Changing patterns in education, employment and marriage along with improved reproductive technologies mean that the average age of childbearing in men and women is increasing while the average family size is falling. Although there are potential advantages to these trends, particularly in terms of financial security, there are also disadvantages, many of which are poorly understood at present. The detrimental effect of increasing maternal age on the health and development of offspring is widely recognised but the effect of increasing paternal age remains largely unexplored. However, there is emerging evidence that pregnancies conceived to older men are more likely to end in spontaneous abortion and that their children may be less intelligent, and be at higher risk of adverse outcomes and developmental disorders independent of the age of their mother.1-2 Moreover, these increased risks are not confined to childhood and advanced paternal age has also been reported to be associated with a number of adverse outcomes in adult offspring, most notably schizophrenia and certain cancers (principally breast, prostate and leukaemia).3-5 It is hypothesised that these associations may be due to the accumulation of chromosomal aberrations and mutations during the maturation of male germ cells.6 Later reproduction is also leading to a trend towards smaller families. While it is known that morbidity and mortality often rise with increasing number of siblings, there is also evidence to suggest that children from smaller families, and in particular only children, have a health experience that is out of line with anticipated gradients with number of siblings, specific examples being high blood pressure and asthma.7-8

Although the individual risks from having an older father or fewer siblings may be low, current trends in childbearing mean that these will increase at a population level and it is important that the risks are fully understood to allow appropriate education and to inform social policy changes. The aim of this project is to systematically investigate the effects of increasing paternal age and decreasing family size on the health and development of offspring throughout the life course. Systematic reviews of the available evidence will be carried out along with original research utilising a wide range of existing datasets.

Research plan

The project will involve a diverse range of existing large, good quality prospective datasets that cover the whole of the life-course, in different populations, over a range of calendar periods. These data sets include: ALSPAC, ProtecT, Swedish record linkage studies, Midspan Family Study, Glasgow Students Cohort, Caerphilly Cohort, and Boyd Orr Cohort. Parental age is available in all cohorts, along with a wealth of additional relevant data such as: mortality (Swedish, Midspan, Glasgow Students), cancer (ProtecT, Swedish, Midspan, Glasgow Students), offspring IQ (ALSPAC, Swedish), other mitogenic exposures (ALSPAC, Midspan), and details of family formation (ALSPAC, Swedish, Midspan, Glasgow Students).

This wide range of studies will form a consistent and complementary body of evidence on the short and longer-term effects of paternal ageing and smaller family size on offspring intelligence, development and health, and will also allow identification of critical periods in the life-course and investigation of how these interact with other risk factors. Examples (not an exhaustive list) of some specific hypotheses of interest include:

• Is greater paternal age associated with an increased risk of neuro-developmental markers of future mental disorder such as low intelligence or delay in obtaining motor milestones? How important is intelligence in setting an individual's life-course in terms of education, future financial attainment and long-term health? These questions will be explored using ALSPAC, Swedish and other datasets.
• Is increasing paternal age is associated with an increased risk of cancer? This will be examined in ProtecT (prostate cancer), Swedish (leukaemia, lymphoma and testicular cancer), and other datasets.
• How do offspring risks from mitogenic exposures in the father, e.g. smoking, alcohol, diet and occupation, combine with those from advancing paternal age? This will be explored using ALSPAC, Midspan and other datasets.

* It has been suggested that poorer health in only children may be a result of a more sedentary lifestyle. However, there are alternative hypotheses: Are only children more likely to be born to older parents and have a poorer health experience as a result? Or are only children the result of poor reproductive experience with hereditary factors responsible for poorer health? (e.g. high blood pressure in pregnancy is associated with high blood pressure in offspring; if a negative experience in pregnancy (e.g. eclampsia) results in a decision not to have any further children then this could explain the apparent pattern of increased blood pressure in only children) These hypotheses will be investigated using ALSPAC and other data on maternal health in pregnancy.

* To what extent are paternal age and family size associations confounded with each other and with other factors, in particular, parental intelligence, maternal age and changing social class? The availability of a wide range of datasets from across the life-course will allow a thorough investigation of the impact of these inter-correlated confounding variables through direct statistical analysis, appropriate simulation work and alternative study designs, e.g. in the Swedish studies data are available on both biological and step-fathers; if associations are restricted to biological father's age then, assuming that parents tend to be similar in age, this will provide evidence that the relationship is independent of maternal age.

The specific assemblage of different cohorts provides additional strength and value to the proposal. For example, the use of cohorts, some historical, from a range of calendar periods will allow a comparison of associations over time and insight into the impact of changing attitudes and societal trends in the reasons for delayed parenthood. In addition, several cohorts (e.g. ALSPAC, Glasgow Students) have repeated sweeps of data collection and these will be used to explore the impact of missing data on the results and conclusions of the analyses.

References

1. Bray I, et al. Advanced paternal age: How old is too old? J Epidemiol Community Health 2006;60:851-3

2. Cannon M. Contrasting Effects of Maternal and Paternal Age on Offspring Intelligence The clock ticks for men too. PLos Med 2009;6

3. Sipos A, et al. Paternal age and schizophrenia: a population based cohort study. BMJ 2004;329:1070-3

4. Zhang Y, et al. Parental Age at Child's Birth and Son's Risk of Prostate Cancer. Am J Epidemiol 1999;150:1208-12

5. Hemminki K, Kyyronen P. Parental age and risk of sporadic and familial cancer in offspring: Implications for germ cell mutagenesis. Epidemiology 1999;10:747-51.

6. Crow JF. The origins patterns and implications of human spontaneous mutation. Nat Rev Genet 2000;1:40-7

7. Okasha M, et al. Determinants of adolescent blood pressure: findings from the Glasgow University student cohort. J Hum Hypertens 2000;14:117-24

8. Rona RJ, et al. Association between asthma and family size between 1977 and 1994. J Epidemiol Community Health 1999;53:15-9