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Hum. Reprod. Advance Access published online on July 8, 2005
Human Reproduction, doi:10.1093/humrep/dei186
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© The Author 2005. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.
Received March 30, 2005
Revised June 6, 2005
Accepted June 9, 2005

Article

Paternal age and congenital malformations

Jin Liang Zhu 1, Kreesten M. Madsen 1, Mogens Vestergaard 2, Anne V. Olesen 2, Olga Basso 3, and Jørn Olsen 4

1 The Danish Epidemiology Science Centre, University of Aarhus
2 Department of Epidemiology, University of Aarhus, Vennelyst Boulevard 6, DK 8000 Aarhus C, Denmark
3 Epidemiology Branch, National Institute of Environmental Health Sciences, Department of Health and Human Services, National Institutes of Health, MD A3-05, P.O.Box 12233, Research Triangle Park, NC 27709
4 The Danish Epidemiology Science Centre, University of Aarhus; Department of Epidemiology, School of Public Health, UCLA, Box 951772, Los Angeles, CA 90095-1772, USA


  Abstract

BACKGROUND: Spontaneous mutations in germ cells increase with male age, but an association between paternal age and congenital malformations is not well established. We conducted a population-based cohort study to estimate this association. METHODS: A study population of couples and their firstborn children were identified in the Danish Fertility Database between 1980 and 1996 (n = 71937). Diagnoses of congenital malformations in children were obtained by linkage to the nationwide hospital register (1980-1999). RESULTS: Overall, there were no differences in the prevalence of malformations as a function of paternal age. However, the prevalence of malformations of extremities and syndromes of multiple systems, as well as Down’s syndrome, increased with increasing paternal age. For example, in comparison with fathers age 20-29 years, adjusted hazard ratio of syndromes of multiple systems was 1.15 [95% confidence interval (CI) 0.81-1.65] for age 35-39 years, 1.33 (95% CI 0.79-2.25) for age 40-44 years, 1.73 (95% CI 0.82-3.65) for age 45-49 years, and 3.20 (95% CI 1.37-7.48) for age ≥50 years (test for trend P = 0.01). CONCLUSIONS: Our data suggest that advanced paternal age may be associated with an excess occurrence of some specific malformations. The association could be caused by mutations of the gametes in men induced by biological or environmental factors.

Keywords: abnormalities/Down’s syndrome/paternal age.
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