California Department of Health Services, Environmental Health Investigations Branch Oakland, CA 94612, USA.
Correspondence: Julie Von Behren, California Department of Health Services, Environmental Health Investigations Branch 1515 Clay Street, Suite 1700, Oakland, CA 94612, USA. E-mail: jvonbehr{at}dhs.ca.gov
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Abstract |
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Methods We obtained 849 invasive central nervous system (CNS) cancer cases, ages 04 years, from Californias population-based cancer registry for 19881997. We matched 746 (88%) of these cases to a California live birth certificate. We randomly selected two control birth certificates for each case, matched on date of birth and gender. We used conditional logistic regression to obtain odds ratios (OR) and 95% CI. The birth characteristics examined included birthweight, gestational age, race, parental age, and parental education.
Results Analysing all CNS tumours combined, we found that children of other racial/ ethnic groups had OR below one compared with non-Hispanic white children. When adjusted for gestational age, race/ethnicity, and mothers place of birth, the OR for high birthweight (4000 g) was 1.05 (95% CI: 0.791.38) compared with children with birthweights of 25003999 g. For astrocytomas (313 cases), the adjusted OR for high birthweight was 1.40 (95% CI: 0.902.18). When parental education was included in the model (available for only a subset of the birth years), the adjusted OR was 1.71 (95% CI: 1.012.90). High birthweight did not appear to be a risk factor for primitive neuroectodermal tumours (PNET).
Conclusions We found high birthweight associated with increased risk of astrocytomas, but not PNET, in young children.
Accepted 7 November 2002
Brain and other central nervous system (CNS) cancers account for 22% of all childhood malignancies in the US.1 These cancers continue to have poorer survival rates than the other most common childhood cancers, leukaemias and lymphomas.1 The causes of CNS malignancies are generally unknown. Between 1973 and 1994, the incidence rate of childhood CNS cancer increased by 35% in the US.2 The cause of this increase has been debated, with some researchers implicating environmental factors, though none has been conclusively identified.3 Others have suggested the rise was due to increased detection through improved medical imaging technology, rather than a true increase in incidence.2
Several studies have investigated the potential relationships between childhood CNS tumours and parental characteristics and birth characteristics. High birthweight has been identified as a potential risk factor for brain tumours, particularly astrocytomas.48 However, many other studies have investigated birthweight and found no significant differences between cases and controls.913 Other birth characteristics, including maternal age, birth order, and previous fetal loss, have been investigated but the results have been conflicting and inconsistent.14,15
We investigated birth characteristics in relationship to the diagnosis of CNS cancers before age 5 years among California children. Because of the relatively large number of cases available, more than in most previous studies, we analysed astrocytomas and primitive neuroectodermal tumours (PNET) separately, as well as looking at all tumours combined. Cancer registry data and birth certificate records were linked to conduct this records-based case-control study.
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Methods |
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The California birth certificates contained information on the age, race, and Hispanic ethnicity of both the mother and father. Maternal pregnancy history was also collected, including number of pregnancies, live births, prior pregnancy losses (spontaneous abortions and stillbirths), and time since last live birth. Information was also available about prenatal care, method of delivery, and complications during pregnancy and delivery. Data on the infants included gender, birthweight, gestational age, and whether a single or multiple birth. Maternal and paternal education were added to the birth certificate starting in 1989, so analyses including education could only be performed on births occurring in that year or later. We determined the highest level of education from the mother or the father to construct a parental education variable.
Odds ratios (OR) and 95% CI were obtained from conditional logistic regression models, which take into account the matched nature of the cases and controls. All analyses were performed in SAS.19 The multivariate models were restricted to those case-control sets where the case and at least one control were singletons. We entered birthweight and gestational age, a factor closely related to birthweight, into all multivariate models. We also included variables that were statistically significant in the univariate analyses. We stratified models by sex to look for differential effects, as reported in the previous literature by Emerson et al.6 Analyses were performed on the cases and controls for of all CNS cancers combined and separately for astrocytomas and PNET.
The study protocol was reviewed and approved by the California Health and Human Services Agency, Committee for the Protection of Human Subjects.
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Results |
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All central nervous system tumours
The number of cases and controls for all the CNS tumours are shown in Table 1. The univariate OR are also shown for each birth characteristic examined. Most of the CI included one, except for parental education, mothers birthplace, and race/ethnicity of the child. The OR for
16 years of parental education was 1.69 (95% CI: 1.252.30) compared with parents who did not complete high school. Children whose mothers were born outside the US appeared to have reduced risk of CNS tumours (OR = 0.66, 95% CI: 0.550.80). Children of other race/ethnicity groups had OR below one when compared with non-Hispanic white children.
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In the analysis of the later birth years (where education information was available), the increased risk for advanced parental education (OR = 1.31 for college graduates, 95% CI: 0.682.51) was greatly reduced compared with the univariate analysis results (OR = 2.68). Among the astrocytoma cases and controls, parental education was strongly related to race/ethnicity. The non-Hispanic whites, who had a higher risk for astrocytoma than the other racial/ethnic groups, had the highest percentage of parents with a college degree (45%). Only 16% of the parents of the black children and 9% of the parents of Hispanic children had a college education. The proportion of Asian/other children whose parents had a college degree was higher, 35%, but still less than that of the non-Hispanic whites.
Primitive neuroectodermal tumours
The number of cases and controls for PNET are shown in Table 5. The univariate OR are also shown for each birth characteristic examined. The point estimates were close to one for most of the birth characteristics examined and the CI included one. High birthweight did not appear to be associated with PNET risk as it was for astrocytoma. The race/ethnicity differences appeared less pronounced for PNET than for all CNS tumours and astrocytomas.
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Infants
Because many infant cancers exhibit unique epidemiological features,20,21 we examined selected birth characteristics and CNS tumours in children under one year of age (99 cases and 198 controls). Older parental age was associated with increased risk for infant CNS tumours. The OR for maternal age 35 years was 1.76 (95% CI: 0.873.55) as compared with mothers under age 35. The OR for paternal age
35 years was 1.75 (95% CI: 0.973.14) as compared with fathers under age 35. The OR for all race/ethnic groups were below one (but CI included one). The OR for birthweight
4000 g was 0.72 (95% CI: 0.321.64) compared with the referent group (birthweight 25003999 g). We also looked at the birth characteristics for astrocytomas, the most common tumour type (41 cases). Though based on small numbers the OR were still elevated for both older maternal and paternal age (for mothers age OR = 4.16, 95% CI: 1.2913.44). Firstborn children were at decreased risk (OR = 0.30, 95% CI: 0.130.70) and the OR for all race/ethnic groups were below one again, as they were for all tumour types combined. The OR for high birthweight was 1.80 (95% CI: 0.575.69).
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Discussion |
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High birthweight has been associated with increased risk of other childhood cancers, including leukaemia,23 neuroblastoma,10 and Wilms tumour.15 Birthweight is a crude proxy for hormone levels during pregnancy and high birthweight is associated with high oestrogen levels.24 Markers of high in utero oestrogen exposure have been associated with breast cancer, prostate cancer, and testicular cancer, possibly due to oestrogens growth promotion or genotoxic effects.25 High birthweight may be an indicator of increased cell division and fast growth. Insulin-like growth factor (IGF) is positively related to birthweight and high levels of IGF may stimulate the proliferation of both normal and malignant cells.23 The rapid proliferation of cells may lead to increased vulnerability to carcinogens and increased mutations.4 Alternatively, high birthweight may be a marker of other conditions, such as maternal diabetes.10
The present study showed that high birthweight was a risk factor for astrocytoma in girls but not boys. In a methodologically similar study done in Washington State, the risk for high birthweight and astrocytoma was also more pronounced in girls than boys.6 However, the authors reported several other significant differences that we did not see, including increased risk for prior fetal loss among boys and older maternal age with firstborn children. It is unclear why high birthweight would be a risk factor among girls but not boys.
The California data showed increased risk with older parental age in infants. Also, firstborn infants appeared at decreased risk for astrocytomas. These findings on infant tumours are based on very small numbers but may be useful for hypothesis generation about the aetiology of CNS tumours in this special age group. The early onset of these cancers is more suggestive of a prenatal origin and genetic factors may be especially important.26
Californias population of children is extremely diverse in terms of race and ethnicity, which allowed us the unique opportunity to examine these factors in relation to this rare cancer. white, non-Hispanic children are at higher risk than all other groups. However, this difference was less pronounced for PNET. Nationally, white children and teenagers have an 18% higher incidence rate of CNS cancers than blacks.27 In a recent study of California childhood cancer incidence rates, Glazer et al. reported significantly lower incidence rates of astrocytomas in Hispanics compared with non-Hispanic white children.28
Education is a proxy for socioeconomic status (SES), which in turn may be a proxy for certain disease risk factors. However, there are few known risk factors for CNS cancer in children and no well-established hypothesis about SES in relation to this disease. In our study of very young children, those whose parents had a college education appeared to have a higher risk of CNS cancer, especially for astrocytoma, than those whose parents did not complete high school. However, the OR for college education was greatly reduced once adjusted for race/ ethnicity, maternal birthplace, and birthweight (from 2.68 to 1.31 for astrocytoma). Socioeconomic status has been examined in a few other CNS cancer studies. Two occupational studies have found increased risk for CNS cancer in children of parents in white collar or managerial/professional occupations.29,30 An ecological study of childhood brain tumours in Scotland found that incidence was greatest in the most affluent areas.31 Two previous case-control studies that examined CNS risk and education have reported decreased risk for higher education. These studies both relied on volunteers for the control interviews, which resulted in women of higher social classes agreeing to participate more than other women.11,12
The occupational exposures hypothesized to increase brain cancer risk in offspring include pesticides, hydrocarbons, and N-nitroso compounds found in rubber, leather, metal, and chemical industries and in mining.15 Highly educated people are more likely to hold managerial and professional jobs, which usually have few known carcinogenic exposures.30 However, children of parents with a high level of education may have better access to diagnostic screening services and therefore be more likely to have their brain cancer detected, or at least detected earlier, than other children. In the US, the use of diagnostic imaging technology, such as magnetic resonance imaging (MRI) increased dramatically during the mid-1980s and is believed to be responsible for the rise in incidence of this disease observed during that time.2
This analysis was restricted to information available from the birth certificates. The data on birth certificates may not always be accurate or complete. We examined the percentage of missing data for each factor of interest and found a high level of completeness for most data elements. For example, mothers age and birthweight were available for all subjects. Most missing data were on paternal factors. Eight per cent of the births were missing information on fathers age. Certain data elements such as complications during pregnancy and delivery and abnormal conditions present in the infant, including Downs syndrome, are most likely incompletely reported. On the other hand, the accuracy of birth certificate data may be quite high for some factors of interest, such as birthweight and race. Birthweight is measured and recorded at the time of the birth. A recent analysis of the validity of race and Hispanic ethnicity information on the California birth certificate found that the information is a valid measure for all groups except Native Americans.32 Data on other birth characteristics, such as gestational age33 and birth defects,34 have not been reported to be as reliable.
Another potential limitation of this study is that the cases were limited to children who were both diagnosed and born in California, excluding highly mobile subjects. However, we did not see any differences in the distribution of unmatched and matched cases by race/ethnicity.
One of the main advantages of this study was that the use of vital records diminishes the problem of recall bias since the data were not self-reported after knowledge of disease status. In addition, the controls were randomly selected from state birth files, eliminating participation bias. The cases were drawn from the statewide, population-based cancer registry which has estimated 99% completeness of ascertainment.35 Also, this study focused on early childhood cancer which has a relatively short latency period and which may have a stronger relationship to perinatal factors than later cancers. With over 700 cases, this is one of the largest childhood CNS case-control studies to date. The relatively large number of cases allowed us to look at specific types of CNS tumours for which there appear to be different risk factors.
Because CNS tumours in children are rare, the literature to date on birth characteristics is limited. This study provided a large sample size with analysis by tumour subtype, an ethnically diverse population, and equivalent data collection for both cases and controls. The risk factors identified in this population, especially high birthweight for astrocytomas which has been observed in some other studies, may provide clues as to the aetiology of these rare but often deadly malignancies.
KEY MESSAGES
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Acknowledgments |
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References |
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2 Smith M, Freidlin B, Ries L, Simon R. Trends in reported incidence of primary malignant brain tumors in children in the United States. J Natl Cancer Inst 1998;90:126977.
3 Carroquino M, Galson S, Licht J et al. The US EPA Conference on preventable causes of cancer in children: a research agenda. Environ Health Perspect 1998;106:86773.[ISI][Medline]
4 Gold E, Gordis L, Tonascia J, Szklo M. Risk factors for brain tumors in children. Am J Epidemiol 1979;109:30919.[Abstract]
5 Linet M, Gridley G, Cnattingius S et al. Maternal and perinatal risk factors for childhood brain tumors (Sweden). Cancer Causes Control 1996;7:43748.[ISI][Medline]
6 Emerson J, Malone K, Daling JR, Starzyk P. Childhood brain tumor risk in relation to birth characteristics. J Clin Epidemiol 1991;44: 115966.[CrossRef][ISI][Medline]
7 Kuijten RR, Bunin GR, Nass CC, Meadows AT. Gestational and familial risk factors for childhood astrocytoma: results of a case-control study. Cancer Res 1990;50:260812.[Abstract]
8 Savitz DA, Ananth CV. Birth characteristics of childhood cancer cases, controls, and their siblings. Pediatr Hematol Oncol 1994;11:58799.[ISI][Medline]
9 Preston-Martin S, Yu MC, Benton B, Henderson BE. N-Nitroso compounds and childhood brain tumors: a case-control study. Cancer Res 1982;42:524045.[Abstract]
10 Daling J, Starzyk P, Olshan A, Weiss N. Birth weight and the incidence of childhood cancer. J Natl Cancer Inst 1984;72:103941.[ISI][Medline]
11 Howe G, Burch J, Chiarelli A, Risch HA, Choi B. An exploratory case-control study of brain tumors in children. Cancer Res 1989;49:434952.[Abstract]
12 McCredie M, Maisonneuve P, Boyle P. Perinatal and early postnatal risk factors for malignant brain tumours in New South Wales children. Int J Cancer 1994;56:1115.[ISI][Medline]
13 Yeazel M, Ross J, Buckley J, Woods W, Ruccione K, Robison L. High birth weight and risk of specific childhood cancers: a report from the Childrens Cancer Group. J Pediatr 1997;131:67177.[ISI][Medline]
14 Kuijten RR, Bunin GR. Risk Factors for Childhood Brain Tumors. Cancer Epidemiology 1993;2:27788.[ISI]
15 Little J. Epidemiology of Childhood Cancer. Lyon: IARC Scientific Publications (Publication No. 149), 1999.
16 Kramarova E, Stiller C. The international classification of childhood cancer. Int J Cancer 1996;68:75965.[CrossRef][ISI][Medline]
17 Jaro M. Probabilistic linkage of large public health data files. Stat Med 1995;14:49198.[ISI][Medline]
18 MatchWare Technologies, Inc. Automatch Generalized Record Linkage System, Version 4.3. Kennebunk, ME: MatchWare Technologies, Inc, 1999.
19 SAS Institute, Inc. SAS, Version 7.00. Cary, NC: SAS Institute, Inc., 1998.
20 Gurney J, Ross J, Wall D, Bleyer W, Severson R, Robison L. Infant cancer in the US: histology-specific incidence and trends, 1973 to 1992. J Pediatr Hematol Oncol 1997;19:42832.[CrossRef][ISI][Medline]
21 Ross JA, Davies SM, Potter JD, Robinson LL. Epidemiology of childhood leukemia, with a focus on infants. Epidemiol Rev 1994;16: 24372.[ISI][Medline]
22 Schuz J, Kaatsch P, Kaletsch U, Meinert R, Michaelis J. Association of childhood cancer with factors related to pregnancy and birth. Int J Epidemiol 1999;28:63139.[Abstract]
23 Ross JA, Perentesis JP, Robison LL, Davies SM. Big babies and infant leukemia: a role for insulin-like growth factor-1? Cancer Causes Control 1996;7:55359.[ISI][Medline]
24 Petridou E, Panagiotopoulou K, Katsouyanni K, Spanos E, Trichopoulos D. Tobacco smoking, pregnancy estrogens, and birth weight. Epidemiology 1990;1:24750.[Medline]
25 Ekbom A. Growing evidence that several human cancers may originate in utero. Semin Cancer Biol 1998;8:23744.[ISI][Medline]
26 Birch JM, Blair V. The epidemiology of infant cancers. Br J Cancer 1992;66:S2S4.
27 Ries L, Smith M, Gurney J et al. Cancer Incidence and Survival among Children and Adolescents: United States SEER Program 19751995. Bethesda, MD: National Cancer Institute, SEER Program (Pub. No. 994649), 1999.
28 Glazer E, Perkins C, Young J, Schlag R, Campleman S, Wright W. Cancer among Hispanic children in California, 198894: comparison with non-Hispanic white children. Cancer 1999;86:107079.[CrossRef][ISI][Medline]
29 Sanders BM, White GC, Draper GJ. Occupations of fathers of children dying from neoplasms. J Epidemiol Community Health 1981;35:24550.[Abstract]
30 Kuijten RR, Bunin GR, Nass CC, Meadows AT. Parental occupation and childhood astrocytoma: results of a case-control study. Cancer Res 1992;52:78286.[Abstract]
31 McKinney PA, Ironside JW, Harkness EF, Arango JC, Doyle D, Black RJ. Registration quality and descriptive epidemiology of childhood brain tumours in Scotland 197590. Br J Cancer 1994;70:97379.[ISI][Medline]
32 Baumeister L, Marchi K, Pearl M, Williams R, Bravemen P. The validity of information on race and Hispanic ethnicity in California birth certificate data. Health Serv Res 2000;35:86983.[ISI][Medline]
33 Emery E, Eaton A, Grether J, Nelson K. Assessment of gestational age using birth certificate data compared with medical record data. Paediatr Perinat Epidemiol 1997;11:31321.[ISI][Medline]
34 Hexter A, Harris J. Bias in congenital malformations information from the birth certificate. Teratology 1991;44:17780.[ISI][Medline]
35 Perkins CI, Cohen R, Morris CR et al. Cancer in California: 19881995. Sacramento, CA: California Department of Health Services, Cancer Surveillance Section, 1998.