The association between birth order and childhood leukemia may be modified by paternal age and birth weight. Pooled results from the International Childhood Cancer Cohort Consortium (I4C) |
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| Authors: | Ora Paltiel Stanley Lemeshow Gary S. Phillips Gabriella Tikellis Martha S. Linet Anne-Louise Ponsonby Per Magnus Siri E. Håberg Sjurdur F. Olsen Charlotta Granström Mark Klebanoff Jean Golding Zdenko Herceg Akram Ghantous Jane Elizabeth Hirst Arndt Borkhardt Mary H. Ward Signe Holst Søegaard Terence Dwyer |
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| Affiliation: | 1. Braun School of Public Health and Community Medicine and Department of Hematology, Hadassah-Hebrew University, Jerusalem, Israel;2. College of Public Health, The Ohio State University, Columbus, OH;3. Statistical consultant, Department of Biomedical Informatics, The Ohio State University, Center for Biostatistics, Retired;4. Murdoch Children's Research Institute, Royal Children's Hospital, University of Melbourne, Melbourne, Australia;5. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD;6. Murdoch Children's Research Institute, Royal Childrens Hospital, University of Melbourne, Melbourne, Australia;7. Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway;8. Centre for Fetal Programming, Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark;9. The Research Institute at Nationwide Children's Hospital, Departments of Pediatrics, Obstetrics and Gynecology, and Epidemiology, The Ohio State University, Columbus, OH;10. Centre for Child and Adolescent Health, University of Bristol, Bristol, United Kingdom;11. Epigenetics Group, International Agency for Research on Cancer, Lyon, France;12. Nuffield Department of Obstetrics & Gynaecology, University of Oxford, Women's Centre, Oxford, United Kingdom;13. Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich Heine University Dusseldorf, Dusseldorf, Germany;14. Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark;15. The George Institute for Global Health, Nuffield Department of Obstetrics & Gynaecology, University of Oxford, Murdoch Children's Research Institute, Royal Children's Hospital, University of Melbourne, Melbourne, Australia |
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| Abstract: | The “delayed infection hypothesis” states that a paucity of infections in early childhood may lead to higher risks of childhood leukemia (CL), especially acute lymphoblastic leukemia (ALL). Using prospectively collected data from six population-based birth cohorts we studied the association between birth order (a proxy for pathogen exposure) and CL. We explored whether other birth or parental characteristics modify this association. With 2.2 × 106 person-years of follow-up, 185 CL and 136 ALL cases were ascertained. In Cox proportional hazards models, increasing birth order (continuous) was inversely associated with CL and ALL; hazard ratios (HR) = 0.88, 95% confidence interval (CI): (0.77–0.99) and 0.85: (0.73–0.99), respectively. Being later-born was associated with similarly reduced hazards of CL and ALL compared to being first-born; HRs = 0.78: 95% CI: 0.58–1.05 and 0.73: 0.52–1.03, respectively. Successive birth orders were associated with decreased CL and ALL risks (P for trend 0.047 and 0.055, respectively). Multivariable adjustment somewhat attenuated the associations. We found statistically significant and borderline interactions between birth weight (p = 0.024) and paternal age (p = 0.067), respectively, in associations between being later-born and CL, with the lowest risk observed for children born at <3 kg with fathers aged 35+ (HR = 0.18, 95% CI: 0.06–0.50). Our study strengthens the theory that increasing birth order confers protection against CL and ALL risks, but suggests that this association may be modified among subsets of children with different characteristics, notably advanced paternal age and lower birth weight. It is unclear whether these findings can be explained solely by infectious exposures. |
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| Keywords: | childhood leukemia acute lymphoblastic leukemia birth order paternal age birth weight cohort studies |
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