Paternal age and offspring congenital heart defects: a national cohort study

PLoS One. 2015 Mar 25;10(3):e0121030. doi: 10.1371/journal.pone.0121030. eCollection 2015.


Paternal age has been associated with offspring congenital heart defects (CHDs), which might be caused by increased mutations in the germ cell line because of cumulated cell replications. Empirical evidences, however, remain inconclusive. Furthermore, it is unknown whether all subtypes of CHDs are affected by paternal age. We aimed to explore the relationship between paternal age and the risk of offspring CHDs and its five common subtypes using national register data in Denmark. A total of 1,893,899 singletons born in Denmark from 1977 to 2008 were included in this national-based cohort study. Cox's proportion hazards model with robust sandwich estimate option was used to estimate the hazards ratio (95% confidence interval) for the associations between paternal age and all CHDs, as well as subtypes of CHDs (patent ductus arteriosus (PDA), ventricular septal defect (VSD), atrial septal defect (ASD), tetralogy of fallot (TOF) and coarctation of the aorta (CoA)). We did not observe an overall association between paternal age and offspring CHDs. However, compared to the paternal age of 25-29 years, paternal age of older than 45 years was associated with a 69% increased risk of PDA (HR45+ = 1.69, 95%CI:1.17-2.43). We observed similar results when subanalyses were restricted to children born to mothers of 27-30 years old. After taking into consideration of maternal age, our data suggested that advanced paternal age was associated with an increased prevalence of one subtype of offspring congenital heart defects (CHDs), namely patent ductus arteriosus (PDA).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age Factors
  • Cohort Studies
  • Denmark
  • Female
  • Heart Defects, Congenital / epidemiology*
  • Heart Defects, Congenital / etiology*
  • Humans
  • Infant
  • Male
  • Maternal Age
  • Middle Aged
  • Paternal Age*
  • Prevalence
  • Registries
  • Risk
  • Young Adult

Grant support

The study was supported by the European Research Council (ERC-2010-StG-260242-PROGEURO), the Danish Medical Research Council (project no. 09-072986), the National Basic Research Program of China (973 program), 2010 CB 529504. XJS is partly supported by a travel grant from Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine and Youth Foundation of Shanghai Municipal Commission of Health and Family Planning (20124y176). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.