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Epidemiology

Maternal and childhood medical history and the risk of childhood brain tumours: a case–control study in Ontario, Canada

British Journal of Cancer volume 129, pages 318–324 (2023)Cite this article

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A Correction to this article was published on 13 September 2023

This article has been updated

Abstract

Background

Studies to date have yielded inconclusive results as to whether maternal medical history during pregnancy, and a child’s early-life medical history contribute to the development of childhood brain tumours (CBTs). This study examined associations between maternal and childhood medical history and the risk of CBTs.

Methods

The Childhood Brain Tumour Epidemiology Study of Ontario (CBREO) examined children 0–15 years of age with newly diagnosed CBTs from 1997 to 2003. Multivariable logistic regression analysis determined associations for prenatal medications and childhood medical history, adjusted for child’s demographics, and maternal education. Analyses were stratified by histology. A latency period analysis was conducted using 12- and 24-month lead times.

Results

Maternal intake of immunosuppressants during the prenatal period was significantly associated with glial tumours (OR 2.73, 95% CI 1.17–6.39). Childhood intake of anti-epileptics was significantly associated with CBTs overall, after accounting for 12-month (OR 8.51, 95% CI 3.35–21.63) and 24-month (OR 6.04, 95% CI 2.06–17.70) lead time before diagnosis. No associations for other medications were found.

Conclusions

This study underscores the need to examine potential carcinogenic effects of the medication classes highlighted and of the indication of medication use. Despite possible reverse causality, increased CBT surveillance for children with epilepsy might be warranted.

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Fig. 1: Odds ratios and 95% confidence intervals for the associations between maternal medication use during pregnancy and histology* of childhood brain tumours.
Fig. 2: Childhood anti-epilepsy medications and childhood brain tumour.

Data availability

Data are available on request due to privacy/ethical restrictions.

Code availability

All statistical analyses were completed using STATA version 15.0. The code is available upon request from the corresponding author.

Change history

References

  1. Ferlay J, Ervik M, Lam F, Colombet M, Mery L, Piñeros M, et al. Global Cancer observatory: cancer today [Internet]. International Agency for Research on Cancer. 2020. https://gco.iarc.fr/today.

  2. Steliarova-Foucher E, Colombet M, Ries LAG, Moreno F, Dolya A, Bray F, et al. International incidence of childhood cancer, 2001–10: a population-based registry study. Lancet Oncol. 2017;18:719–31.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Association of the Nordic Cancer Registries. NORDCAN [Internet]. 2023. https://nordcan.iarc.fr/en.

  4. Youlden DR, Baade PD, Green AC, Valery PC, Moore AS, Aitken JF. The incidence of childhood cancer in Australia, 1983–2015, and projections to 2035. Med J Aust. 2020;212:113–20.

    Article  PubMed  Google Scholar 

  5. Ostrom QT, Fahmideh MA, Cote DJ, Muskens IS, Schraw JM, Scheurer ME, et al. Risk factors for childhood and adult primary brain tumors. Neuro Oncol. 2019;21:1357–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Johnson KJ, Cullen J, Barnholtz-Sloan JS, Ostrom QT, Langer CE, Turner MC, et al. Childhood brain tumor epidemiology: a brain tumor epidemiology consortium review. Cancer Epidemiol Biomark Prev. 2014;23:2716–36.

    Article  Google Scholar 

  7. Ostrom QT, Francis SS, Barnholtz-Sloan JS. Epidemiology of brain and other CNS tumors. Curr Neurol Neurosci Rep. 2021;21:1–12.

  8. Leong C, Chateau D, Dahl M, Falk J, Katz A, Bugden S, et al. Prescription medication use during pregnancies that resulted in births and abortions (2001-2013): a retrospective population-based study in a Canadian population. PLoS ONE. 2019;14:e0211319.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Mitchell AA, Gilboa SM, Werler MM, Kelley KE, Louik C, Hernández-Díaz S. Medication use during pregnancy, with particular focus on prescription drugs: 1976-2008. Am J Obstet Gynecol. 2011;1:e1–8.

    Google Scholar 

  10. Brender JD, Kelley KE, Werler MM, Langlois PH, Suarez L, Canfield MA. Prevalence and patterns of nitrosatable drug use among U.S. women during early pregnancy. Birth Defects Res A Clin Mol Teratol. 2011;91:258–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Schüz J, Weihkopf T, Kaatsch P. Medication use during pregnancy and the risk of childhood cancer in the offspring. Eur J Pediatr. 2007;166:433–41.

    Article  PubMed  Google Scholar 

  12. Momen NC, Olsen J, Gissler M, Kieler H, Haglund B, Li J. Exposure to systemic antibacterial medications during pregnancy and risk of childhood cancer. Pharmacoepidemiol Drug Saf. 2015;24:821–9.

    Article  PubMed  Google Scholar 

  13. Bonaventure A, Simpson J, Ansell P, Roman E, Lightfoot T. Prescription drug use during pregnancy and risk of childhood cancer—is there an association. Cancer Epidemiol. 2015;39:73–8.

    Article  CAS  PubMed  Google Scholar 

  14. Fitton CA, Steiner MFC, Aucott L, Pell JP, Mackay DF, Fleming M, et al. In-utero exposure to antihypertensive medication and neonatal and child health outcomes: a systematic review. J Hypertens. 2017;35:2123–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lydakis C, Lip GYH, Beevers M, Beevers DG. Atenolol and fetal growth in pregnancies complicated by hypertension. Am J Hypertens. 1999;12:541–7.

    Article  CAS  PubMed  Google Scholar 

  16. Anderson KN, Lind JN, Simeone RM, Bobo WV, Mitchell AA, Riehle-Colarusso T, et al. Maternal use of specific antidepressant medications during early pregnancy and the risk of selected birth defects. JAMA Psychiatry. 2020;77:1246–55.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Tanoshima M, Kobayashi T, Tanoshima R, Beyene J, Koren G, Ito S. Risks of congenital malformations in offspring exposed to valproic acid in utero: a systematic review and cumulative meta-analysis. Clin Pharm Ther. 2015;98:417–41.

    Article  CAS  Google Scholar 

  18. Fan H, Gilbert R, O’Callaghan F, Li L. Associations between macrolide antibiotics prescribing during pregnancy and adverse child outcomes in the UK: population based cohort study. BMJ. 2020;368:m766.

    Google Scholar 

  19. Fan H, Li L, Wijlaars L, Gilbert RE. Associations between use of macrolide antibiotics during pregnancy and adverse child outcomes: a systematic review and meta-analysis. PLoS ONE. 2019;14:e0212212.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Vuong AM, Shinde MU, Brender JD, Shipp EM, Huber JC, Sharkey JR, et al. Prenatal exposure to nitrosatable drugs, dietary intake of nitrites, and preterm birth. Am J Epidemiol. 2016;183:634–42.

    Article  PubMed  Google Scholar 

  21. Cardy AH, Little J, McKean-Cowdin R, Lijinsky W, Choi NW, Cordier S, et al. Maternal medication use and the risk of brain tumors in the offspring: The SEARCH international case-control study. Int J Cancer. 2006;118:1302–8.

    Article  CAS  PubMed  Google Scholar 

  22. Connelly JM, Malkin MG. Environmental risk factors for brain tumors. Curr Neurol Neurosci Rep. 2007;7:208–14.

    Article  PubMed  Google Scholar 

  23. Hjorth S, Hemmingsen CH, Bénévent J, Broe A, Pottegaard A, Mørch LS, et al. Maternal medication use and childhood cancer in offspring—systematic review and considerations for researchers. Am J Epidemiol. 2021;190:2487–99.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Preston-Martin S, Yu MC, Benton B, Henderson BE. N-nitroso compounds and childhood brain tumors: a case-control study. Cancer Res. 1982;42:5240–5.

    CAS  PubMed  Google Scholar 

  25. Cahoon EK, Inskip PD, Gridley G, Brenner AV. Immune-related conditions and subsequent risk of brain cancer in a cohort of 4.5 million male US veterans. Br J Cancer. 2014;110:1825–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Oksuzyan S, Crespi CM, Cockburn M, Mezei G, Kheifets L. Birth weight and other perinatal factors and childhood CNS tumors: a case-control study in California. Cancer Epidemiol. 2013;37:402–9.

    Article  CAS  PubMed  Google Scholar 

  27. Volkova A, Ruggles K, Schulfer A, Gao Z, Ginsberg SD, Blaser MJ. Effects of early-life penicillin exposure on the gut microbiome and frontal cortex and amygdala gene expression. iScience. 2021;24:102797.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Howe GR, Burch JD, Chiarelli AM, Risch HA, Choi BCK. An exploratory case-control study of brain tumors in children. Cancer Res. 1989;49:4349–52.

  29. Gumey JG, Mueller BA, Preston-Martin S, Mc Daniel AM, Holly EA, Pogoda JM, et al. A study of pediatric brain tumors and their association with epilepsy and anticonvulsant use. Neuroepidemiology. 1997;16:248–55.

    Article  Google Scholar 

  30. Goldhaber MK, Selby JV, Hiatt RA, Quesenberry CP. Exposure to barbiturates in utero and during childhood and risk of intracranial and spinal cord tumors. Cancer Res. 1990;50:4600–3.

    CAS  PubMed  Google Scholar 

  31. Cordier S, Iglesias M‐J, Le Goaster C, Guyot M‐M, Mandereau L, Hemon D. Incidence and risk factors for childhood brain tumors in the Ile de France. Int J cancer. 1994;59:776–82.

    Article  CAS  PubMed  Google Scholar 

  32. Olsen JH, Boice JD, Jensen JPA, Fraumeni JF. Cancer among epileptic patients exposed to anticonvulsant drugs. J Natl Cancer Inst. 1989;81:803–9.

    Article  CAS  PubMed  Google Scholar 

  33. Cheng S, McLaughlin JR, Brown MC, Al-Sawaihey H, Rutka J, Bouffet E, et al. Childhood head trauma and the risk of childhood brain tumours: a case-control study in Ontario, Canada. Int J Cancer. 2021;150:795–801.

    Article  PubMed  Google Scholar 

  34. Yanik EL, Smith JM, Shiels MS, Clarke CA, Lynch CF, Kahn AR, et al. Cancer risk after pediatric solid organ transplantation. Pediatrics. 2017;139:20163893.

    Article  Google Scholar 

  35. Gerstung M, Jolly C, Leshchiner I, Dentro SC, Gonzalez S, Rosebrock D, et al. The evolutionary history of 2,658 cancers. Nature. 2020;578:122–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Zhang Y, Chen F, Donehower LA, Scheurer ME, Creighton CJ. A pediatric brain tumor atlas of genes deregulated by somatic genomic rearrangement. Nat Commun. 2021;12:937.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ullrich NJ, Pomeroy SL, Kapur K, Manley PE, Goumnerova LC, Loddenkemper T. Incidence, risk factors, and longitudinal outcome of seizures in long-term survivors of pediatric brain tumors. Epilepsia. 2015;56:1599–604.

    Article  PubMed  Google Scholar 

  38. Sánchez Fernández I, Loddenkemper T. Seizures caused by brain tumors in children. Seizure. 2017;44:98–107.

    Article  PubMed  Google Scholar 

  39. Salminen J, Tammela T, Auvinen A, Murtola T. Antiepileptic drugs with histone deacetylase inhibition activity and prostate cancer risk: a population-based case-control study. Cancer Causes Control. 2016;27:637–45.

    Article  PubMed  Google Scholar 

  40. Singh G, Driever PH, Sander JW. Cancer risk in people with epilepsy: the role of antiepileptic drugs. Brain 2005;128:7–17.

    Article  PubMed  Google Scholar 

  41. Günaldi M, Paydaş S, Afşar ÇU, Duman BB, Erçolak V, Haksöyler V. Karbamazepin ve multipl miyelom: Olasi i̇lişki. Turkish J Hematol. 2013;30:83–4.

    Article  Google Scholar 

  42. Kristensen KB, Pedersen SA, Schmidt SAJ, Pottegård A. Use of antiepileptic drugs and risk of skin cancer: a nationwide case-control study. J Am Acad Dermatol. 2020;82:326–35.

    Article  PubMed  Google Scholar 

  43. Stritzelberger J, Lang JD, Mueller TM, Reindl C, Westermayer V, Kostev K, et al. Anti-seizure medication is not associated with an increased risk to develop cancer in epilepsy patients. J Neurol. 2021;268:2185–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kim H-B, Myung S-K, Park YC, Park B. Use of benzodiazepine and risk of cancer: a meta-analysis of observational studies. Int J Cancer. 2017;140:513–25.

    Article  CAS  PubMed  Google Scholar 

  45. Miyawaki I, Moriyasu M, Funabashi H, Yasuba M, Matsuoka N. Mechanism of clobazam-induced thyroidal oncogenesis in male rats. Toxicol Lett. 2003;145:291–301.

    Article  CAS  PubMed  Google Scholar 

  46. McCredie M, Maisonneuve P, Boyle P. Antenatal risk factors for malignant brain tumours in new south wales children. Int J Cancer. 1994;56:6–10.

    Article  CAS  PubMed  Google Scholar 

  47. Stålberg K, Haglund B, Strömberg B, Kieler H. Prenatal exposure to medicines and the risk of childhood brain tumor. Cancer Epidemiol. 2010;34:400–4.

    Article  PubMed  Google Scholar 

  48. Bauer AZ, Swan SH, Kriebel D, Liew Z, Taylor HS, Bornehag CG, et al. Paracetamol use during pregnancy — a call for precautionary action. Nat Rev Endocrinol. 2021;17;757–766.

  49. Kramer S, Ward E, Meadows A, Malone K. Medical and drug risk factors associated with neuroblastoma: a case-control study. J Natl Cancer Inst. 1987;78:797–804.

    CAS  PubMed  Google Scholar 

  50. Momen NC, Munk-Olsen T, Li J, Ingstrup KG, Olsen J, Bergink V, et al. Antidepressant use during pregnancy and childhood cancer in the offspring. Pharmacoepidemiol Drug Saf. 2018;27:114–8.

    Article  CAS  PubMed  Google Scholar 

  51. Centers for Disease Control and Prevention (CDC). Prevalence of self-reported epilepsy—United States, 1986–1990. JAMA. 1994;272:1893.

  52. Zack MM, Kobau R. National and state estimates of the numbers of adults and children with active epilepsy—United States, 2015. MMWR Morb Mortal Wkly Rep. 2017;66:821–5.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Hales CM, Kit BK, Gu Q, Ogden CL. Trends in prescription medication use among children and adolescents-United States, 1999-2014. J Am Med Assoc. 2018;319:2009–20.

    Article  Google Scholar 

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Acknowledgements

This study was supported by a research grant with funds provided by the Canadian Institute of Health Research and the Canadian Cancer Society. We thank E. Badalian, H. White, J. Polzer, R. Gaudet, and W. Medved for their contributions to conducting the study interviews.

Funding

None.

Author information

Authors and Affiliations

  1. Prosserman Centre for Population Health Research, Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, ON, Canada

    Sierra Cheng, M. Catherine Brown, Hamad Al-Sawaihey & Rayjean J. Hung

  2. Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada

    Sierra Cheng

  3. Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada

    John R. McLaughlin & Rayjean J. Hung

  4. Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada

    M. Catherine Brown

  5. Department of Surgery, University of Toronto, Toronto, ON, Canada

    James Rutka

  6. Division of Hematology/Oncology, The Hospital for Sick Children Toronto, Toronto, ON, Canada

    Eric Bouffet, Mark Greenberg & David Malkin

  7. Division of Pathology, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada

    Cynthia Hawkins

  8. Children’s Hospital, London Health Sciences Centre, London, ON, Canada

    A. Elizabeth Cairney & Adrianna Ranger

  9. McMaster Children’s Hospital, Hamilton Health Sciences, Hamilton, ON, Canada

    Adam J. Fleming

  10. Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada

    Donna Johnston

  11. Pediatric Oncology Group of Ontario, Toronto, ON, Canada

    Mark Greenberg

  12. Department of Medicine, University of Toronto, Toronto, ON, Canada

    Mark Greenberg

  13. Department of Pediatrics, University of University of Toronto, Toronto, ON, Canada

    David Malkin

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Contributions

RJH conceived the study and its design. JRM, MCB, JR, EB, MG and DM contributed to the data collection. SC completed the statistical analysis and drafted the manuscript with RJH and MCB. All authors contributed to study organisation and result interpretation. All authors reviewed the manuscript and approved the final version of the manuscript.

Corresponding author

Correspondence to Rayjean J. Hung.

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Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

Informed consent was obtained from all participants. The study was approved by the Mount Sinai Hospital Research Ethics Board (REB 20-0055-E).

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The original online version of this article was revised: In this article the name of Mark Greenberg has been corrected.

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Cheng, S., McLaughlin, J.R., Brown, M.C. et al. Maternal and childhood medical history and the risk of childhood brain tumours: a case–control study in Ontario, Canada. Br J Cancer 129, 318–324 (2023). https://doi.org/10.1038/s41416-023-02281-3

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