Int. J.
Cancer: 123, 436–443 (2008)
' 2008 Wiley-Liss, Inc.
Fetal growth and the risk of childhood CNS tumors and lymphomas
in Western Australia
Elizabeth Milne1*, Crystal L. Laurvick1, Eve Blair1, Nicholas de Klerk1, Adrian K. Charles2,3 and Carol Bower1
1
Telethon Institute for Child Health Research, Centre for Child Health Research,
The University of Western Australia, Perth, Western Australia
2
Princess Margaret Hospital and King Edward Memorial Hospital for Women, Subiaco, Perth, Western Australia
3
Schools of Paediatrics and Child Health, and Women and Infants Health, University of Western Australia
The etiology of childhood cancers is largely unknown, although
the early age at diagnosis has led to particular interest in in utero
and perinatal factors. Birth weight is the most frequently studied
perinatal factor in relation to risk of childhood cancers, and
results have been inconsistent. We investigated whether the risk of
CNS tumors and lymphomas in children was associated with three
measures of the appropriateness of intra-uterine growth: propor-
tion of optimal birth weight (POBW), birth length (POBL) and
weight for length (POWFL). A cohort of 576,633 infants born in
Western Australia in 1980–2004 were followed from birth to diag-
nosis of a CNS tumor (n 5 183) or lymphoma (n 5 84) before age
15, death, or December 31, 2005, and analyzed with Cox regres-
sion. Overall, there was little evidence of any association between
fetal growth and risk of CNS tumors, although risk of ependy-
moma/choroid plexus tumors was positively associated with
POBL and negatively associated with POWFL. The risk of Hodg-
kin and Burkitt lymphoma increased with increasing fetal growth
among boys only, whereas the increased risk observed with non-
Hodgkin lymphoma was only in girls. These associations between
fetal growth and disease risk were also observed among children
not classified as high birth weight, suggesting that accelerated
growth is more important than birth weight per se. Results were
similar when cases were compared with their unaffected siblings,
suggesting that the increased growth associated with cancer risk
was not general to the family. The associations we observed are
consistent with causal pathways involving fetal growth factors.
' 2008 Wiley-Liss, Inc.
Key words: CNS tumors; lymphoma; childhood; cohort study; intra-
uterine growth
The etiology of childhood cancers is largely unknown, although
the early age at diagnosis has led to a growing interest in both
in utero and perinatal factors. Birth weight is the perinatal factor
that has been most frequently studied in relation to childhood
cancer risk, and it is one of the few for which positive associations
have been reported. Positive associations with birth weight
have generally been reported for acute lymphoblastic leukemia
(ALL),1–9 while the findings for other cancer types have been con-
flicting. For example, studies of childhood lymphomas have vari-
ously reported associations with low birth weight,9,10 high birth
weight,4,11,12 or have shown no relationship.13,14 The variation in
the findings for any given childhood cancer may be due in part to
differences in study design, sources of data, case definitions,
method of categorization of birth weight, and whether adjustment
is made for gestational age. The latter is required to differentiate
between an association with birth weight per se and one with
intra-uterine growth.
The mechanism(s) underlying the observed association between
birth weight and some childhood cancers has not been well eluci-
dated. Birth weight has been positively correlated with insulin-like
growth factor-I (IGF-I) and to a lesser extent with insulin-like
growth factor-II (IGF-II),15,16 which could be explained by their
roles in regulating the normal growth and differentiation of cells
and tissues during fetal development.17 Some tumors have been
shown to produce IGF-I, IGF-II or their binding proteins, or to
possess IGF receptors18–21; IGF-I, in particular, has been shown to
inhibit the normal process of programmed cell death (apopto-
Publication of the International Union Against Cancer
sis).22,23 The mitotic properties of IGFs, coupled with their ability
to inhibit cell death, are thought to enhance tumor growth.24–27
We recently reported a moderately strong positive association
between the risk of ALL and proportion of optimal birth weight.28
These findings are consistent with a biologically plausible mecha-
nism of accelerated growth associated with the growth-promoting
effects of IGFs in normal as well as cancer cells, and/or failure of
apoptosis of pre-leukemic cells initiated by an in utero ‘first hitÕ.29
A study of fetal growth and risk of non-CNS solid tumors is cur-
rently under way within our group. The aim of the present study
was to investigate whether the risk of childhood CNS tumors or
lymphomas is associated with the appropriateness of fetal growth.
Material and methods
We used the Western Australian Data Linkage System30 to
obtain information on all births from the midwives’ notifications
and birth registrations in Western Australia for the period 1980–
2004 and cancer registrations for children diagnosed in 1980–
2005 while aged 0–14 years. Linkage to the Birth Defects Regis-
try31 identified all children with a birth defect. The data were
organized into mother-child pairs with a unique encrypted identi-
fier for each individual. The case/noncase status for each child
was also determined. Siblings of cases were identified as those
individuals who had the same maternal identifier as a cancer case.
The final linked data file was de-identified to protect patient confi-
dentiality and was current as at May 2006.
There were 613,613 birth registrations between 1980 and 2004.
The exclusions applied to the data in defining the study cohort are
depicted in Figure 1. There were 29,969 noncases and 101 cancer
cases with birth defects, including Down syndrome, that were
excluded from the study. However, cancer cases with a birth
defect caused by the cancer, such as hydrocephalus caused by a
congenital brain tumor, or whose sole birth defect was the cancer
(n 5 46), were retained in the dataset. We excluded children with
other birth defects because of the potential for confounding of the
relationship between cancer risk and POBW; for example, some
birth defects are known to be related to both birth weight and risk
of some cancers.32,33 The cohort of eligible subjects comprised
Abbreviations: ALL, acute lymphoblastic leukemia; CNS, central nerv-
ous system; HR, hazard ratio; ICCC3, International Classification of Child-
hood Cancer 3rd Edition; IGF, insulin-like growth factor; IRR, incidence
rate ratio; NHL, non-Hodgkin lymphoma; OR, odds ratio; PNET, primitive
neuroectodermal tumour; POBL, proportion of optimal birth length;
POBW, proportion of optimal birth weight; POWFL, proportion of optimal
weight for length; RR, relative risk; SD, standard deviation.
Grant sponsor: National Health and Medical Research Council of Aus-
tralia; Grant number: 404086. Grant sponsor: NHMRC; Grant numbers:
353628, 353514.
*Correspondence to: Telethon Institute for Child Health Research, PO
Box 855, West Perth, Western Australia 6872, Australia.
Fax: 161-08-9489-7700. E-mail: lizm@ichr.uwa.edu.au
Received 27 November 2007; Accepted after revision 22 January 2008
DOI 10.1002/ijc.23486
Published online 15 April 2008 in Wiley InterScience (www.interscience.
wiley.com).
 RISK OF CHILDHOOD CNS TUMORS AND LYMPHOMAS
FIGURE 1 – Flow chart of cohort selection.
576,366 noncases, 183 cases of CNS tumors and 84 cases of lym-
phoma. Children with other cancer diagnoses (n 5 614) were
included in the noncase group, as they were considered to be at
risk of the cancers under study.
The outcomes of interest in this study were CNS tumors or lym-
phomas diagnosed before age 15 years. We used the International
Classification of Childhood Cancer 3rd Edition (ICCC3) codes34 to
determine the specific cancer groupings to be investigated; these
were astrocytoma, medulloblastoma/primitive neuroectodermal tu-
mor (PNET), ependymoma/choroid plexus tumor, other gliomas,
other intracranial/spinal tumors, Hodgkin lymphoma, non-Hodgkin
lymphoma (except Burkitt lymphoma) (referred to as ‘NHLÕ hereon
in this paper) and Burkitt lymphoma. The ICCC3 categories are
shown in Appendix 1. The following categories were not analyzed
individually as there were too few cases: four intracranial/spinal
germ cell tumors, one unspecified CNS tumor, five miscellaneous
lymphoreticular neoplasms and one unspecified lymphoma. How-
ever, the five cases from the first two categories were included in the
analysis of ‘All CNS tumors combinedÕ. Children were followed-up
from birth to their date of diagnosis, 15th birthday, date of death, or
31 December 2005 – whichever occurred first.
The main explanatory variable was ‘proportion of optimal birth
weightÕ (POBW) whose calculation is described in detail else-
where.35 Briefly, it is an estimate of the appropriateness of intra-
uterine growth and is the ratio of the observed birth weight to the
‘optimal birth weightÕ. Optimal birth weight is calculated from a
regression equation including terms for gestational duration,
maternal height, parity and infant sex, derived from a total popula-
tion of singleton births that excluded risk factors for intra-uterine
growth restriction, including maternal smoking. To identify the
437
nature of any growth deviation more specifically, we also investi-
gated the comparable measure of the appropriateness of longitudi-
nal growth ‘proportion of optimal birth lengthÕ (POBL) (primarily
reflecting skeletal growth); and the similarly derived ‘proportion
of optimal weight for lengthÕ (POWFL), a measure of the appro-
priateness of birth weight for length (primarily reflecting soft tis-
sue growth). To assess the importance of each of these measures
of intra-uterine growth to the risk of each childhood cancer, they
were examined separately in the analysis. z-scores of POBW,
POBL and POWFL were calculated so that the estimated change
in the risk of a specific cancer was per standard deviation (SD),
allowing the regression estimates of each measure to be compared
directly. The population means and SDs used in the calculation of
the z-score for each variable were those shown for the noncase
group in Table I. Additional explanatory variables that were inves-
tigated include sex and birth order (‘first bornÕ compared with
‘subsequently bornÕ).
Cox proportional hazard regression models were initially fitted
in STATA version 9.036 using the fractional polynomial procedure
to determine the appropriate form of each continuous variable to
include in the models. In each case, a linear term was found to be
the most appropriate. The PHREG procedure in SAS version 9.137
was used for Cox regression analyses to determine the association
between the explanatory variables and the risk of being diagnosed
with each cancer. Where appropriate, we investigated possible
effect modification by sex and birth order, and produced sex- and
birth order-specific estimates. The ‘discreteÕ option in the PHREG
procedure was used to perform a conditional logistic regression of
cancer cases matched to their unaffected siblings. All confidence
intervals (CIs) presented are 95% CIs.
438 MILNE ET AL.

Results

97.6 (10.4)
96.9 (10.6)

96.0 (10.6)
97.1 (11.4)
96.3 (10.2)

100.1 (12.0)
93.7 (8.8)
97.1 (9.1)

99.8 (7.7)
97.5 (8.1)
A total of 183 CNS tumors and 84 lymphomas were identified.

Mean (SD)
POWFL
The numbers of each type are shown in Table I, along with other

Includes 18 Ependymomas and 3 choroid plexus tumors.–2Includes 32 Medulloblastomas and 6 PNETs.–3Includes 4 intracranial/spinal germ cell tumors and 1 unspecified CNS tumor.
descriptive characteristics. As previously indicated, some very
rare tumours—including 6 lymphomas—were not analysed indi-
vidually and are not presented in the tables.
The majority of CNS tumors and all but four of the lymphoma
cases were diagnosed at or after 2 years of age (data not shown).
99.5 (4.5)
99.6 (4.8)
101.0 (4.0)
99.3 (3.5)
98.5 (4.1)
100.2 (5.0)
99.4 (4.5)
101.3 (4.2)
100.0 (4.5)
98.7 (5.0)
Mean (SD)

Mean parental age was similar among the noncases and all cancer
POBL

categories, while a higher proportion of all categories (except

‘Other intracranial/spinalÕ tumors) were of Caucasian ethnicity

SD, Standard deviation; POBW, proportion of optimal birth weight; POBL, proportion of optimal birth length; POWFL, proportion of optimal weight for length.
compared with noncases (data not shown).
The results of the univariate Cox regression analysis are shown
in Table II. The risk of CNS tumors was similar in boys and girls,
97.5 (12.5)
96.9 (13.5)
95.0 (10.7)
96.7 (10.6)
94.9 (12.3)
97.6 (12.4)
96.2 (12.5)

98.1 (11.9)
99.2 (13.7)
TABLE I – DESCRIPTIVE CHARACTERISTICS OF STUDY COHORT BY ICCC3 CNS TUMOUR AND LYMPHOMA CATEGORIES

101.4 (9.9)
while boys appeared to have a higher risk of Burkitt and Hodgkin
Mean (SD)
POBW

lymphomas than girls. There was some evidence that higher birth
order was associated with an increased risk of ‘Other gliomasÕ,
and a reduced risk of ‘Other intracranial/spinal tumorsÕ (Table II).
Overall, there was little evidence of any association between the
three measures of fetal growth and risk of CNS tumors, although
there was a suggestion that risk of ependymoma/choroid plexus
280,449 (48.7)
32 (40.5)
9 (42.9)
14 (63.6)
18 (47.4)
4 (22.2)
80 (43.7)
15 (50.0)
14 (50.0)
9 (45.0)

tumours may be positively associated with POBL (HR 1.37) and

Subsequent

negatively associated with POWFL (HR 0.68) (Table II). There

was also some suggestion that the risk of medulloblastoma/PNET
was inversely associated with each of the three growth measures.
There was weak evidence of an increased risk of Hodgkin lym-
Birth order

phoma with increasing POBW and POBL (Table II). Inclusion of

maternal ethnicity and parental age in the regression models for
POBW, POBL, and POWFL and any of the cancers produced no
295,917 (51.3)
47 (59.5)
12 (57.1)
8 (36.4)
20 (52.6)
14 (77.8)
103 (56.3)
15 (50.0)
14 (50.0)
11 (55.0)

material change in the hazard ratios (data not shown).

First born

Univariate analyses indicated that high birth weight was not

associated with any CNS tumor or lymphoma (data not shown).
There was some suggestion of an increased risk of astrocytoma
with birth weight <2,500 g (RR 1.88:0.72–4.91), although the
estimate was imprecise
The potential for interactions between sex and POBW, POBL
282,608 (49.0)
40 (50.6)
10 (47.6)
11 (50.0)
16 (42.1)
8 (44.4)
85 (46.4)
10 (33.3)
12 (42.9)
4 (20.0)

and POWFL was explored, and the results were suggestive of an

Females N (%)

increased risk of ‘Other intracranial/spinalÕ tumors associated with

an increase in each of the three measures in boys only (Table III).
No other associations with CNS tumors were apparent in either
sex. The increased risk of Hodgkin lymphoma associated with an
increase in each of the three measures was only evident in boys.
Sex

Male-only associations were also observed between risk of Burkitt

lymphoma and POBW and POWFL. Conversely, the positive
293,758 (51.0)
39 (49.4)
11 (52.4)
11 (50.0)
22 (57.9)
10 (55.6)
98 (53.6)
20 (66.7)
16 (57.1)
16 (80.0)

association between risk of NHL and POBW and POBL was only
Males N (%)

evident in girls (Table III).

Possible interactions between birth order and POBW, POBL
and POWFL were also investigated (Table IV). There was no dif-
ference in the association between any of the measures of intra-
uterine growth and risk of CNS tumors by birth order, other than
POBL which appeared to be positively associated with risk of
‘Other intracranial/spinalÕ tumors among first-borns but inversely
576,366
79
21
22
38
18
30
28
20
183

associated with risk among subsequent births. There was weak

N

evidence that the associations between increasing POBW and

POWFL and risk of Hodgkin and Burkitt lymphoma only applied
to subsequently born children.
Similar to the approach taken in our previous report of fetal
growth and childhood ALL,28 we then examined the association
Ependymoma/choroid plexus1

All CNS tumors combined3

between increasing POBW and risk of Hodgkin and Burkitt lym-

Medulloblastoma/PNETs2

Non-Hodgkin lymphoma
Other intracranial/spinal

phomas (in boys) and NHL (in girls) who did not have ‘high birth
weightÕ according to two commonly used definitions: >3,500 g
Hodgkin lymphoma

and >4,000 g. The HRs for Hodgkin lymphoma for a 1 SD

Burkitt lymphoma

increase in POBW were: 2.26 (1.39–3.68), among boys weighing

Other gliomas

<3,500 g at birth, and 2.19 (1.56–3.07) among boys weighing

Astrocytoma

<4,000 g at birth. For Burkitt lymphoma, these HRs were 1.38

Non-cases

(0.57–3.33) and 1.49 (0.83–2.68), respectively. The HRs for NHL

for a 1 SD increase in POBW were: 1.50 (0.58–3.86) among girls
weighing <3,500 g at birth, and 1.68 (0.95–2.95) among girls
1

weighing <4,000 g at birth.

 TABLE II – COX UNIVARIATE REGRESSION ANALYSIS BY ICCC3 CNS TUMOUR AND LYMPHOMA CATEGORIES
Sex* Birth order* POBW z score POBL z score POWFL z score
HR CI HR CI HR CI HR CI HR CI

Astrocytoma 1.07 0.69–1.66 0.80 0.51–1.25 0.95 0.76–1.19 0.99 0.79–1.23 0.95 0.76–1.18
Ependymoma/choroid plexus1 0.95 0.40–2.23 0.82 0.34–1.94 0.82 0.53–1.26 1.37 0.90–2.06 0.68 0.44–1.06
Other gliomas 1.04 0.45–2.40 2.05 0.86–4.90 0.94 0.62–1.43 0.93 0.62–1.39 0.97 0.63–1.47
Medulloblastoma/PNETs2 0.76 0.40–1.44 1.01 0.53–1.91 0.81 0.59–1.12 0.81 0.62–1.06 0.86 0.62–1.20
Other intracranial/spinal 0.83 0.33–2.11 0.34 0.11–1.04 1.01 0.63–1.59 1.12 0.71–1.76 0.97 0.61–1.54
All CNS tumors combined3 0.90 0.68–1.21 0.90 0.67–1.20 0.90 0.77–1.04 0.96 0.83–1.11 0.89 0.77–1.04
Hodgkin lymphoma 0.52 0.24–1.11 1.28 0.63–2.62 1.34 0.95–1.88 1.38 0.98–1.94 1.25 0.88–1.76
Non-Hodgkin lymphoma 0.78 0.37–1.65 1.18 0.56–2.48 1.05 0.73–1.51 1.09 0.76–1.57 1.00 0.69–1.45
Burkitt lymphoma 0.26 0.09–0.78 0.95 0.39–2.30 1.15 0.75–1.76 0.84 0.57–1.23 1.27 0.84–1.94
HR, Hazard Ratio; CI, 95% Confidence interval; POBW, proportion of optimal birth weight; POBL, proportion of optimal birth length; POWFL, proportion of optimal weight for length.
1
Includes 18 Ependymomas and 3 choroid plexus tumors.–2Includes 32 Medulloblastomas and 6 PNETs.–3Includes 4 intracranial/spinal germ cell tumors and 1 unspecified CNS tumor.
*Reference categories: male sex and first born.

TABLE III – SEX-SPECIFIC COX REGRESSION ANALYSIS

POBW z score POBL z score POWFL z score
Males HR (CI) Females HR (CI) Interaction p-value Males HR (CI) Females HR (CI) Interaction p-value Males HR (CI) Females HR (CI) Interaction p-value
RISK OF CHILDHOOD CNS TUMORS AND LYMPHOMAS

Astrocytoma 0.94 (0.69–1.29) 0.96 (0.70–1.32) 0.94 1.12 (0.82–1.53) 0.88 (0.66–1.17) 0.25 0.87 (0.63–1.20) 1.02 (0.75–1.40) 0.48
Ependymoma/choroid plexus1 0.77 (0.42–1.40) 0.87 (0.47–1.64) 0.77 1.17 (0.65–2.12) 1.59 (0.90–2.80) 0.46 0.68 (0.37–1.25) 0.68 (0.37–1.28) 0.99
Other gliomas 1.07 (0.60–1.93) 0.82 (0.45–1.49) 0.53 1.18 (0.66–2.11) 0.78 (0.54–1.14) 0.25 1.03 (0.57–1.86) 0.91 (0.50–1.64) 0.77
Medulloblastoma/PNETs2 0.88 (0.57–1.34) 0.73 (0.44–1.20) 0.57 0.87 (0.58–1.31) 0.77 (0.58–1.03) 0.63 0.90 (0.59–1.38) 0.81 (0.48–1.34) 0.72
Other intracranial/spinal 1.37 (0.77–2.44) 0.66 (0.33–1.34) 0.12 1.43 (0.80–2.57) 0.83 (0.47–1.46) 0.19 1.27 (0.70–2.31) 0.68 (0.34–1.36) 0.18
All CNS tumors combined3 0.93 (0.77–1.14) 0.85 (0.69–1.06) 0.54 1.05 (0.86–1.27) 0.88 (0.72–1.07) 0.23 0.90 (0.74–1.10) 0.88 (0.71–1.10) 0.90
Hodgkin lymphoma 1.67 (1.14–2.43) 0.81 (0.43–1.51) 0.05 1.65 (1.11–2.45) 0.95 (0.53–1.71) 0.13 1.54 (1.03–2.30) 0.79 (0.42–1.47) 0.08
Non-Hodgkin lymphoma 0.76 (0.46–1.25) 1.53 (0.91–2.55) 0.05 0.76 (0.54–1.08) 1.85 (1.12–3.06) 0.006 0.82 (0.50–1.35) 1.28 (0.75–2.18) 0.23
Burkitt lymphoma 1.35 (0.85–2.14) 0.56 (0.21–1.50) 0.11 0.91 (0.56–1.46) 0.74 (0.49–1.10) 0.51 1.50 (0.95–2.35) 0.61 (0.23–1.64) 0.10
HR, Hazard Ratio; CI, 95% Confidence interval; POBW, proportion of optimal birth weight; POBL, proportion of optimal birth length; POWFL, proportion of optimal weight for length.
1
Includes 18 Ependymomas and 3 choroid plexus tumors.–2Includes 32 Medulloblastomas and 6 PNETs.–3Includes 4 intracranial/spinal germ cell tumors and 1 unspecified CNS tumor.
439
440 MILNE ET AL.

Apart from ‘other intracranial/spinalÕ tumors, over 80% of each

Interaction p-value
cancer group had at least one sibling (Table V). The matched sib-
ling analyses for ependymoma/choroid plexus tumor were indica-

0.77
0.79
0.88
0.41
0.78
0.82
0.20
0.87
0.10
HR, Hazard Ratio; CI, 95% Confidence interval; POBW, proportion of optimal birth weight; POBL, proportion of optimal birth length; POWFL, proportion of optimal weight for length.
tive of an increased risk with higher POBL (OR: 2.97 per 1 SD

Includes 18 Ependymomas and 3 choroid plexus tumors.–2Includes 32 Medulloblastomas and 6 PNETs.–3Includes 4 intracranial/spinal germ cell tumors and 1 unspecified CNS tumor.
increase) and a reduced risk with higher POWFL (OR: 0.59) (Ta-
ble VI). POBL appeared to be positively related to risk of ‘Other
intracranial/spinal tumorsÕ (OR: 1.87), and inversely related to risk
0.98 (0.69–1.39)
0.73 (0.37–1.42)
1.01 (0.59–1.70)
0.74 (0.46–1.20)
0.83 (0.31–2.26)
0.87 (0.70–1.09)
1.56 (0.99–2.46)
1.04 (0.61–1.75)
1.78 (1.06–2.98)
Subsequent HR (CI)

of medulloblastoma/PNET (OR: 0.52), when cases were compared

POWFL z score

with their nonaffected siblings. Risk of Hodgkin lymphoma was

higher with increases in each measure of intra-uterine growth,
while there was a suggestion that risk of Burkitt lymphoma may
be slightly elevated with increased POBW and POWFL compared
with siblings. NHL appeared to be inversely associated with
POWFL (OR: 0.43) (Table VI).
0.92 (0.69–1.23)
0.65 (0.37–1.15)
0.94 (0.47–1.89)
0.98 (0.63–1.52)
0.98 (0.58–1.65)
0.90 (0.74–1.10)
1.00 (0.60–1.65)
0.97 (0.58–1.65)
0.91 (0.50–1.65)
First born HR (CI)

Discussion
This study provides some new insights into the relationship
between intra-uterine growth and specific childhood cancers by
Interaction p-value

using relatively novel measures of the appropriateness of fetal

growth: POBW, POBL and POWFL. All three measures are inde-
0.009
0.85
0.63
0.71
0.33
0.18
0.45
0.61
0.73

pendent of gestational age and take account of the major nonpa-

thological determinants of intra-uterine growth, which represents
TABLE IV – BIRTH ORDER-SPECIFIC COX REGRESSION ANALYSIS

an improvement on the analysis of birth weight alone or birth

weight adjusted for gestational age. Consistent with our previously
0.96 (0.67–1.36)
1.53 (0.82–2.86)
1.00 (0.59–1.69)
0.70 (0.48–1.01)
0.60 (0.40–0.90)
0.86 (0.69–1.07)
1.20 (0.72–2.00)
1.21 (0.72–2.03)
0.77 (0.42–1.41)

reported findings for childhood ALL,28 we observed a positive

Subsequent HR (CI)

association between intra-uterine growth and risk of some specific

POBL z score

CNS tumors and lymphomas in children.

We observed a higher risk of ependymoma/choroid plexus tu-
mor among children with greater than expected skeletal growth
(length) at birth, and among children with less soft tissue (weight)
than expected for their birth length. We also observed, among
1.00 (0.75–1.32)
1.24 (0.72–2.16)
0.86 (0.48–1.54)
0.92 (0.61–1.39)
1.41 (0.87–2.30)
1.04 (0.86–1.26)
1.56 (0.99–2.43)
1.00 (0.60–1.65)
0.89 (0.52–1.51)
First born HR (CI)

boys, an increased risk of ‘Other intracranial/spinalÕ tumors asso-

ciated with greater than expected birth weight and length. Similar
patterns of results were observed when the cases were compared
with their nonaffected siblings, suggesting that the rates of specific
aspects of fetal growth associated with risk of these tumors are
individual rather than familial characteristics. We found little or
Interaction p-value

no evidence of associations between intra-uterine growth and risk

of other CNS tumors. The results of previous studies of birth
0.82
0.70
0.72
0.31
0.32
0.55
0.44
0.79
0.25

weight and CNS tumors have been inconsistent, and effect esti-
mates have generally lacked precision because of small numbers
of cases. Von Behren and Reynolds reported an increased risk of
astrocytoma among girls (but not boys) with birth weight >4,000 g
0.98 (0.69–1.38)
0.89 (0.46–1.74)
1.02 (0.60–1.72)
0.68 (0.42–1.09)
0.62 (0.23–1.69)
0.85 (0.68–1.06)
1.54 (0.97–2.45)
1.11 (0.66–1.86)
1.49 (0.82–2.69)

(OR 2.21: 1.08–4.49).38 An increased risk of astrocytoma in high

Subsequent HR (CI)

birth weight children was also observed in studies by Emerson

POBW z score

et al. (>4,000 g: RR 1.9 (1.1–3.1),39 Kuijten et al. (>4,000 g: RR

2.9 (0.9–9.3),40 Lee et al. (>3,500 g: IRR 1.4 (0.3–7.1)4 and Mog-
ren et al. (>4,500 g: SIR 4.44 (1.19–11.38).41 Overall, there has
been less support for an association between high birth weight and
risk of other CNS tumors, although a recent study by Schuz
0.93 (0.69–1.24)
0.75 (0.43–1.34)
0.86 (0.43–1.74)
0.95 (0.61–1.47)
1.10 (0.66–1.85)
0.93 (0.76–1.13)
1.18 (0.73–1.92)
1.00 (0.60–1.69)
0.91 (0.50–1.65)

reported a RR of 1.34 (0.97–1.85) for birth weight >4000 g in

First born HR (CI)

relation to all CNS tumors combined,9 while two earlier studies by

the same author reported that both low birth weight (<2,500 g)
and high birth weight (>4,000 g) were associated with some ele-
vation in risk of all CNS tumors combined,10 and of astrocytoma,
ependymoma and medulloblastoma separately.42 Savitz et al.
reported a similar pattern of results with RRs for CNS tumors of:
Ependymoma/choroid plexus1

1.6 (0.6–4.2) for birth weight <2,500 g, and 2.3 (0.9–6.1) for birth
All CNS tumors combined3
Medulloblastoma/PNETs2

weight >4,000 g.11 Other studies have reported no associa-

Non-Hodgkin lymphoma
Other intracranial/spinal

tion.12,13 Only the Singaporean study by Lee et al.4 adjusted for

Hodgkin lymphoma

gestational age. As indicated earlier, it is not possible to distin-

Burkitt lymphoma

guish between the possible effects of accelerated intra-uterine

growth and high birth weight per se without taking account of
Other glioma
Astrocytoma

gestational age. Previous studies of the risk of CNS tumors

have not directly compared birth weight among cases and their
siblings.
Emerson et al.39 have suggested two possible explanations for a
1

relationship between high birth weight and risk of CNS tumors.

 RISK OF CHILDHOOD CNS TUMORS AND LYMPHOMAS 441
TABLE V – CHARACTERISTICS OF CASES WITH CNS TUMOURS AND LYMPHOMA AND THEIR SIBLINGS
N cases with Total N Mean Case Mean Mean Case Mean Mean Case Mean
a sibling (%) siblings POBW Sibling POBW POBL Sibling POBL POWFL Sibling POWFL

Astrocytoma 65 (82.3) 118 96.9 (12.9) 94.8 (11.1) 99.6 (4.6) 98.7(4.5) 96.9 (10.4) 95.7 (9.1)
Ependymoma/choroid plexus1 17 (81.0) 33 93.7 (9.1) 93.5 (14.2) 100.6 (4.3) 97.9 (4.0) 92.7 (6.8) 94.9 (12.2)
Other gliomas 20 (90.9) 31 97.1 (11.1) 97.1 (11.3) 99.4 (3.6) 98.5 (6.6) 97.4 (9.5) 98.8 (15.3)
Medulloblastoma/PNETs2 31 (81.6) 62 94.3 (11.9) 97.5 (12.5) 98.1 (4.0) 99.7 (4.0) 95.8 (10.2) 97.6 (10.4)
Other intracranial/spinal 12 (66.7) 24 95.1 (13.6) 94.1 (8.0) 99.6 (4.7) 97.7 (3.8) 95.2 (13.1) 96.4 (6.9)
All CNS tumors combined3 149 (81.4) 279 95.5 (12.0) 95.4 (11.5) 99.2 (4.4) 98.7 (4.5) 95.9 (10.0) 96.4 (10.4)
Hodgkin lymphoma 25 (83.3) 42 101.4 (10.2) 96.2 (12.8) 101.1 (4.4) 99.7 (4.7) 99.9 (8.1) 96.1 (10.2)
Non-Hodgkin lymphoma 24 (85.7) 51 98.1 (12.3) 99.2 (11.3) 100.3 (4.4) 98.7 (6.9) 97.2 (8.5) 99.4 (8.9)
Burkitt lymphoma 19 (95.0) 32 99.9 (13.8) 98.2 (11.0) 98.9 (5.0) 99.5 (4.4) 100.4 (12.2) 98.3 (9.4)
1
Includes 14 Ependymomas and 3 choroid plexus tumors.–2Includes 25 Medulloblastomas and 6 PNETs.–3Includes 4 intracranial/spinal germ
cell tumours and 1 unspecified CNS tumor.

TABLE VI – CONDITIONAL LOGISTIC REGRESSION ANALYSIS OF CASES WITH

CNS TUMOURS AND LYMPHOMA MATCHED TO THEIR SIBLINGS
POBW z score POBL z score POWFL z score
OR (95% CI) OR (95% CI) OR (95% CI)

Astrocytoma 1.17 (0.75–1.82) 1.22 (0.82–1.82) 1.08 (0.70–1.67)

Ependymoma/choroid plexus1 0.83 (0.37–1.89) 2.97 (1.03–8.56) 0.59 (0.26–1.30)
Other gliomas 0.81 (0.30–2.16) 1.16 (0.72–1.86) 0.77 (0.40–1.45)
Medulloblastoma/PNETs2 0.70 (0.42–1.18) 0.52 (0.25–1.07) 0.78 (0.48–1.28)
Other intracranial/spinal 1.31 (0.49–3.54) 1.87 (0.75–4.68) 0.90 (0.36–2.23)
All CNS tumours combined3 0.90 (0.68–1.18) 1.11 (0.88–1.41) 0.84 (0.65–1.08)
Hodgkin lymphoma 2.42 (0.99–5.93) 1.73 (0.88–3.41) 2.04 (0.88–4.73)
Non-Hodgkin lymphoma 0.73 (0.32–1.66) 1.31 (0.79–2.18) 0.43 (0.17–1.11)
Burkitt lymphoma 1.49 (0.66–3.34) 0.72 (0.33–1.55) 1.76 (0.80–3.88)
1
Includes 14 Ependymomas and 3 choroid plexus tumors.–2Includes 25 Medulloblastomas and
6 PNETs.–3Includes 4 intracranial/spinal germ cell tumors and 1 unspecified CNS tumor.

The first was that in utero exposure to excess glucose would tend
to increase fetal weight, while also modifying the trans-placental
response to carcinogenic factors. The second was that augmented
rates of cell division and growth may increase the sensitivity of
the fetus to carcinogenic agents in utero. Schuz and Forman sug-
gested that regulators of embryonic brain development, such as
the TWIST transcription factor, might remain up-regulated by
IGF-I.9 Another possibility is that increased growth factors may
prevent apoptosis occurring in cells that have had a ‘first hitÕ,
while also giving rise to larger babies.
We found that the risk of Hodgkin lymphoma was associated
with higher than expected birth weight, birth length, and birth
weight for length, particularly in boys. These findings were repli-
cated in the combined-sexes matched siblings analysis, suggesting
that the increased fetal growth associated with risk of Hodgkin
lymphoma is an individual rather than a familial characteristic.
The relationship between intra-uterine growth (POBW) was even
stronger among boys who did not have ‘high birth weightÕ, despite
the small number of cases in the analysis. This finding supports
the notion that risk of Hodgkin lymphoma is associated with
accelerated growth rather than high birth weight per se. To our
knowledge, only three previous studies have examined birth
weight in relation to risk of Hodgkin lymphoma separately from
other lymphomas,12,43,44 and none found an association.
Our results were consistent with the risk of NHL being
higher—among girls only—primarily with greater skeletal growth
but also with somewhat more soft tissue at birth than expected.
However, compared with their siblings, NHL cases tended to have
lower birth weight for their length, though with small numbers the
confidence interval is wide. Together, these findings suggest that
NHL cases may belong to families with a tendency toward accel-
erated fetal growth. Similar to the findings for Hodgkin lymphoma
in boys, the fact that the association between fetal growth and risk
of NHL tended to be elevated among girls who did not have ‘high
birth weightÕ suggests that the pertinent risk factor is accelerated
growth. Previous studies of NHL in relation to birth weight have
produced conflicting results. The results of two studies by Schuz
and coworkers,9,10 a study by McKinney et al.45 and two studies
by Roman and coworkers43,46 were indicative of some increased
risk of NHL with low birth weight (<2,500 g). None of these stud-
ies adjusted for gestational age. On the other hand, Yeazel et al.
reported an OR of 1.5 (1.0–2.5) among children at least 2 years
old at diagnosis with birth weight >4,000 g, after adjustment for
gestational age.12 Petridou et al. reported a 42% (4–92%) increase
in risk of NHL for each 500 g increase in birth weight,
after adjustment for ‘socioeconomic, perinatal and sun exposure
variablesÕ (p 1035).44
Burkitt lymphoma was more common in boys, and risk
appeared to be somewhat elevated among boys who had higher
than expected birth weight and weight for length. Similar findings
were seen in the combined-sexes matched analysis of siblings,
suggesting that the increased fetal growth associated with risk of
Burkitt lymphoma is specific to the individual and not general to
the family. Similar to the findings for Hodgkin lymphoma in boys
and NHL in girls, the fact that the risk of Burkitt lymphoma
tended to be elevated among boys who did not have ‘high birth
weightÕ suggests that accelerated growth is the more important
factor. To our knowledge, only one study has reported an associa-
tion between birth weight and Burkitt lymphoma specifically4;
that study also reported an increased risk with high birth weight
(>3,500 g) (IRR 10.5:1.1–102.6), after adjustment for gestational
age.
Three other previous studies have combined all lymphomas into
one group for analysis. Savitz and Ananth reported a positive asso-
ciation with birth weight >4,000 g compared with 2,500–4,000 g,
although there were only 26 cases in the analysis and confidence
intervals were wide.11 McKinney et al. presented weak evidence
of an increased risk with low birth weight (<2,500 g),13 and
Adami et al. reported no association.14 None of these three studies
adjusted for gestational age. No previous studies appear to have
directly compared the birth weight or intra-uterine growth of
lymphoma cases with that of their siblings.
442
As in other studies, our results were based on relatively small
numbers of cases, so many of our findings are inconclusive. We
also acknowledge that there is heterogeneity within some of the
ICCC3 tumor categories, such as in the ‘other gliomaÕ category;
however, there were insufficient cases to conduct some of the sub-
group analyses that would have been of interest. In addition, we
investigated at least three explanatory variables and their interac-
tions with sex and birth order for each of several cancer groups, so
that some of the observed associations may be due to chance
because of multiple comparisons. However, we believe we have
been appropriately conservative in the description and interpreta-
tion of our findings.
The use of administrative health data generally involves some
level of compromise in terms of the variables available for inclu-
sion in the analysis, as the data are often collected for purposes
other than research. For example, we would have liked to investi-
gate whether there was any association between head circumfer-
ence at birth and risk of CNS tumors in childhood. Samuelsen
et al.47 reported an increased risk of pilocytic astrocytoma (RR
1.34:95% CI: 1.09–1.65) and ependymoma (RR 1.36:95% CI:
0.92–2.01) per 1-cm increase in head circumference, after adjust-
ment for birth weight, gestational age and sex, among children
aged 0–15 years. Although we had data on head circumference for
children born from 1990 onwards, it was missing for 53% of CNS
tumors over the entire time period.
This study has some important strengths. The examination of
the risk of childhood cancer associated with the appropriateness of
intra-uterine growth—rather than birth weight per se—represents
an advance relative to previous studies, particularly on those that
did not adjust for gestational age. Our approach also obviated the
need to assign an arbitrary cut-off for ‘high birth weightÕ. Further-
more, we were able to investigate the risk of childhood cancers in
relation to three distinct aspects of intra-uterine growth: propor-
tion of optimum weight, proportion of optimum length and the
proportion of optimum weight for length. To the extent possible,
1. Hjalgrim LL, Rostgaard K, Hjalgrim H, Westergaard T, Thomassen
H, Forestier E, Gustafsson G, Kristinsson J, Melbye M, Schmiegelow
K. Birth weight and risk for childhood leukemia in Denmark, Sweden,
Norway, and Iceland. J Natl Cancer Inst 2004;96:1549–56.
2. Hjalgrim LL, Westergaard T, Rostgaard K, Schmiegelow K, Melbye
M, Hjalgrim H, Engels EA. Birth weight as a risk factor for childhood
leukemia: a meta-analysis of 18 epidemiologic studies. Am J Epide-
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3. Jourdan-Da Silva N, Perel Y, Mechinaud F, Plouvier E, Gandemer V,
Lutz P, Vannier JP, Lamagnere JL, Margueritte G, Boutard P, Robert
A, Armari C, et al. Infectious diseases in the first year of life, perinatal
characteristics and childhood acute leukaemia. Br J Cancer 2004;
90:139–45.
4. Lee J, Chia K-S, Cheung K-H, Chia S-E, Lee H-P. Birthweight and
the risk of early childhood cancer among Chinese in Singapore. Int J
Cancer 2004;110:465–7.
5. Ma X, Metayer C, Does MB, Buffler PA. Maternal pregnancy loss,
birth characteristics, and childhood leukemia (United States). Cancer
Causes Control 2005;16:1075–83.
6. McLaughlin CC, Baptiste MS, Schymura MJ, Nasca PC, Zdeb MS.
Birth weight, maternal weight and childhood leukaemia. Br J Cancer
2006;94:1738–44.
7. Paltiel O, Harlap S, Deutsch L, Knaanie A, Massalha S, Tiram E,
Barchana M, Friedlander Y. Birth weight and other risk factors for
acute leukemia in the Jerusalem Perinatal Study cohort. Cancer Epide-
miol Biomarkers Preview 2004;13:1057–64.
8. Podvin D, Kuehn CM, Mueller BA, Williams M. Maternal and birth
characteristics in relation to childhood leukaemia. Paediatr Perinat
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9. Schuz J, Forman MR. Birthweight by gestational age and childhood
cancer. Cancer Causes Control 2007;18:655–63.
10. Schuz J, Kaatsch P, Kaletsch U, Meinert R, Michaelis J. Association
of childhood cancer with factors related to pregnancy and birth. Int J
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MILNE ET AL.
we investigated associations between the measures of fetal growth
and the risk of specific cancer subtypes. Analyzing CNS tumors or
lymphomas as a group (as in some previous studies) may mask
important associations with specific subtypes.
Selection bias is unlikely to have affected our results. The study
included the entire population of children born in Western Aus-
tralia between 1980 and 2004, although some outward migration
will have occurred resulting in a loss to follow-up. However, there
is no evidence to indicate that outward migration of children is
related to the appropriateness of intra-uterine growth, a diagnosis
of childhood cancer, or both. Recall bias is not a threat to validity
as information on risk factors was collected prior to diagnosis.
To our knowledge, ours is the first population-based study to
have examined appropriateness of fetal growth in relation to the
risk of childhood CNS tumors and lymphomas, and to have
directly compared fetal growth among cases and their siblings.
Given the rarity of these childhood cancers, collaborative studies
involving data pooling are most likely to produce precise esti-
mates of the associations with fetal growth. We recommend that
future studies take account of gestational age (at least) in the anal-
ysis of associations between fetal growth and cancer risk, and
compare cases with their siblings, as such an approach is
more likely to elucidate possible causal pathways. Further
research into the underlying biological mechanisms suggested by
the observed associations for these childhood cancers is also of a
high priority.
Acknowledgements
The authors acknowledge the assistance provided by Ms. Diana
Rosman and Ms. Carol Garfield at the Western Australian Data
Linkage Unit and Drs. Tim Threlfall and Judith Thompson at the
Western Australian Cancer Registry. The authors also thank
Ms. Margaret Wood for extracting the linked data files and provid-
ing advice on the cleaning and preparation of the data for analysis.
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APPENDIX 1: ICCC3 CANCER CATEGORIES AS DEFINED by ICD-O-3 CODES

–
ICD-Oncology-3 codes
ICCC3 cancer category
Morphology Topography

Astrocytoma 9,380 C72.3

9,384, 9,400–9,411, 9,420–9,424, 9,440–9,442
Ependymoma and choroid 9,383, 9,390–9,394
plexus tumour
Other gliomas 9,380 C70.0–C72.2, C72.4–C72.9,
C75.1, C75.3
9,381, 9,382, 9,430, 9,444, 9,450, 9451, 9,460
Medulloblastoma & PNETs 9,470–9,474, 9,480, 9,508
9,501–9,504 C70.0–C72.9
Other specified intracranial and 8,270–8,281, 8,300, 9,350–9,352, 9,360–9,362, 9412,
intraspinal neoplasms 9,413, 9,492, 9,493, 9,505–9,507, 9,530–9539, 9582
Intracranial and intraspinal germ 9,060–9,065, 9,070–9,072, 9,080–9,085, 9,100, 9,101 C70.0–C72.9, C75.1–C75.3
cell tumours
Hodgkin lymphomas 9,650–9,655, 9,659, 9,661–9,665, 9,667
Non-Hodgkin lymphomas 9,591, 9,670, 9,671, 9,673, 9,675, 9,678–9,680, 9684,
9,689–9,691, 9,695, 9,698–9,702, 9,705, 9708, 9709,
9,714, 9,716–9,719, 9,727–9,729, 9731–9734,
9,760–9,762, 9,764–9,769, 9,970
Burkitt lymphoma 9,687
Miscellaneous lymphoreticular neoplasms 9,740–9,742, 9,750, 9,754–9,758
Unspecified lymphomas 9,590, 9,596