It’s Not Just Women’s Age – A Word On Older Fathers (Part 2)
A Word on Older Father’s Part 2 of 2: How Old is Old; What Couples Need to Know.
While there is no accepted definition of advanced paternal age (APA), a commonly used criteria is any male greater than or equal 40 yrs old at time of conception. The US population mean paternal age is 27 years old. However, as more women pursue pregnancy at an older age, paternal age inevitably follows this trend. Couples typically pursing fertility treatments are older than the national norms for pregnancy; The average paternal age at Reproductive Medicine Associates of New Jersey is 36.4 yrs. old.
As men age, there is a well-documented decline in their sperm parameters and a concomitant increase in their contribution to a couple’s infertility. Past studies have demonstrated that men over 35yo are twice as likely to be infertile (achieve a pregnancy within 12 mo) as men under 25yo. Another report found that after controlling for maternal age, couples where the man is over 35yo have a 50% reduction in pregnancy rates compared to couples where the man is less than 30 yo. Despite this decline, most men remain capable of achieving pregnancy through their life span. The oldest male documented to have achieved a natural pregnancy was 96yo.
Advanced paternal age is also associated with an increase in new genetic mutations. These mutations, often resulting in a single DNA base substitution or point mutations, are thought to be a direct result of the high number of germ cell division that sperm precursor germ cells undergo compared to female germ cells. The risk in the male for some types of these mutations parallels the number of germ cell divisions and increase linearly.
Some genetic abnormalities are seen at a higher than expected rate from just random errors in cell division and are seen to increase exponentially with age. It appears that some of these types of mutations while causing a disease in a resultant pregnancy, actually enhance the survival of the stem cells that carry these new mutations. Thus the enhanced survival of these “selfish” stem cells with these specific types of mutations, result in an increase number of abnormal germ cells sequestered in the testicle that carry the mutation. These mutations involve single base substitutions in the FGFR2, FGFR3, and RET genes, resulting in the autosomal disorders of multiple endocrine neoplasia 2A and 2B (MEN2A and MEN2B) as well as Pfeiffer syndrome, Crouzon syndrome, Apert syndrome, achondroplasia, and thanatophoric dysplasia. While the relative risk of these disorders is quite high and range from an 8x to 12x increase in risk compared to younger men, given the rarity of these conditions, the estimated risk for an such an autosomal disorder affecting a child of a father greater than 40yo is estimated to be between 0.3% to 0.5%.
There is also a growing body of data implicating advanced paternal age in some complex, multifactorial disorders such as schizophrenia, autism spectrum disorders, some forms of cancer and congenital abnormalities. Unlike the female, there is appears to be a very small paternal age contribution to abnormalities due to abnormal chromosome number (aneuploidy). The only possible exceptions include Down syndrome (trisomy 21) and Klinefelter syndrome (47XXY karyotype).
There is one report that demonstrated that only in older women (>35 yo) paternal age was a contributing factor in over 50% of the cases of Down syndrome. A similar result was seen in a multicenter study looking at pregnancy loss rates with advancing maternal and paternal age. In this report looking at over 3000 couples, the loss rate for women between 20yo and 29yo was the same, regardless of the paternal age. However for women between 30yo and 34yo the risk of miscarriage increased if the male was ≥ 40yo. As expected, as the women’s age increase above 35yo her risk of loss increase but was dramatically higher if her male partner was ≥ 40yo. The fact that these effects were not seen in younger women suggests that young eggs, may somehow correct or compensate for older sperm in early embryonic development.
Unfortunately as these mutations are spontaneous with the formation of the sperm, there is no test that can be done on the male to screen for these conditions. Also, it is currently impossible to screen embryos for a range of possible disorders. However, it is conceivable with advances in technology that sometime in the not so distant future, we will be able to screen embryos with such an “advanced paternal age” screening panel.
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