Older Dads and Male Fertility Potential
Advanced Paternal Age
How Male Age Relates to Sperm Quality and Fertility Potential
In recent decades, both men and women have been delaying having children until later in life. For a variety of socioeconomic reasons, many couples are simply choosing to wait longer to start a family than couples did in the past. Since 1980, birth rates in the United States have increased by 40 percent for men ages 35-49 years and decreased by 20 percent for men under thirty. [Humm KC. FertSteril 2013] The proportion of men pregnancies from couples in which the man was 40 years or older increased from 1 in 11 in 1996 to 1 in 7 in 2010, and this percentage just continues to grow.
Unlike women who eventually hit menopause (usually in their 40’s) and stop ovulating, spermatogenesis in men generally continues throughout their lifetime. [Ramasamy R. FertSteril 2015]. Although stories abound of men fathering children well into their 80’s (and even 90’s in some circumstances), male fertility potential clearly decreases with age in the vast majority of men. In terms of sperm production, the number of Leydig cells (which make testosterone) and spermatogenic cells have been shown to decrease with age. [Ramasamy R. FertSteril 2015]. This invariably leads to decreases in testosterone levels and sperm counts. A 2018 study evaluated semen parameters based on age in 11,706 men who had a mean age of 35.9 years. For men less than 40 years of age, the average total motile count (TMC) was 126.0 million sperm, and this dropped to 80.69 for men aged 40+, while motility dropped from 44.9% to 34.7% in the older age group. [Veron LG. FertSteril 2018]. Increased time-to-pregnancy for couples trying to conceive naturally has been noted in couples where the male partner is older. [Humm KC. FertSteril 2013]. Pregnancy rates with standard IVF have also been shown to be lower in older men, though this effect seems to be mitigated somewhat if the female partner is young (consistent with the theory that the eggs of younger women have the ability to repair some degree of sperm DNA damage after fertilization). [Humm KC. FertSteril 2013]. The use of ICSI with IVF appears to lower the impact of male age on outcomes, but success rates still decrease with the male partner’s increasing age, especially if the woman is older as well. [Chapuis A. BasicClinAndrol 2017]. A woman’s oocyte is known to have the ability to repair DNA damage within sperm cells, but this ability generally decreases as the age of the woman increases. Miscarriage rates are known to be higher in women age 35 and above, and this impact is even greater when the male partner is also 40 years or older. [Ramasamy R. FertSteril 2015]
The mechanism for increased risk of genetic and health problems in offspring is thought to be primarily through the accumulation of de novo point mutations within the sperm. These are part of the normal process of natural selection, with different genetic mutations conveying positive, negative, or neutral effects on the subsequent offspring. Most of the point mutations come from copy errors which occur during stem cell cycling. Because sperm production continues throughout most of a man’s life (vs. a woman who is born with all of her eggs), the mutations accumulate over time. It is estimated that there are 1-2 de novo point mutations in each child for each additional year of the age of the father. Most of these mutations are in locations that have no clinical impact, so the overall increased risk to the child with increasing paternal age remain present but small. [Wood KA. FertSteril 2021]
CAUSES OF AGING-ASSOCIATED CHANGES IN MALE FERTILITY
A large number of factors associated with aging can play a role in decreasing reproductive potential in men. [Avellino G. FertSteril 2017][Humm KC. FertSteril 2013][Kaarouch I. MolReprodDev 2018] These include:
1) Hormonal abnormalities, including decreased testosterone levels
2) Sexual problems including erectile and ejaculatory dysfunction
3) Accumulated environment toxin exposure
4) Increased oxidative stress on sperm cells
5) Increased sperm aneuploidy
6) Increases in body fat and higher rates of obesity
7) Chronic health problems that can impact fertility (e.g. diabetes)
8) Prostate problems such as cancer and BPH (benign enlargement)
9) Medication side effects
10) Decreased ejaculate volume
11) Increased levels of sperm DNA fragmentation (DFI)- see below
Sperm DNA Fragmentation and Paternal Age
Levels of sperm DNA fragmentation (DFI) have been shown to consistently increase with male age, especially after age 40. [Kaarouch I. MolReprodDev 2018].
Age Average DFI
20–29 12.9%
30–39 16.3%
40–49 23.2%
50–59 35.4%
60–80 49.6%
[A. J. Wyrobek et al., Proceedings of the National Academy of Sciences, 2006]
For more information on the clinical impact of elevated levels of sperm DFI, see “Advanced Sperm Testing” section of this website.
INCREASED RISK OF INHERITED DISORDERS
Traditionally, babies of older mothers are thought to have an elevated risk of birth defects and chromosomal abnormalities. Recently, however, increasing attention has been focused on how the age of the father affects rates of birth defects and other developmental abnormalities. A 2019 paper reviewed the relationship between increased paternal age and child outcomes and the following is a summary of this study’s findings. [Bergh C. FertSteril 2019]
Chromosomal Aberration- Down Syndrome (Trisomy 21)
1/800 live births- only 6-10% felt to be due to sperm DNA problems
Relationship to maternal age: 1/2000 at 20 years, 1/100 at 40 years, 1/10 for women in upper 40’s
Relationship to paternal age: 13% increased risk in men 40 years and older
Any birth defects- 5% increased risk with paternal age of 35 years or older.
Heart defects- No association with paternal age.
Orofacial clefts- 14% increased risk in men ager 45 years and older
Gastroschisis (congenital abdominal wall defect)- Increased risk with younger male age (12% decreased risk in men age 35 years and older.
Spina bifida/Anencephaly- No association with paternal age.
Hypospadias- No association with paternal age.
Any childhood cancer- Weak but significantly increased risk of childhood cancer. 5-15% increased chance in older dads vs. men <25 years of age.
Childhood leukemia and lymphoma- 4% increased risk of acute lymphocytic leukemia (ALL) in children of older dads
Central nervous system (CNS) tumors- conflicting results on impact of paternal age
Diabetes mellitus (DM)- Conflicting results for Type I DM. Weak but significant increase in Type II DM.
Asthma- Increased risk of asthma in the children of younger dads.
Cerebral palsy- Unclear, no good data.
Autism- Risk increases by 21% for each 10 years of increased male age, with no clear age cut-off. By paternal age 55-59 there is a 39% increase in the risk of having a child with autism.
Schizophrenia- The risk of developing schizophrenia has been shown to be higher among children of older fathers. Men ages 45 years and above have a 38% increased chance of a child with schizophrenia, while men 55 years of age and older have 2.11 times the risk of this problem in their children.
Bipolar disorder- No evidence of an association with paternal age.
Mental retardation- No association with paternal age.
Other studies have found an association between advanced paternal age and an increased risk for achondroplasia, Noonas Syndrome, Aperts Syndrome, depression/anxiety disorders, ADHD, neurodevelopmental disorders, bipolar disorder (in contrast to the above quoted study), and decreased performance on cognitive assessments. [Zweifel JE. FertSteril 2022][Wood KA. FertSteril 2021]
SCREENING THE FETUS FOR ABNORMALITIES
Although the vast majority of older men will have normal children, the above described data shows the accumulating evidence that the risk of certain abnormalities does increase with the age of the male partner. This increased risk for many of these medical problems seems to be amplified when the female partner is also older. At this point in time, there are no screening tests available to detect an elevated risk of many problems such as autism or schizophrenia. Known genetic disorders can potentially be screened for with IVF cycles (before embryo transfer) using preimplantation genetic diagnosis (PGD). Currently, there are no guidelines recommending the use of PGD for increased paternal age. [Jennings M. FertSteril 107].
Several methods are commonly utilized to screen for abnormalities in the developing fetus once a pregnancy has been established. These include ultrasound evaluations for structure defects as well as the quad screen blood test (which looks for an increased risk of Downs Syndrome, neural tube defects, and abdominal wall abnormalities). Chorionic villus sampling (at 10–12 weeks of gestation), amniocentesis (at 15–20 weeks of gestation), and percutaneous umbilical cord blood sampling (after 17 weeks of gestation) are examples of other more invasive tests that can be used to look for genetic abnormalities in the fetus. These tests can provide fairly accurate and potentially valuable data on the current and future health risks of that fetus. However, they also come with the difficulties associated with making decisions about whether or not to let a pregnancy progress if a significant genetic abnormality is discovered, as well as a small increase in the risk of pregnancy loss with the more invasive testing.
DEFINITION OF “ADVANCED PATERNAL AGE”
In women there is a fairly general consensus that fertility potential and increased risk to the health of offspring begins at about the age of 35 years, even though most women older than 35 are successful at establishing a pregnancy and subsequently have healthy children. [Ramasamy R. FertSteril 2015]. No such consensus currently exists in defining when advanced paternal age starts in men. From a fertility potential standpoint, although semen parameters appear to start to decline after age 40 years, most men retain good fertility potential well into their 50’s and beyond. The risks for health problems in offspring have clearly shown to increase with age, though the majority of children born to older men do not have developmental abnormalities and are healthy. The American College of Medical Genetics currently does not specify an age limit for men who want to try and conceive and does not recommend any additional precautions or extra testing in couples where the man is older. [Ramasamy R. FertSteril 2015].
Recommendations for Advanced Paternal Age
The vast majority of children born to older males are healthy, but increasing paternal age is associated with clear decreases in fertility potential as well as an increased risk of health problems in their offspring.
As more data accumulates, future guidelines may provide more recommendation guidelines on advanced paternal aging. At this point in time, 2 potential recommendations include starting the infertility evaluation process earlier for couples having difficulty conceiving when the male partner is older (e.g. semen analysis testing after 6 months of trying instead of the standard 12 months). Also, couples may want to talk with their Ob/Gyn provider about the option of a more aggressive approach for fetal health screening (e.g. ultrasounds, quad screen, chorionic villus sampling/amniocentesis).