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There is no clearly accepted definition of advanced paternal age. A frequently used criterion is any man aged 40 years or older at the time of conception. The current population mean paternal age is 27 years.

Advanced paternal age is associated with an increased risk of new gene mutations. Because of the large number of cell divisions during spermatogenesis, the mutation rate for base substitutions is much higher in men than women, and increases with paternal age. The risk for genetic defects increases linearly for some conditions, and exponentially for others.1–3 The conditions most strongly associated with advanced paternal age are those caused by mutations in the form of single base substitutions in the FGFR2, FGFR3, and RET genes, and include Pfeiffer syndrome, Crouzon syndrome, Apert syndrome, achondroplasia, thanatophoric dysplasia, as well as MEN2A and MEN2B.4 Some dominant conditions that are caused by gene changes that include both point mutations and base pair deletions (e.g., neurofibromatosis) show a lesser association with paternal age. Other dominant conditions show no association with increased paternal age.5 Although Friedman6 had estimated that the risk for autosomal dominant disorders affecting offspring of fathers aged 40 or more was 0.3–0.5%, it is now thought that the actual risk is lower.7 There is also a growing body of evidence that advanced paternal age is associated with an increased risk for complex disorders such as some congenital anomalies, schizophrenia, autism spectrum disorders, and some forms of cancer.8–12 For most conditions the relative risk is two or less. However, the mechanism for the increased risk is unknown, and in some cases, the observed paternal age effect may be an artifact of some other causative factor.

In general, for autosomes and sex chromosomes, there is no compelling evidence that chromosomal aberrations (aneuploidy or structural chromosome abnormalities) are significantly increased in newborns as paternal age increases. The low incidence of paternally derived extra chromosomes in trisomies combined with the relatively small number of children fathered by older men makes it difficult to demonstrate a paternal age effect. Two possible exceptions are trisomy 21 and Klinefelter syndrome. Recent data on Down syndrome suggest a paternal age effect, either acting alone or in combination with a maternal age effect.13,14 This observation is supported by reports of increased aneuploidy rates in sperm for some of the chromosomes, including 21 and the sex chromosomes.15–17 In summary, there is a wide range of genetic disorders that may be related to advanced paternal age (Table 1). Overall, it seems that the risk of birth defects and some chromosome disorders may be minimally increased, and the risk for later onset disorders may also show a small increase with advanced paternal age. There are currently no screening or diagnostic test panels which specifically target those conditions that increase with paternal age. If the older male's partner is currently pregnant, the pregnancy should be treated as any other according to prenatal diagnosis guidelines established by the American College of Medical Genetics and American College of Obstetricians and Gynecologists,18–20 with the prenatal counseling session including a discussion about the potentially increased risk of Down syndrome attributable to increased paternal age. Because of this and the possibility of ultrasound detection of some of the features of the autosomal dominant conditions noted above (e.g., thanatophoric dysplasia), an ultrasound is recommended at 18–20-weeks gestation to evaluate fetal growth and development. However, it is unlikely to detect many of the conditions of interest. Prospective couples should receive individualized genetic counseling to address specific concerns.

Table 1 Paternal age risks
Full size table

RESOURCES

  1. 1

    Archer NP, Langlois PH, Suarez L, Brender J, et al. Association of paternal age with prevalence of selected birth defects. Birth Defects Res A Clin Mol Teratol 2007;79:27–34.

  2. 2

    Cedergren MI, Selbing AJ, Kallen BA. Risk factors for cardiovascular malformation—a study based on prospectively collected data. Scand J Work Environ Health 2002;28:12–17.

  3. 3

    Dzurova D, Pikhart H. Down syndrome, paternal age and education: comparison of California and the Czech Republic. BMC Public Health 2005;5:69.

  4. 4

    MacDonald M, Hassold T, Harvey J, Wang LH, et al. The origin of 47, XXY and 47, XXX aneuploidy: heterogeneous mechanisms and the role of aberrant recombination. Hum Mol Genet 1994;3:1365–1371.

  5. 5

    Sherman SL, Freeman SB, Allen EG, Lamb NE. Risk factors for nondisjunction of Trisomy 21. Cytogenetic Genome Res 2005;111:273–280.

  6. 6

    Xue F, Colditz GA, Willett WC, Rosner BA, et al. Parental age at delivery and incidence of breast cancer: a prospective cohort study. Breast Cancer Res Treat 2007;104:331–340.