Study question: Do children born to fathers of advanced age have an increased risk of dying before the age of 5 years? Summary answer: Children born to fathers aged 40 years or more have an increased risk of dying in early childhood due to an excess risk of fatal congenital anomalies, malignancies and external causes. What is known already: Advanced paternal age has previously been associated with adverse reproductive outcomes and some long term health problems in the offspring. This is possibly due to specific point mutations, a condition known to increase in the sperm with increasing paternal age. Study design, size, duration: A Danish population-based register study, designed as a prospective cohort study, of 1 575 521 live born children born from 1978 to 2004. The age of the child (in days) was used as the underlying time and the children entered the cohort the day they were born and were followed until 31 December 2009. The children were censored on date of turning 5 years, date of death or date of emigration, whichever occurred first. Participants/materials, setting, methods: Data from population-covering registers from Statistics Denmark including the Integrated Database for Labour Market Research, the Medical Birth Registry and the Registry of Causes of Death was linked using the unique civil registry number. Hazard ratios (HR) with 95% confidence intervals (CI) were used to estimate the risk of under-five mortality. The effect of paternal age was examined using restricted cubic splines and paternal age groups. Main results and the role of chance: Compared with children born to fathers aged 30–34 years, a statistically significant excess risk was found for children born to fathers aged 40–44 years [HR: 1.10 (95% CI: 1.00–1.21)] and children born to fathers aged 45+ years [HR: 1.16 (95% CI: 1.02–1.32)]. When only looking at 1–5 year olds, the relative risk (HR) among children born to fathers aged 40–44 years increased to 1.24 (95% CI: 1.00–1.53) and the risk in the oldest paternal age group (45+ years) rose to 1.65 (95% CI: 1.24–2.18). The results suggest that the elevated risk for children of fathers aged 40 years or more was primarily attributed to an elevated risk of dying from congenital malformations, malignancies and external causes. Limitations, reasons for caution: Specific causes of death might be misclassified; however, this is not likely to be dependent on paternal age. In some cases, the biological father may differ from the father registered. This misclassification is most likely non-differential. Wider implications of the findings: The excess risk of mortality among children born to older fathers is in accordance with the literature. The association needs further attention as it can provide valuable knowledge of the etiology of genetic diseases. Also, the association could become of greater importance in the future if the proportion of fathers aged 40+ years keeps growing.
Human Reproduction, 2014, Vol 29, Issue 2, p. 343-350