Mixed associations observed between advanced paternal age
and psychiatric morbidity in offspring
Ranjith Ramasamy, Larry I Lipshultz
Department of Urology, Baylor College of Medicine, Houston, Texas, USA
Larry I Lipshultz; email@example.com
WHAT IS ALREADY KNOWN ON THIS TOPIC?
Advanced maternal age has long been acknowledged as a risk factor
for genetic disorders such as Down
s syndrome. Owing to the large
number of cell divisions that occur during spermatogenesis, we can
speculate that advanced paternal age (APA) can contribute to an
increased number of
Autosomal dominant diseases
such as achondroplasia and multiple endocrine neoplasia syndrome are
strongly associated with APA. However, the association between APA
and complex disorders such as cancer and psychopathology is less
WHAT DOES THIS PAPER ADD?
This is the largest population-based investigation to date to address
the association between advanced paternal age and psychiatric
morbidity in the offspring. Previous studies have demonstrated
ndings on the association between
psychiatric disorders and parental (both paternal and maternal)
APA was associated with an increased risk for autism, psychosis
and bipolar disorder and reduced risk of attention de
ity disorder (ADHD), suicidal behaviour, substance abuse, failing
grades in school, low-educational attainment and low IQ.
Sibling-comparison analysis demonstrated offspring of fathers older
than 45 years were at signi
cantly higher risk for autism, ADHD,
psychosis, bipolar disorder, suicide attempts, substance abuse,
failing grades and low-educational attainment, than offspring of
fathers aged 20
24 years. Interestingly, the analyses demonstrated
response relationship for increasing risk of mental health
disorders with increasing paternal age.
Even though the sibling design obviates the need for data on parent-
ing behaviours of older versus younger fathers, estimates can be
severely biased by confounders not shared between the siblings.
Diagnoses (except for ADHD and autism) relied on inpatient
records. Potential cases of bipolar and other psychotic disorders
managed in the outpatient setting could have been missed.
The study included premature infants (aged 23
36 weeks), who are
at greater risk for mental and intellectual disorders.
WHAT NEXT IN RESEARCH?
The underlying genetic and molecular causes of why APA could contrib-
ute to increased psychiatric morbidity need to be determined.
COULD THESE RESULTS CHANGE YOUR PRACTICES
Yes, couples with an older male partner can be counselled regarding
the small but increased risk of
mutations and psychiatric disor-
ders. Nevertheless, the pregnancy should be treated as any other
according to prenatal diagnosis guidelines.
The clinical message is
important; APA should not be a contraindication for conception. There
are currently no screening or diagnostic test panels that speci
target those conditions that increase with paternal age.
RR is an NIH K12 Scholar supported by a Male Reproductive
Health Research Career, Development Physician-Scientist Award (HD073917-01) from
the Eunice Kennedy Shriver National Institute of Child Health and Human
Frigge ML, Masson G,
. Rate of de novo mutations and the
importance of father
s age to disease risk.
Petersen L, Agerbo E,
. A comprehensive assessment of parental
age and psychiatric disorders.
Class QA, Rickert ME,
. Preterm birth and mortality and
morbidity: a population-based quasi-experimental study.
Meck JM; Professional Practice and Guidelines Committee. Statement
on guidance for genetic counseling in advanced paternal age.
Onofrio BM, Rickert ME, Frans E,
. Paternal age at childbearing and offspring psychiatric and academic mor-
(n=2 615 081)
Sweden between 1973 and 2001. Data obtained from births, deaths, migra-
tion, patient and other registers.
Paternal age at childbearing (grouped into seven categories of
5-year intervals, from 20 years or younger to older than 45 years).
Paternal age 20
24 years. A
xed-effects model compared
paternal siblings to account for shared genetic and environmental factors,
with additional adjustment for various other child and parental covariates.
2009, or date of death if prior to 2009.
Prevalence of morbidity
Six indices of psychiatric morbidity were assessed
(ICD criteria): autism spectrum disorder (ASD) and ADHD, psychosis,
bipolar disorder, suicide attempt and substance use problem. Overall preva-
lence of psychiatric morbidity among children ranged from 0.27% to 3.04%.
Four indices of academic morbidity were assessed: failing grades, low-
educational attainment (less than 10 years), high-educational attainment
(more than 3 years postsecondary education) and low IQ. Prevalence of aca-
demic morbidity ranged from 9.77% to 28.86%.
Children of fathers aged 45 years or older were at
increased risk of developing ASD (HR=3.45, 95% CI 1.62 to 7.33), ADHD
(13.13, 6.85 to 25.16), psychosis (2.07, 1.35 to 3.20), bipolar disorder (24.70,
12.12 to 50.31), suicide attempt (2.72, 2.08 to 3.56) and substance use pro-
blems (2.44, CI 1.98 to 2.99).
Children of fathers aged 45 years or older were at
increased risk of failing a grade (OR=1.59, 95% CI 1.37 to 1.85) and low-
educational attainment (1.70, CI 1.50 to 1.93).
Evid Based Mental Health
February 2015 Vol 18 No 1
on February 12, 2016 - Published by