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)

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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5 Citations (Scopus)


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 × 10 6 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.

Original languageEnglish
Pages (from-to)26-33
Number of pages8
JournalInternational Journal of Cancer
Issue number1
Publication statusPublished - 1 Jan 2019
Externally publishedYes


  • acute lymphoblastic leukemia
  • birth order
  • birth weight
  • childhood leukemia
  • cohort studies
  • paternal age

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