Neuroblastoma and Leukemia after
Induction of Maternal Ovulation
Motoi Nishi, Masako
Tanimura
Motoi Nishi, Department of Fundamental Health
Sciences, Health Sciences University of Hokkaido, 1757 Tobetsu, Hokkaido
061-0293 Japan
Masako Tanimura, Department of Pediatrics, School of
Medicine, Kyorin University, Japan
Correspondence to: Motoi
Nishi, Department of Fundamental Health
Sciences, Health Sciences University of Hokkaido, 1757 Tobetsu, Hokkaido
061-0293, Japan. motoi@hoku-iryo-u.ac.jp
Tel: +81-133-23-1211
Fax: +81-133-23-1669
Received: September 5, 2013
Revised: October 3, 2013
Accepted: October 10, 2013
Published online: November 18, 2013
ABSTRACT
AIM: To estimate the contribution of ovulatory agents to the occurrence of
neuroblastoma and leukemia in children.
MATERIALS AND METHODS: We studied cases registered in the
Japan Children's Cancer Registry from 1985 to 2004. Among them, the mothers of
15155 pediatric patients received no medications before pregnancy (group
without medications) and those of 95 patients were given ovulatory medications
(ovulatory group). The frequency of each disease (%) in the groups was
calculated. If medications before pregnancy make no contribution to the
occurrence of malignant neoplasms of children, the frequency of each disease in
the ovulatory group should be the same as that in the group without
medications. Based on this assumption, an expected value was calculated for
each disease. P values were calculated through Poisson distribution, employing
"expected numbers" and "observed numbers."
RESULTS: In the ovulatory group, there were significantly more neuroblastoma
patients (31 cases) than expected (18.32) (P=0.001), and significantly
less acute lymphocytic leukemia patients (19) than expected (26.78) (P=0.037).
There was no significant difference concerning acute non-lymphocytic leukemia
patients (5 vs 9.00) (P=0.074). In the subgroup whose ages ranged
from 1 to 4 years, there were significantly more neuroblastoma patients, too.
In the subgroups of both males and females, there were significantly more
neuroblastoma patients. In the subgroup of females, the number of cases with
acute lymphocytic leukemia was significantly low.
CONCLUSIONS: Ovulatory agents promote the occurrence of
neuroblastoma whereas they suppress the occurrence of acute lymphocytic
leukemia.
© 2013 ACT. All rights reserved.
Key words: Cancer registry; Children; Leukemia; Neuroblastoma;
Ovulatory agents
Nishi M, Tanimura M. Neuroblastoma and Leukemia after Induction of Maternal Ovulation. Journal
of Tumor 2013; 1(6): 49-51 Available from: URL: http://www.ghrnet.org/index.php/JT/article/view/520
INTRODUCTION
The causes of
malignancies, including environmental ones, for the most part remain unknown.
In Australia, 5 children with neuroectodermal tumors (3 neuroblastomas, 1
medulloblastoma, and 1 PNET) who were born through artificial fertilization
were reported, and the necessity of investigating the relation between
artificial fertilization and these malignancies was pointed out[1].
The mothers of these 5 children had taken ovulatory agents. Considering this
fact, we examined the intake of ovulatory agents with regard to 6236 cases of
malignancies that were registered in the Japan Children's Cancer Registry from
1985 to 1989. There was a significant correlation between neuroectodermal
malignant tumors of children and ovulatory agent intake[2-3].
In the present study, we report the
relationships between intake of ovulatory agents and neuroblastoma and
leukemia, employing many more cases from the Japan Children's Cancer Registry
with other analytical methods.
The registration form of the
Japan Children's Cancer Registry has a record of medications of mothers before
pregnancy. A total of 23011 cases were registered from 1985 to 2004. The present subjects were 17218 whose
mothers' histories of medications before pregnancy were recorded. Among them,
there were 15155 cases with a record of their mothers having received no
medications before pregnancy (group without medications). For 95 cases the
mothers had been given ovulatory medications (ovulatory group).
MATERIALS AND METHODS
Analysis as a whole
Malignant neoplasms
were classified using the ICD 9. If medications before pregnancy make no
contribution to the occurrence of malignant neoplasms of children, the
frequency of each disease in the ovulatory group should be the same as that in
the group without medications.
The frequency of each
disease (%) in the group without medications was calculated. The frequency (%)
multiplied by 95 was regarded as the "expected number" of cases for
each disease in the ovulatory group. P values were calculated through
Poisson distribution, employing "expected numbers" and "observed
numbers."
Analysis of subgroups
The age distribution
of occurrence is different among diseases. For example, most cases of
neuroblastoma, are found at under 5 years. Moreover, in the period of the
present study, many cases found by mass screening for neuroblastoma and
consequently diagnosed at 0 years of age were included. The accuracy of
mothers' recall of things before or during pregnancy is different among those
whose childrens’ ages at diagnosis are, e.g., 1 year and 10 years. Therefore,
we performed analysis for subgroups whose ages at diagnosis were 0 years, 1-4
years and 5-14 years of age, in addition to the subgroups of males and of
females.
RESULTS
Table 1 shows the
percentages of each of the diseases in the group without medications.
Table 2 shows the number of
each of the diseases, the expected numbers, and P values in the ovulatory
group. In the ovulatory group, there were significantly more neuroblastoma
patients (31 cases) than expected (18.32) (P=0.001), and significantly
less acute lymphocytic leukemia patients (19) than expected (26.78) (P=0.037).
There was no significant difference concerning acute non-lymphocytic leukemia
patients (5 vs 9.00) (P=0.074).
In the subgroup whose ages
ranged from 1 to 4 years, there were significantly more neuroblastoma patients
as well. In both the male and female subgroups there were significantly more
neuroblastoma patients. In the female subgroup, the number of cases with acute
lymphocytic leukemia was significantly low.
DISCUSSION
Yanaihara et al[4]
estimated that the number of women who were taking ovulatory agents in February
1999 in Japan was 165500. According to the national census in 2000, the number
of married women aged from 20 to 49 years was 15687392. The percentage of those
who take ovulatory agents in Japan is, therefore, about 1%.
The risk of developing
neuroblastoma was significantly high in the ovulatory group. Since the present
study employed many more cases than previous studies, its reliability does not
seem to be inferior to them. Therefore, ovulatory agents are probably one of
the risk factors for the development of neuroblastoma.
In a case-control study of
504 neuroblastoma cases conducted in the USA and Canada, the odds ratio was
1.4, though it was not significant[5]. The odds ratio of the group
aged 1-2 years was higher than that of the group aged 0 years. Their results
are not contradictory to ours.
In Denmark, 51 malignancies
occurred in 30364 children born from 1960 to 1990 whose mothers took ovulatory
agents. In that study the incidences of sympathetic nervous tumors including
neuroblastoma was high (observed, 7 cases; expected, 3.3; relative risk, 2.14),
though it was not significant (95% CI, 0.9-4.4)[6]. Since the number
of observed cases was only 7, and the lower limit of the 95% CI was 0.9 which
is very near to 1.0, their findings do not completely deny the effects of
ovulatory agents to promote the occurrence of neuroblastoma.
There are several factors
associated with an increased risk of neuroblastoma in offspring, such as two or
more prior induced abortions[7], a shorter gestational duration and
low birth weight[8]. Bluhm et al[9] reported that
maternal recreational drug use and marijuana use during pregnancy increased the
risk of neuroblastoma. (In Japan, however, marijuana use is strictly prohibited,
and there are very few pregnant women who use it). Since the present study is
not a case-control one, we could not take account of confounding factors. In
this sense, the present conclusion is not necessarily decisive.
For the purpose of the
present study, the most precise method was to longitudinally follow those who
were given medications before/during pregnancy and those who were not given any
medications, and to observe the occurrence of malignant diseases in their
children. This method was, however, not practical, since it required a long
period, and since the incidence of malignant diseases during childhood is low.
In the present analysis, therefore, we regarded the frequency of each malignant
disease in the group without medications as the "natural frequency",
and we compared the natural frequency and the frequency in the group with
medications.
Generally, 30-40% of the
malignant neoplasms occurring in the children younger than 15 years of age are
leukemia, and about 10%, neuroblastoma. However, the distribution of
malignancies in the group without medications was different from this general
one. Since the present study period included the years when a nationwide
program of mass screening for neuroblastoma was performed, the percentage of neuroblastoma
in the group without medications was relatively high. These conditions,
however, had no influence on the present calculations. In the group aged 1-4
years, where the risk was significantly high, there were smaller numbers of
neuroblastoma patients found through mass screening for neuroblastoma than in
group aged 0 years. Thus the influence of the mass screening on the group aged
1-4 years was not large.
The reason why a single
agent has a protective effect on one cancer type and a promoting effect on
another type cannot be clarified in the present study. But growth factors, such
as the vascular endothelial growth factor, induced by clomiphene especially in
ovarian hyperstimulation syndrome, might have something to do with the
promotion of neuroblastoma which is a solid tumor. Bruinsma et al[10]
reported that children conceived using in-vitro fertilization and related
procedures did not have a significantly increased incidence of cancer. 24.3%
(1060 cases) of their subjects were given clomiphene, and 3 male cases with
leukemia, but no female cases with it were found. This is not contradictory to
the present results that the number of female cases with acute lymphocytic
leukemia was significantly low.
Using the same analytical
methods as in the present study, one of us[11] reported that
children with Down syndrome did not develop neuroblastoma, whereas they
developed significantly more leukemia. The present study showed that ovulatory
medications promoted the occurrence of neuroblastoma, whereas they suppressed
the occurrence of acute lymphocytic leukemia. Thus, the contribution of
ovulatory agents is nearly inverse to that of Down syndrome.
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Peer reviewers:
Thomas
Roujeau, Head of the Pediatric Neurosurgical Unit, Department of Neurosurgery,
Hôpital Gui de Chauliac, 80 av Augustin Fliche, 34 295 Montpellier cedex 5,
France; Daniel satgé MD, PhD, Institut Universitaire de Recherche clinique,
equipe epidemiologie biostatistiques sante publique (EA 2415), 641 avenue du
doyen Gaston Giraud, 34 094 Motpellier France.
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