Male Factor Infertility

As a field, there are two common questions when it comes to studying the implications of men trying to conceive as they grow older.

The first question is whether it becomes harder for that man to father a child. The answer appears to be yes, though at later ages than when it becomes problematic for a woman.

The second question is whether offspring of older men are any different than those of younger men. The answer appears to be yes. For the moment, this is most concentrated around the development of psychosocial disorders, but it’s important to remember that the absolute risk is still low. That said, the AUA guidelines recommend considering advanced paternal age counseling at age 40 and for those experiencing recurrent pregnancy loss.

While women are born with a finite number of eggs, which helps explain the drop-off in fertility in a woman’s 30’s and 40’s, men continually produce new sperm. This is why the impact of age on male infertility is more gradual and, frankly, harder to characterize.

The American Urological Association (AUA) and the American Society for Reproductive Medicine (ASRM) recommend that men 40 and older be counseled on the potential health risks to their offspring associated with advanced paternal age.

Time To Conception

Around a man’s mid-40’s age seems to become a factor. Below is a study looking at the length of time required to conceive for couples, broken down by the man’s age. As you can see, the amount of time rises sharply around age 45. The data comes from a study in the UK of over 2,000 births and the results were statistically significant.

Many studies plotting male age against their ability to conceive are unhelpful because the investigators don’t isolate out the fact that older men tend to have older female partners. This study isolates out those variables. To further adjust for the female-age confounder, the study’s investigators looked solely at the data for men who had partners under the age of 25. The cohort of men over the age of 35 are clearly negatively impacted.

There is good reason to believe that an older man’s challenges in conceiving can be counterbalanced if his female partner has especially good fertility.

Conception To Live Birth

To this point we’ve shown that older men require a longer time to conception. After conception, the risk of miscarriage remains relatively flat until the man enters his 50’s.

IVF

As always, we’re left to wonder how this impacts couples going through IVF. Said differently, can IVF help older men overcome the challenges of age to conceive. Frankly, the data is divided. We’ve seen compelling studies that both prove and disprove that paternal age plays a role in IVF success rates.

At what age does it become ill-advised for a man to reproduce for fear it will impact the health of his offspring? The truth is, that’s still hard to say. It's still uncommon for men to father children after, say, the age of 50 (only 1% of births), and the downstream conditions linked to genetic anomalies (for instance, autism) are still relatively rare, so we need much larger datasets to derive strong insight. That said, here’s what we know, or think we know.

A study on this topic is a 2007 Kaiser Permanente review of the 150,000+ births in their system. The team did a nice job disaggregating a lot of variables and came to the conclusion that children born to fathers over age 40 had an 0.8%–0.9% chance of developing Autism, up from around 0.2%–0.5% for children born to men in younger age brackets.

One large population study out of Israel noted that children fathered by men over the age of 40 were five times more likely to develop Autism Spectrum Disorder. A meta-analysis of multiple studies pegged the increased relative risk at closer to 55%. While either relative risk is high, ASD is uncommon and so the absolute level of risk equated to about 3 in 1,000 babies. That said, there are studies that suggest the heightened risk is handed down not just to offspring but also grandchildren.

There are a number of global studies that show a tight correlation between “advanced paternal age” and bipolar disorder in the offspring. For instance studies in Finland and Thailand show anywhere between a 90%—190% increased incidence amongst offspring with fathers ages 50-and-over.

One Swedish study of 14,000 people found that children born to men over the age of 50 had a 37% higher likelihood of developing bipolar disorder, even after correcting for variables like the mother’s age (which had a slight effect) and socio-economic status. Roughly 1 in 100 people are diagnosed with bipolar disorder, and so the absolute raised level of risk is still likely well below 3%.

Over 15 studies have found a correlation between advanced paternal age and the incidence of schizophrenia amongst offspring. One meta-analysis estimated the “rate of risk” was over twice as high amongst offspring born to men over age 50.

One seminal study investigating advanced paternal age and schizophrenia (acquired by age 34) comes out of Israel. This study showed a steady, but mild, increase in progressive risk that ultimately jumped up when men fathered children after the age of 50.