Prof Martha Dirnfeld

Department of OB/Gyn , Head Division of Reproductive

Endocrinology-IVF Faculty of Medicine Technion , Haifa Israel

Disclosure of Interest: Nothing to Disclose

XII Annual Meeting of the Mediterranean

Society for Reproductive Medicine (MSRM) &

the World Congress on Building Consensus

out of Controversies in Obstetrics, Gynecology

& Infertility (COGI)

April 24-26, 2014, in Barcelona, Spain.

Prof Martha Dirnfeld

Department of OB/Gyn ,

Head Division of Reproductive

Endocrinology-IVF Faculty of Medicine

Technion , Haifa Israel

Disclosure of Interest: Nothing to Disclose

There is a social phenomena of delaying family planning and parenthood to the mid or late thirties.

ART enables older couples materialize

their aspirations for healthy offspring

later in life.

The adverse effects of

advancing maternal age are well understood

However

Much less is known about the impact of paternal age on the health and development of their offspring

Source: Birth Statistics, England and Wales, Series FM1 no. 32, 2003

(Office for National Statistics, 2003).

Decreasing trends

Increasing trends

The public health implications of this trend have not been widely anticipated or debated.

Changes in the population structure and trends

Advances in reproductive technologies.

( 3%–6% of births from ART)

Socio-economic changes have led to

both men and women beginning families later.

Focus is mainly on the risks of maternal,

rather than paternal, aging.

Change with age: semen Volume , infections, erectile dysfunction & time to conceive

No significant change with age: semen concentration, motility and morphology

However:

Age-related decline in testicular function

could be overcome by the use of ART (ICSI)

Dain L. Dirnfeld M et al, Fertil Steril 2011

Most autosomal trisomies arise from maternal origin.

No clear association

between fathers’ age (>50 years) and the occurrence of Down Syndrome or several other chromosomal aneuploidies

36 older men (61–102 years old)

10 younger men (29–40 years old)

The rate of aneuploidy in older

subjects was not different from

that found in the control group

Dakouane et al, A histomorphometric and cytogenetic study of testis from men 29–102 years old. Fertil Steril 2005

Advanced paternal age and cell aging

Prolonged periods of exposure to environmental toxicants Age-dependent decrease in anti-oxidant mechanisms Positive selection of mutated spermatozoa May lead to the accumulation of mutations

However

Offspring of older fathers will tend to have longer telomeres, which may imply better preparation for an environment with a higher expected age at reproduction.

PAE related Syndromes: point mutations in the Fibroblast growth factor receptors

(FGFR2 and FGFR3) on chromosome 10 Mutations are associated with numerous medical conditions that include abnormal bone development (e.g. craniosynostosis syndromes) and cancer. Branchial arch syndrome (craniostenosis , syndatility, sculp disorders) Apert Crouzon Pfeiffer Muenke

Other FGFR3 mutations : achondroplasia and hypochondroplasia

spermatogonial replication errors that accumulate with increased age.

All mutations were associated with increased paternal age and molecularly proved to be a paternal origin of mutation.

Retrospective analysis of 5,213,248 subjects in the USA Increased risk for

heart defects circulatory/respiratory defects diaphragmatic hernia tracheo-oesophageal fistulas musculo-sceletal anomalies

(data extracted from Yang et al, Hum Rep , 2007).

Spontaneous germline mutations in X-linked genes

More common with advancing paternal age

These mutations would be transmitted from carrier daughters to affected grandsons and have thus been called " the grandfather effect."

Examples of such diseases include hemophilia A and Duchenne muscular dystrophy

Advanced paternal age and Cancer

Germ line cell mutations have been associated with aging and may be a cause of childhood cancer among children of older parents.

Paternal age was associated with a small, but statistically significant increased risk of leukemia and central nervous system cancers

Yip Bh et al Parental age and risk of childhood cancers: a population-based cohort study from Sweden. Int J Epidemiol 2006; 35:1495.

The “u shape “ pattern presents a challenge for the clinical translation of paternal age effect on several offspring outcomes

Has been documented in numerous biological, toxicological, and pharmacological investigations :

Homeopathy studies

Body weight

Cholesterol levels

Ethanol consumption and the risk of MI

Longevity

Cancer incidence

Advanced paternal age and neurologic disorders

Reported to be associated with:

Epilepsy (Vestergaard M Paternal age and epilepsy in the offspring. Eur J Epidemiol,2005)

Bipolar disorder (Frans EM ,Arch Gen Psychiatry,2008)

Autism (Hultman CN,. Mol Psychiatry, 2010)

Dyslexia (Jayasekara R, J Biosoc Sci 1978)

Neurocognitive impairments (Saha S, PLoS Med 2009)

Deficits in social functioning (Weiser Schizophr Bull, 2008)

U shape pattern effects and paternal age

Offspring’s Intelligence The lowest IQ scores associated with both younger and older fathers whreas most studies report a linear association between older maternal age and superior neurocognitive ability.

Lower offspring intelligence has been found at the two paternal age extremes 772 participants - West of Scotland

Elise Whitley E et al , PLoS One. 2012

Major depressive disorder Increased odds in offspring’s born to both younger and older fathers

Schizophrenia Risk Both older and younger paternal age <25 increase the risk of schizophrenia Malaspina et al Arch Gen Psychiatry , 2001 ,

Schizophrenia Risk

Endophenotype : a genetic epidemiology term which is used to parse behavioral symptoms into more stable phenotypes with a clear genetic connection.

Data from the Consortium on the Genetics of Schizophrenia (COGS) , 293 cases vs 382 unaffected siblings Factors other than advanced paternal age at birth may account for endophenotypic deficit levels in schizophrenia. Tsuang D et al. Is there an association between advanced paternal age and endophenotype deficit levels in schizophrenia? PloS One , Feb 2014

In the same population study :

Older fathers or under 25 years of age were also at increased risk of:

Spina bifida/meningocele,

Microcephalus,

Omphalocele

Gastroschisis

Musculoskeletal anomalies.

Spontaneous abortions

Increasing paternal age is significantly associated with spontaneous abortion, independent of maternal age

The risk of spontaneous abortion was almost twice higher among men aged > 45 years than among those aged < 25 years.

Slama R, et al. Influence of paternal age on the risk of spontaneous abortion.Am J Epidemiol 2005; 1: 816–23.

Linear Correlations

Compared with infants born to younger fathers 25-29 years: infants born to fathers aged 40-45 and >45 years had a 24% and 48% increased risk of late stillbirth . However Fathers aged < 24 years had an elevated likelihood of experiencing these same adverse outcomes.

Amina P et al ,Am J Mens Health 2012 vol. 6 no. 5 427-435

Offspring of men aged 55 years and older were 1.37 times more likely to be diagnosed as having bipolar disorder than the offspring of men aged 20–24 years

Frans EM, et al. Advancing paternal age

and bipolar disorder. Arch Gen Psychiatry 2008

In contrast,

Others found NO association between

paternal age and bipolar disorder

Buizer-Voskamp JE et al, findings from a Dutch population registry. Schizophr Res, 2011

Epidemiological studies:

In 132,271 males : Offspring of men > 40 years were 5.75 times more likely to have ASD compared with offspring of men < 30 years.

Reichenberg A et al. Advancing paternal age and autism. Arch Gen Psychiatry 2006

Dutch registry using 14,231 patients : ASD was significantly associated with increased paternal age. Fathers >40 years have 3.3 times increased odds of having a child with ASD compared to fathers < 20 years of age

Buizer-Voskamp JE et al. Paternal age and psychiatric disorders: findings from a Dutch population registry. Schizophr Res, 2011

Genetic studies:

Gene expression pathways involved in transcriptional regulation are down regulated in children with autism and children of older fathers.

Are we confused? Recent publications 2014 :

Analysis in 268 individuals with an autism spectrum in New Jersey : No significant differences across maternal and paternal age groups.

Maramara LA et al J . Child Neurol, January 2014

Children born to fathers of advanced age (>40) have an increased risk of dying before the age of 5 years.

Urhoj SK et al , Hum Reprod, February 2014

Note: The statistically significant excess risk found for children born to fathers aged 40-44 years reported : Hazard Ratio: 1.10 (95% CI: 1.00-1.21)

In some cases, the biological father may differ from the father registered (10%)

In view of the rise in late parenthood combined with these powerful techniques, it is inevitable that other aspects may emerge regarding late parenthood and be expressed in the offspring.

Higher maternal age is an indication for intensive prenatal and invasive diagnostics There are no clear definitions or guidelines on genetic risk assessment and counseling for advanced paternal age Current evidence suggests:

Paternal age itself provides no

rationale for invasive procedures

The genetic risk for progeny from older fathers is increased, the risk to the individual is probably low

ART technologies circumvent male age related decreased fertility - The impact of is not clear

Unexplained “U shape phenomena” have been found in many aspects of adverse outcomes related to paternal age

Some adverse health outcomes for children born to older

parents are linear and age related.

Advanced paternal and maternal age should be weighed up against social advantages and disadvantages

Policy implication is challenging : Socio - demographic effects are complex and are likely to change over time