title: Advanced paternal age and stillbirth rate: a nationwide register-based cohort study of 944,031 pregnancies in Denmark.
abstract: Advanced paternal age has been associated with a variety of rare conditions and diseases of great public health impact. An increased number of de novo point mutations in sperm with increasing age have been suggested as a mechanism, which would likely also affect fetal viability. We examined the association between paternal age and stillbirth rate in a large nationwide cohort. We identified all pregnancies in Denmark from 1994 to 2010 carried to a gestational age of at least 22 completed weeks (n = 944,031) as registered in national registers and linked to individual register data about the parents. The hazard ratio of stillbirth according to paternal age was estimated, adjusted for maternal age in 1-year categories, year of outcome, and additionally parental educational levels. The relative rate of stillbirth (n = 4946) according to paternal age was found to be J-shaped with the highest hazard ratio for fathers aged more than 40 years when paternal age was modelled using restricted cubic splines. When modelled categorically, the adjusted hazard ratios of stillbirth were as follows: <25, 1.16 (95% confidence interval, CI 1.01-1.34); 25-29, 1.03 (95% CI 0.95-1.11); 35-39, 1.16 (95% CI 1.07-1.26); 40-44, 1.41 (95% CI 1.26-1.59); 45-49, 1.20 (95% CI 0.97-1.49); 50+, 1.58 (95% CI 1.18-2.11), compared with fathers aged 30-34 years. These estimates attenuated slightly when further adjusted for parental education. Our study showed that paternal age was associated with the relative rate of stillbirth in a J-shaped manner with the highest hazard ratios among fathers aged more than 40 years.
authors.affiliation: Section of Social Medicine, Department of Public Health, University of Copenhagen, Oster Farimagsgade 5, POB 2099, 1014, Copenhagen K, Denmark. stur@sund.ku.dk.
authors.forename: Stine Kjaer
authors.initials: SK
authors.lastname: Urhoj
authors.affiliation: Section of Biostatistics, Department of Public Health, University of Copenhagen, Oster Farimagsgade 5, POB 2099, 1014, Copenhagen K, Denmark.
authors.forename: Per Kragh
authors.initials: PK
authors.lastname: Andersen
authors.affiliation: Section of Social Medicine, Department of Public Health, University of Copenhagen, Oster Farimagsgade 5, POB 2099, 1014, Copenhagen K, Denmark.|Methods and Analysis, Statistics Denmark, Sejrøgade 11, 2100, Copenhagen Ø, Denmark.
authors.forename: Laust Hvas
authors.initials: LH
authors.lastname: Mortensen
authors.affiliation: MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK.
authors.forename: George
authors.initials: G
authors.lastname: Davey Smith
authors.affiliation: Section of Social Medicine, Department of Public Health, University of Copenhagen, Oster Farimagsgade 5, POB 2099, 1014, Copenhagen K, Denmark.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Nybo Andersen
mesh_terms: D000328:Adult; D015331:Cohort Studies; D003718:Denmark / Q000453:epidemiology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010331:Paternal Age; D011247:Pregnancy; D016016:Proportional Hazards Models; D012042:Registries / Q000706:statistics & numerical data; D012307:Risk Factors; D050497:Stillbirth / Q000453:epidemiology*; D055815:Young Adult
keywords: Cohort study; Germline mutations; Paternal age; Perinatal epidemiology; Stillbirth