When to Be—or Not to Be—A Father: How To Look at Epigenetics and Advanced Paternal Age

The Case of the Month is an actual patient from “Doc, Let me be blunt. I’m 71 years old. Can I have kids?”
“Sir, that’s not too difficult to determine. Just a
few simple tests can tell us.”
“Well, if I can, are the kids more likely to have birth defects because of my age?

 The Older Father

Now there’s the start of a pretty involved discussion.  Just as older moms bring genetic issues to pregnancies, so in fact do older dads. Pregnancies in older moms are associated with chromosomal issues in offspring, as a mother’s eggs are as old as mom herself. Men, however, make 1000 new sperm per heartbeat, so the issues they bring to bear on offspring are different, and more complex.
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The Laundry List of Risk

I am giving a lecture on this topic at our international fertility meetings this October on precisely this topic. After extensive research of the literature, here is my understanding of the laundry list of risk that older fathers (over 40 years of age) bring to offspring:

  • 2-fold increased risk of miscarriage
  • 2-fold increased risk of pre-term birth
  • 1.9-fold increased risk of pre-term death
  • 25% increased risk of birth defects
  • 2-fold increased risk of chromosomal abnormalities
  • 8-10-fold increased risk of disease due to single gene mutations
  • Up to 5-fold increased risk of adult diseases (i.e. schizophrenia, bipolar, epilepsy)

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Paternal Age, Autism and Schizophrenia

Quite concerning is the fact that being an older father may put offspring at risk of diseases as adults. Since 2001, population studies from six different countries have confirmed that the risk of schizophrenia in offspring is correlated with advanced paternal age. Compared to that of a 24-year old father, the adult offspring of a 55-year old father have a 4-fold higher risk of having this serious and disabling psychiatric condition. Similarly, the risk of autism, a childhood condition that has increased 10-fold in the last 30 years, is estimated to increase by 5-6-fold in offspring of older fathers.

Harder Science, Same Findings

Last week, a significant paper was published in Nature that analyzed this risk in a different way, using molecular genetics instead of population science. And, lo and behold, it came to a similar conclusion: that a father’s age is linked to the risk of both schizophrenia and autism in offspring.
This study, performed by DeCode Genetics, looked at new, random mutations found in the entire genomic DNA of 78 parent-child trios in Iceland and 1859 controls. The technological approach was powerful, easily able to detect the equivalent of a single error in a single word in a 1000 page book. It focused on families in which parents had no signs of mental conditions but gave birth to children affected by either autism or schizophrenia. Examining new mutations in offspring is relevant because they are critical for evolution as we know it and roughly half of them are linked to brain development. The findings:

  • The number of new mutations observed in offspring increased by 2 for every year of a father’s age, such that 65 mutations were found in offspring of 40-year old men.
  • The average number of mutations derived from the mother was 15 and did not increase with her age.

Based on this, the authors calculated that 20-30% of new cases of autism and schizophrenia could be due simply to older paternal age. However it is also clear that the overall risk of having affected offspring for a father greater than 40 years old is still quite low at 2%.
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What’s Going on with Men?

Sperm are not eggs. Women are born with all of the eggs they will ever have. Men make fresh sperm daily, and as a consequence of this tremendous amount of cell division, quality control processes are highly taxed when making sperm. Mechanistically, being as busy as it is, for as long as it is, quality control within the testicle slowly decompensates over time. Much as an old car engine eventually leaks oil or blows smoke, the supervisory programs that oversee DNA replication lose fidelity with age and permit small errors to get through that wouldn’t have done so earlier. The result is an increase in new mutations in sperm that are then transmitted to offspring.

The Hard Choices

My belief is that this data is real and game-changing. If this worries you, then consider these 3 options: (1) have kids when you are young; (2) bank sperm when young to use for conception later in life, (3) control the things you can in life and don’t worry, as the overall risk is still very low and there is currently no genetic screening available to assess individual risk.
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