mothers
had less than a high school education
(OR,3
2.2; 95% CI, 0.8–6.3). There was also some indication of cases
being more likely than controls to have lived in a household with an
income either <$10,000 or >$50,000 in the year of the birth. There
was some indication of an increased risk of advanced maternal age (
40
years), although the estimate was imprecise. The pattern of
case-control difference was similar for paternal demographic
characteristics (data not shown).
Overall, 40% of women in the case group and 38% of women in the
control group had ever smoked (OR, 1.0; CI, 0.7–1.3). No association
with smoking around pregnancy (1 month before pregnancy through
breastfeeding; OR, 1.1; CI, 0.8–1.4) was found (Table 2)
. Smoking before pregnancy, during pregnancy (three trimesters), or
during breastfeeding did not show any increased risk. Further
evaluation of the average number of cigarettes smoked per day during
the first and second trimesters did not show any pattern of
association, although the estimates were imprecise. Similar results
were found for the amount of smoking during other time periods and the
duration of smoking during pregnancy (data not shown).
Overall, there was no association observed for women who ever
drank alcohol around pregnancy (OR, 1.1; CI, 0.8–1.4; Table 3
). There were moderate associations with drinking during the first,
second, and third trimesters, with the strongest effect in the second
trimester (OR = 1.6; CI = 1.0–2.4). However, when the amount
of alcohol consumption during those specific periods was evaluated, a
strong dose-response gradient was not found, although the category
1.5–5 g/day showed elevated but imprecise ORs in the first (OR, 1.9;
CI, 0.9–3.9) and second (OR, 2.1; CI, 0.8–5.3) trimesters. No
association was found with the type of alcohol (wine, beer, or liquor)
that women consumed.
With respect to paternal smoking, 46.4% of case fathers and
45.5% of control fathers ever smoked, on average, at least one
cigarette per day for at least 6 months during their lifetime (OR, 1.0;
CI, 0.7–1.3; Table 4
). No elevated ORs were observed for smoking around pregnancy (OR, 1.0;
CI, 0.7–1.4) and during each trimester (Table 4)
. Dose-response
relationships were not found for average number cigarette per day,
pack-years, or duration of smoking. However, a weak association was
found for smoking more than 20 cigarettes per day during the month
before pregnancy (OR, 1.5; CI, 0.8–2.7). There was no association with
smokeless tobacco use. Cigar and pipe smoking could not be evaluated
because of the small number of users. Additional analyses of paternal
smoking among offspring of nonsmoking mothers did not reveal any
important elevations in risk. No differences were found using only
paternal self-reported data.
No associations were found for lifetime paternal drinking (OR, 0.8; CI,
0.5–1.1), drinking 2–12 months before pregnancy (OR, 1.1; CI,
0.8–1.6), or one month before pregnancy (OR, 1.0; CI, 0.7–1.4; Table 5
). There was no suggestion of a dose-response relationship for amount of
alcohol consumption per day or variation in risk according to type of
alcohol consumed. Analysis of smoking and alcohol consumption history
using only the direct self-reported information gave similar results
(data not shown). No substantial changes were shown from the analysis
controlling for maternal smoking and drinking status.
The joint effects of maternal smoking and paternal smoking as well as
maternal drinking and paternal drinking were also examined (data not
shown). Using nonsmokers (or nondrinkers) as the reference category, we
found no increased risk for any separate or joint effect. For example,
with a history of both parents having smoked around pregnancy the OR
was 1.3 (CI, 0.9–2.0) and for both parents having reported drinking
around pregnancy the OR was 1.2 (CI, 0.8–1.8). The results did not
differ for other time periods or using only paternal self-report data.
The evaluation of parental smoking and alcohol consumption did
not show heterogeneity based on age at diagnosis (data not shown). We
also analyzed case subgroups based on case MYCNamplification status or stage and did not find a consistent
pattern of association. For example, maternal smoking around pregnancy
was associated with an imprecise risk estimate among cases with a tumor
that had MYNC amplification (maternal smoking and MYCN+ OR,
0.7; CI, 0.3–1.9; maternal smoking and MYCN– OR, 1.0; CI,
0.7–1.5).
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Discussion
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Our study was the first to comprehensively evaluate the effect of
parental smoking and alcohol consumption on the risk of neuroblastoma,
including the evaluation of timing of exposure, type of tobacco and
alcohol used, and joint effects of both parents’ smoking and alcohol
consumption. Overall, we did not find any consistent pattern of
association with parental smoking or alcohol consumption during
specific periods before, during, or after pregnancy.
Two studies have investigated parental smoking and alcohol
consumption as potential risk factors for neuroblastoma, but the
results were inconsistent. A study of 104 neuroblastoma cases
identified by the Greater Delaware Valley Registry (14)
reported an elevated OR for maternal alcohol consumption of one or more
drinks per day during pregnancy (OR, 9.0; CI, 2.16–37.56) and for
maternal binge alcohol consumption of three or more drinks per day
during pregnancy (OR, 6.0; CI, 1.26–28.54). No association with
maternal cigarette smoking before or during pregnancy was found (OR,
1.3; CI, 0.8–2.1). Another study (15)
based on 101 cases
and children with other cancers as controls found an elevated risk with
maternal smoking during the year before the child’s birth (OR, 1.9;
CI, 1.1–3.2), but it did not find an association with maternal alcohol
consumption (OR, 0.7; CI, 0.4–1.1). Random error, the time period when
the studies were conducted, and variation in control groups may explain
some of the differences among study findings. The relatively small
sample size is the major limitation of those studies. In addition, they
did not obtain detailed information on the amount of tobacco and
alcohol used during different time periods before, during, and after
pregnancy. Our relatively large study size allowed us to evaluate
changes in consumption levels before and during pregnancy.
The response proportions in both case and control groups were below
75%, which may indicate potential selection bias. We do not have
direct information to characterize nonresponders. However, the age at
diagnosis in our case group is similar to the distribution in
Surveillance, Epidemiology, and End Results data
(1)
.
Misclassification of parental smoking and drinking behaviors is also a
concern. Studies with cotinine measurements have shown that pregnant
women accurately report whether they had smoked (20
, 21)
;
however, they do not accurately report the actual number of cigarettes
smoked. In general, good agreement between self-reported alcohol
consumption and detailed records for both women and men has
been found (22)
. Onestudy examined potential
misclassification of alcohol and cigarette use during pregnancy in
relation to several adverse outcomes, including congenital
malformations, and reported little differential reporting bias
(23)
.
In our case group, we had fewer fathers with proxy data (12%)
compared with control fathers (28%). To evaluate the effect of this
potential problem, we repeated the analyses using only paternal
self-reported information and no substantial differences were observed.
Although we examined the risk of paternal smoking among children of
nonsmoking mothers and the risk of maternal smoking with nonsmoking
fathers, we did not directly measure passive smoking exposure from
relatives or others in the household. In conclusion, the results of our
large comprehensive study indicate that parental smoking or alcohol
consumption does not increase the risk of neuroblastoma.
Appendices
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Acknowledgments
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We thank Joanna Smith for programming help and David Savitz for
comments on an earlier
draft.
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Footnotes
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This study was supported in part by Grant
CA57004 from the National Cancer Institute and by numerous grants from
the Division of Cancer Treatment, National Cancer Institute, NIH
Department of Health and Human Services to Children’s Cancer Group and
Pediatric Oncology Group investigators, listed with their institutions
and grant numbers in the . 
2 To whom requests for reprints should be
addressed, at Children’s Cancer Group, P. O. Box 60012, Arcadia, CA
91066-6012.
3 The abbreviations used are: OR, odds ratio; CI,
confidence interval.
Received 3/22/00;
revised 6/ 6/00;
accepted 6/19/00.
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Abstract
Introduction
