Paternal Age at Childbearing and Offspring Psychiatric and Academic Morbidity

April 2014, Vol 71, No. 4 >

Paternal Age at Childbearing and Offspring Psychiatric and Academic Morbidity

Brian M. D’Onofrio, PhD1; Martin E. Rickert, PhD1; Emma Frans, MSc2; Ralf Kuja-Halkola, MSc2; Catarina Almqvist, MD2,3; Arvid Sjölander, PhD2; Henrik Larsson, PhD2; Paul Lichtenstein, PhD2

[+] Author Affiliations

JAMA Psychiatry. 2014;71(4):432-438. doi:10.1001/jamapsychiatry.2013.4525.

Text Size: A A A

Article

Figures

Tables

References

Comments (2)

Abstract

ABSTRACT | METHODS | RESULTS | DISCUSSION | CONCLUSIONS | ARTICLE INFORMATION | REFERENCES

Importance  Advancing paternal age is associated with increased genetic mutations during spermatogenesis, which research suggests may cause psychiatric morbidity in the offspring. The effects of advancing paternal age at childbearing on offspring morbidity remain unclear, however, because of inconsistent epidemiologic findings and the inability of previous studies to rigorously rule out confounding factors.

Objective  To examine the associations between advancing paternal age at childbearing and numerous indexes of offspring morbidity.

Design, Setting, and Participants  We performed a population-based cohort study of all individuals born in Sweden in 1973-2001 (N = 2 615 081), with subsets of the data used to predict childhood or adolescent morbidity. We estimated the risk of psychiatric and academic morbidity associated with advancing paternal age using several quasi-experimental designs, including the comparison of differentially exposed siblings, cousins, and first-born cousins.

Exposure  Paternal age at childbearing.

Main Outcomes and Measures  Psychiatric (autism, attention-deficit/hyperactivity disorder, psychosis, bipolar disorder, suicide attempt, and substance use problem) and academic (failing grades and low educational attainment) morbidity.

Results  In the study population, advancing paternal age was associated with increased risk of some psychiatric disorders (eg, autism, psychosis, and bipolar disorders) but decreased risk of the other indexes of morbidity. In contrast, the sibling-comparison analyses indicated that advancing paternal age had a dose-response relationship with every index of morbidity, with the magnitude of the associations being as large or larger than the estimates in the entire population. Compared with offspring born to fathers 20 to 24 years old, offspring of fathers 45 years and older were at heightened risk of autism (hazard ratio [HR] = 3.45; 95% CI, 1.62-7.33), attention-deficit/hyperactivity disorder (HR = 13.13; 95% CI, 6.85-25.16), psychosis (HR = 2.07; 95% CI, 1.35-3.20), bipolar disorder (HR = 24.70; 95% CI, 12.12-50.31), suicide attempts (HR = 2.72; 95% CI, 2.08-3.56), substance use problems (HR = 2.44; 95% CI, 1.98-2.99), failing a grade (odds ratio [OR] = 1.59; 95% CI, 1.37-1.85), and low educational attainment (OR = 1.70; 95% CI, 1.50-1.93) in within-sibling comparisons. Additional analyses using several quasi-experimental designs obtained commensurate results, further strengthening the internal and external validity of the findings.

Conclusions and Relevance  Advancing paternal age is associated with increased risk of psychiatric and academic morbidity, with the magnitude of the risks being as large or larger than previous estimates. These findings are consistent with the hypothesis that new genetic mutations that occur during spermatogenesis are causally related to offspring morbidity.