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Parental smoking and maternal alcohol and caffeinated beverage consumption are prevalent exposures which may play a role, either directly or through their influence on metabolism, in the aetiology of childhood malignant Central Nervous System (CNS) tumours. The hypothesis was investigated in the ESCALE study, a national population-based casecontrol study carried out in France in 2003–2004.
The study included 209 incident cases of CNS tumours and 1681 population-based controls, frequency matched with the cases by age and gender. The data were collected through a standardized telephone interview of the biological mothers.
No association between maternal smoking during pregnancy and CNS tumours (OR = 1.1 [0.8–1.6]) was observed. Paternal smoking during the year prior to birth was associated with CNS tumours (p for trend = 0.04), particularly astrocytomas (OR = 3.1 [1.3–7.6]). Maternal alcohol consumption during pregnancy was not associated with CNS tumours. Associations between ependymomas and the highest consumption of coffee (OR = 2.7 [0.9–8.1]) and tea (OR = 2.5 [1.1–5.9]) were observed. A strong association between CNS tumours and the highest maternal consumption of both coffee and tea during pregnancy was observed (OR = 4.4 [1.5–13]).
The results constitute additional evidence for a role of paternal smoking and suggest that maternal coffee and tea consumption during pregnancy may also increase the risk of CNS tumours. The study does not suggest an increased risk of CNS tumours related to alcohol consumption during pregnancy.
Central nervous system (CNS) tumours are the second most common pediatric cancer in developed countries. In France, the annual incidence rate is 29.1 per million children, equivalent to about 350 new cases per year (Desandes et al., 2004). Except for ionizing radiation and a few rare genetic factors, the aetiology of CNS tumours remains largely unknown (Baldwin and Preston-Martin, 2004). The central nervous system is more vulnerable to carcinogens early in life and the relatively young age at onset suggests that prenatal and early post-natal exposures may be considered potential risk factors (Rice and Wilbourn, 2000). Pre-conception exposure of germ cells to carcinogens, especially in the father, is also suspected of being related to an excess of tumours in the offspring (Anderson et al., 2000). The influence of exposure to tobacco smoke on the risk of CNS tumours has been investigated in numerous studies and a recent review has summarized the epidemiologic evidence (Baldwin and Preston-Martin, 2004). While no or a limited association has been found with maternal smoking during pregnancy, there is some evidence for an association between CNS tumours and pre-conception paternal smoking. Maternal alcohol and caffeinated beverage consumption during pregnancy have been shown to be associated with other childhood cancers, especially childhood leukaemia (Severson et al., 1993; Van Duijn et al., 1994; Shu et al., 1996; Ross et al., 1998; Menegaux et al., 2005; Menegaux et al., 2007). For childhood CNS tumour, those factors have been less investigated. No consistent association with maternal alcohol drinking during pregnancy has been detected for childhood CNS tumours (Little, 1999). However, two studies reported a link with maternal beer drinking during pregnancy (Howe et al., 1989; Bunin et al., 1993), supporting the hypothesis that N-nitroso compounds play a role. To the authors’ knowledge, only two studies have investigated the role of maternal caffeinated beverage consumption during pregnancy with respect to childhood CNS tumours (Bunin et al., 1993; Bunin et al., 1994; Cordier et al., 1994). Neither reported a significant association.
The present paper analyzes the role of parental tobacco smoking and maternal alcohol and caffeinated beverage consumption during pregnancy with respect to childhood CNS tumours using data generated by the ESCALE study. The latter investigated the role of environmental and genetic factors with regard to the 4 most frequent types of childhood cancers: leukaemias, lymphomas, CNS tumours and neuroblastomas.
Details of the study have been published elsewhere (Rudant et al., 2007). For the present analysis, the eligible cases comprised all children aged less than 15 years, residing in mainland France at the time of diagnosis of a primary malignant CNS tumour in 2003–2004. The tumours were defined as per the International Classification of Diseases for Oncology, third version (ICD-O-3). Investigators, assigned to each French pediatric oncology hospital department, directly recruited CNS tumour cases with the support of the French National Registry of Childhood Haematopoietic Malignancies (NRCH) (Clavel et al., 2004) and the French National Registry of Childhood Solid Tumours (NRCST) (NRCST website). Adopted children (5 cases) and children whose mother did not speak French (14 cases) or had a serious psychiatric disorder (5 cases) were not eligible. For ethical reasons, children who had died or were receiving palliative care before the inclusion date (58 cases) were not eligible either. Out of the 343 cases identified, 261 were eligible, 19 of them refused to participate and 33 could not be contacted by the interviewers. Thus, 209 (80%) incident cases classified as malignant CNS tumours (/3 behaviour) according to ICD-O-3 were included and grouped using the International Classification of Childhood Cancer (Steliarova-Foucher et al., 2005). The cases consisted of 100 cases (48%) of embryonal tumour (ICD-O-3 codes 9470/3, 9471/3, 9473/3, 9474/3, 9480/3, 9508/3), 33 cases (16%) of ependymoma (9390/3-9393/3), 26 cases (12%) of astrocytoma (9380/3, 9400/3, 9420/3, 9424/3, 9440/3) and 45 cases (21%) of other glioma (9380/3, 9382/3, 9430/3, 9450/3, 9451/3). The remaining cases were distributed as follows: 3 (2%) not otherwise specified tumours and 2 (1%) otherwise specified tumours.
A random sample of French children (up to age 14 years) was obtained from a representative list of 60,000 addresses provided by the French national telephone company, enriched by random generation of unlisted phone numbers. Quotas were designed a priori to make the control group representative of, first, all cases of childhood cancer (leukaemia, lymphoma, neuroblastoma and central nervous system tumour) in terms of age and gender, and, secondly, the French population with regard to the number of children under 15 years of age living in the household. Out of the 50,217 phone numbers dialed, 46,994 were non-eligible numbers (22,584 businesses or inactive numbers, 18,456 households without children, 5,277 outside of the quotas, 677 unreliable interviews). The eligibility of 862 phone numbers could not be determined. Finally, out of the 2361 children who were eligible as controls, 1681 (71%) were included in the study (679 parents refused and 1 child had a prior history of neuroblastoma).
Trained interviewers conducted telephone interviews with the biological mothers of the cases and controls. The mean interview duration was 40 minutes. The standardized questionnaire sought information on demographic and socioeconomic characteristics, parental occupational history, parental lifestyle, family and personal medical history, history of pregnancy and childhood environment. The present study particularly focused on parental tobacco smoking and maternal alcohol and caffeinated beverage consumption. Mothers were asked whether they had ever smoked or drunk alcohol, coffee, tea, chocolate or cola during pregnancy. If so, further questions were asked to elicit the daily or weekly amount consumed, for each of the items. The period of interest for paternal smoking was the year prior to the index child’s birth.
The SAS® software package (version 9.1, Cary, North Carolina) was used for all the analyses. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated by non-conditional logistic regression for all CNS tumours, with systematic adjustment for the stratification variables, age and gender. Adjustment for potential confounding factors, such as the place of residence at the time of diagnosis, maternal and paternal educational level and socioeconomic category, was also conducted. The countries of birth of the 4 grandparents were used as surrogates of ethnic origin (Europe, Africa/the Caribbean, Asia, North Africa, mixed). Analyses of tumour histologic subgroups were conducted using polytomous regression models.
The cases and controls did not differ with respect to gender (Table 1). Since the age quotas for control selection had been defined so as to be representative of all types of cancer and not only of CNS cases, there was a small age discrepancy between the CNS cases and controls. However, the mean ages of the cases and controls were very similar (6.3 vs 6.0 years). There were at least 5 controls for each case in each age group. No significant difference between the cases and controls was observed with respect to parental educational level or socioeconomic category.
No association between maternal smoking during pregnancy and CNS tumours in the children was detected (OR = 1.1 [0.8–1.6]). No association or trend with the number of cigarettes smoked per day was observed (Table 2).
Paternal smoking was associated with CNS tumours, and the ORs increased with the number of cigarettes smoked (< 20 cig/day: OR = 1.1 [0.8–1.6]; ≥ 20 cig/day: OR = 1.4 [1.0– 2.1]; p for trend = 0.04). When both the mother’s and the father’s smoking was considered, the OR was 1.3 [1.0–1.9] for only the father smoking, 1.6 [0.9–3.0] for only the mother smoking, and 1.2 [0.7–1.8] for both parents smoking.
None of the histological subgroups was significantly associated with maternal smoking during pregnancy, whereas paternal smoking of more than 20 cigarettes per day during the year prior to pregnancy was associated with astrocytoma (OR = 3.2 [1.2–9.1]) and ependymoma (OR = 2.6 [1.2–5.9]) (Table 3). In contrast, neither embryonal tumors nor other gliomas appeared to be linked to paternal smoking.
There was no association between CNS tumours taken as a whole and consumption of caffeinated beverages by the mother during pregnancy (table 4). Slightly, but not significantly, increased ORs were associated with the highest consumptions of coffee (OR = 1.4 [0.8–2.4]) and tea (OR = 1.4 [0.9–2.1]). Higher ORs were observed for ependymoma, but the number of cases was small. The associations were more marked for the highest maternal consumptions of both coffee (>3 cups per day) and tea (>1 cup per day). Adjustment for maternal and paternal smoking did not change the results.
No association between CNS tumors and maternal consumption of any kind of alcohol during pregnancy was detected (OR = 0.9 [0.7–1.3]) (Table 5).
The results remained unchanged after adjusting for parental educational level and socioeconomic category.
In this study, paternal smoking during the year prior to pregnancy was associated with CNS tumours, and the association was more pronounced for astrocytoma. On the whole, there was no significant association with maternal smoking during pregnancy, although a borderline association with maternal smoking in the absence of paternal smoking was found. Maternal alcohol consumption during pregnancy was not associated with childhood CNS tumours, while maternal coffee and tea consumption during pregnancy were significantly associated with CNS tumours and particularly with ependymomas.
The size of the present study enabled detection of minimum odds ratios of 1.5 and 1.6 for exposure prevalence in controls of 30 and 20%, respectively, i.e. of the same order of magnitude as those of maternal alcohol drinking during pregnancy or parental smoking.
The cases were identified through the data collection system of the French National Registries of Childhood Cancer (NRCH, NRCST), making selection of cases at the identification step unlikely. Cases who had died or were receiving palliative care were not eligible, which might have lead to survival bias. Nevertheless, we were able to compare the prevalence of parental smoking of 19 cases that died after their mothers’ interviews with the prevalence of parental smoking of the survivors. The prevalence of parental smoking, either for maternal and paternal smoking, did not differ between the non-surviving and surviving children making a survival bias unlikely in the present study.
Eighteen percent of the eligible cases did not answer the questionnaire. However, the age and gender distributions were similar for the respondent and non-respondent cases.
The controls were randomly selected from the general population, based on the national telephone directory. Unlisted numbers were randomly generated in order to avoid the selection of controls with listed numbers.
There were no differences between the cases and controls with regard to gender or age (considering all the types of cancer covered by the ESCALE study), or between the controls and overall population, particularly with regard to birth order, number of children living in the household and socio-demographic characteristics, indicating that quota sampling was successful. The socioeconomic status and educational level of the control parents were very similar to those of the cases and the French population (Blondel et al., 1997; Blondel et al., 2006). Adjustments for those variables did not change the results. Additional adjusment for ethnic origin (countries of birth of the 4 grand-parents) of the index child did not change the results as well.
All the information was based on the child’s mother’s interview. The mothers could have misreported their smoking habits and those of the father. However, the number of cigarettes smoked by the control mothers was comparable to that of the French population (Blondel et al., 1997; Blondel et al., 2006), as was the number smoked by the control fathers (Guilbert P et al., 2005). The results are therefore unlikely to be explained by under-reporting of smoking by the controls. In addition, the case mothers may have under-reported their own smoking, leading to under-estimation of the association with maternal smoking. However, the results reported herein are consistent with 2 meta-analyses that found no association between CNS tumours and maternal smoking during pregnancy (Boffetta et al., 2000; Huncharek et al., 2002). One recent cohort study (Brooks et al., 2004) reported a significantly increased risk related to maternal smoking, but this association was found to be significant for low grade astrocytomas, which were not eligible in the present study, and not for malignant brain tumours. However, an association with maternal smoking during pregnancy cannot be completely ruled out, given the slightly increased OR with maternal smoking in the absence of paternal smoking observed herein.
Case mothers may have over-reported smoking by the father, which would explain the relationship with paternal smoking. However, the paternal smoking habits of the controls were very similar to those of the French population (Guilbert P et al., 2005). Moreover, several previous studies, that investigated paternal smoking by interviewing the father himself also found positive associations (McCredie et al., 1994; Ji et al., 1997; Fillipini et al., 2002; Cordier et al., 2004). Two meta-analyses estimated ORs of 1.22 [1.05–1.40] and 1.29 [1.07–1.53] for paternal smoking during pregnancy (Boffetta et al., 2000; Huncharek et al., 2001; respectively). Cordier et al. reported an increased risk of malignant astrocytoma among children whose father was exposed to PAH from smoking, before the conception (Cordier et al., 2004). In the study by McCredie et al., malignant brain tumours were associated with pre-conception paternal smoking and maternal exposure to side-stream smoke from the father during pregnancy (McCredie et al., 1994). Two biologically-plausible mechanisms have been proposed to explain those findings. A direct hypothesis, supported by both animal and human data (Baldwin and Preston-Martin, 2004), suggests an impact of pre-conception paternal germ-cell exposure. Spermatogenesis is a continuous process, with intense replication of DNA, making germ cells more vulnerable to mutagenic changes (Anderson et al., 2000). The second hypothesis suggests that paternal smoking may act through the mother’s passive exposure to side-stream smoke during pregnancy. Biochemical studies showed that some constituents of environmental tobacco smoke may cross the placenta and interact with fetal DNA (Tredaniel et al., 1994; Anderson et al., 2000; Rice, 2004). However, the epidemiological data on this question are contradictory. Among the studies that explicitly addressed the role of passive exposure to tobacco smoke, some evidenced an association between CNS tumor and maternal exposure to side-stream smoke (Preston-Martin et al., 1982; McCredie et al., 1994; Filippini et al., 2002) while as many others did not (Kuijten et al., 1990; Cordier et al., 1994; Hu et al., 2000). It is noteworthy that paternal smoking remains difficult to differentiate from maternal smoking. Similarly, there are strong correlations between pre-conception, gestational and post-natal maternal and paternal smoking that make it difficult to elucidate the actual exposure with certainty in the context of paternal pre-conception smoking. However, the literature has not reported any evidence of an association with passive smoking during childhood (Ji et al., 1997; Little, 1999; Filippini et al., 2002).
The present study did not generate any evidence of an association between alcohol consumption during pregnancy and malignant CNS tumours. Alcohol consumption is difficult to quantify by questionnaires, and an information bias may have occurred, even though its extent would have been reduced by the use of a detailed standardized questionnaire. Guilt feelings may have led the cases’ mothers to minimize their alcohol consumption during pregnancy and the resulting recall bias may have masked an association. However, the bias is more likely to affect the dose-response relationship than the ever/never relationship. The literature on maternal alcohol drinking during pregnancy and CNS tumours is very limited and shows no consistent association. However, two studies evidenced that beer drinking during pregnancy was associated with CNS tumours (Howe et al., 1989) or with primitive neuroectodermal tumours (PNET) (Bunin et al., 1993). Beer is a known source of N-nitroso compounds (NOC), which are suspected to play a role in childhood brain tumours. In the present study, beer consumption was slightly, but not significantly, related to CNS tumours and particularly to PNET and other gliomas.
The results for maternal coffee and tea consumption raise some questions. A recall bias is unlikely given that there is no particular public concern with those habits. Wilkins et al. reported no differences between cases and controls for mothers recalling their own diet in a case-control study on childhood brain tumours (Wilkins and Bunn, 1997). Furthermore, associations with maternal consumption of coffee and tea during pregnancy were limited to ependymomas, which makes bias less likely. Cordier et al. found an increased OR associated with coffee (1.9 [0.9–3.9]), but nor with tea (0.7 [0.3–1.4]) (Cordier et al., 1994).
In conclusion, the findings reported herein constitute additional evidence for a role of paternal smoking during the year prior to birth in childhood CNS tumours. The results also suggest that maternal coffee and tea consumption may increase the risk of CNS tumours, directly or through an influence on the metabolism of unknown risk factors. Further investigations are needed in order to elucidate the role of those factors further and account for their possible synergy.
This work was supported by grants from INSERM, the Fondation de France, the Association pour la Recherche contre le Cancer (ARC), the Agence Française de Sécurité Sanitaire des Produits de Santé (AFSSAPS), the Agence Française de Sécurité Sanitaire de l’Environnement et du Travail (AFSSET) and the association ‘Cent pour sang la vie’.
We are grateful to Marie-Hélène Da Silva and Christophe Steffen (INSERM, U754), who coordinated the recruitment of the cases; Sandra Guissou, Emmanuel Désandes and the staff of the French National Registry of Childhood Solid Tumours, who contributed to case detection and verification; Sabine Mélèze and Marie-Anne Noël (Institut CSA), who coordinated the selection of the controls and the interviews; Catherine Tricoche (Callson) and the team of interviewers, who interviewed the cases and the controls; and Andrew Mullarky for his skilful revision of the manuscript.