Reproductive risks of advanced paternal age

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Table 1

With the growing trend of couples choosing to start their families at a later age, ob/gyns must be prepared to counsel patients regarding the effects of advanced paternal age (APA) on reproductive outcomes and on their future offspring. Compared to data from 1993, the proportion of live births to fathers aged 35 to 54 increased by 15% over 10 years, with the trend continuing to climb.¹ In the United States, among fathers aged 35 to 39, 40 to 44, and 45 to 49 years, birth rates increased 61%, 63%, and 52%, respectively.² Socioeconomic factors, increased life expectancy, and growing accessibility of assisted reproductive techniques (ART) all have contributed to the rise in paternal age.³ Although a woman’s natural fertility terminates with menopause, spermatogenesis continues throughout life.⁴

Although APA is commonly defined as age 40 years or older, no universally accepted criteria for it exist. The American College of Medical Genetics (ACMG) has not established an age cutoff for APA and does not currently recommend additional screening or diagnostic intervention for offspring of older men.⁵ Specifying a clear paternal age for APA is complicated by the heterogeneity of the reproductive outcomes and offspring risks noted in the literature. As noted by Ramasamy et al., many studies do not define an age threshold for APA and those that establish a threshold span a wide range of ages.⁶

While fathering children at an older age remains a viable option, couples should be counseled on the effects of APA that could impair conception, such as altered sperm parameters and reproductive hormones, and data supporting increased risk of adverse outcomes such as congenital birth defects, neurocognitive disorders, and fetal deaths. This review summarizes recent findings surrounding the reproductive risks of APA.

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Reproductive outcomes

Possible impairment of reproductive outcomes is an important implication of APA. With an age-related decrease in testosterone, older men experience decreases in libido, sexual function, and sexual frequency, reducing opportunities for conception.^7–10 Further, a review of the literature from 1980 to 1999 found a decrease in semen volume (3%-22%), sperm motility (3%-37%), and percent normal sperm (4%-18%) in 50-year-old men compared with 30-year-old men.¹¹ In addition, controlling for female age, actual rates of pregnancy fathered by men over age 50 years were 23% to 38% lower than those in men younger than age 30.¹¹ Similarly, a meta-analysis of 90 studies quantifying the effect of male age on ejaculate traits (n=93,839) found statistically significant age-associated declines in semen volume, percent motility, progressive motility, morphology, and unfragmented cells, while sperm concentration had no associated changes with increasing male age.¹² A retrospective study performed by Hossain et al. also identified significant decreasing trends in semen volume and sperm motility with increased paternal age.¹³ Similarly, a large prospective study identified decreases in sperm motility with increased paternal age.¹⁴ Further, lifestyle factors accrued over the life of the male-such as obesity, smoking, and marijuana use-also may contribute to impaired reproductive outcomes, though this remains an active area of research.^15–17 These changes in semen parameters can be associated with fertility impairment in older men, but the association remains unproven.

Paternal age and ART outcomes

The changes in semen parameters seen in older men may impact outcomes of ART. In couples who underwent ART, McPherson et al. found that women aged 35 with a partner older than age 40 had an approximately 10% decrease in live birth rate compared with women of similar age who had younger partners (n=4,057).¹⁸ In a retrospective study of 859 cycles of in vitro fertilization (IVF) and 1632 of intracytoplasmic sperm injection (ICSI), Chapuis et al. identified a significantly decreased rate of clinical pregnancies in men older than age 51 (28.2%) compared with men aged 20 to 29 (41.5%).¹⁹ However, this result may be confounded by the older maternal age in this study (36.5±4.9 years). 

After adjusting for female age, a retrospective study of 4,025 embryos from 1,169 IVF cycles found a significant decrease in euploidy rate in males older than age 40 compared to men aged 35 to 40 and younger than age 35.²⁰ However, a recent multicenter study of 1,202 IVF/ICSI cycles (6,934 embryos) found no association between advancing paternal age and embryo aneuploidy.²¹ Furthermore, a large retrospective study of 2,204 intrauterine insemination cycles, 1,286 standard IVF/ICSI cycles, and 1,412 ovum donation IVF/ICSI cycles identified no association between male age and implantation, pregnancy, and miscarriage rates among maternal age groups.²² APA does not appear to conclusively impact ART outcomes, and certainly not to the extent contributed by advanced maternal age, but it remains an area of active research.

Paternal age and fetal health

APA may also increase the risk to the fetus during pregnancy-particularly increased risk of spontaneous abortion and very preterm birth. Adjusting for maternal age, Kleinhaus et al. (2006) identified a 60% increase in odds of spontaneous abortion in fathers aged 40 or older when compared with fathers aged 25 to 29.²³ Compared with that in men aged 20 to 24, a risk of very preterm birth (< 32 weeks) was increased by 70% in men aged 40 to 44 whose partners were aged 20 to 29.²⁴ Similarly, another study demonstrated increased odds of very preterm births among fathers aged 45 to 49 compared with fathers aged 25 to 29, for both mothers aged 20 to 24 (91%) and mothers aged 25 to 29 (72%).²⁵

Altered reproductive outcomes in older men may be related to increased DNA fragmentation in sperm, with as much as 80% of DNA fragmentation attributed to oxidative stress.³ Singh et al identified a 15% increase in highly damaged DNA and 20% increase in DNA break number in sperm from men aged 36 to 57 compared with men aged 20 to 35 (n=66).²⁶ A similar study found a significantly higher DNA fragmentation index (DFI) in men aged ≥ 45 compared with men aged < 45 years (P < 0.01 for all comparisons , n=1,125); in particular, men aged ≥ 45 had a more than two-fold increase in DFI compared with men aged < 30 (32.0±17.1% vs. 15.2±8.4%).²⁷ In addition, a recent meta-analysis of 26 studies identified a strong negative effect of male age on the percentage of sperm cells with unfragmented DNA (r = -0.209, 95% CI -0.287, -0.128).¹² Interestingly, the effect size of male age on DNA fragmentation was the largest of the study. However, while sperm from older men have a loss of DNA integrity, likely secondary to oxidative stress, conclusions about the impact on reproductive outcomes remain unclear.

Medical comorbidities

Because spermatogenesis is a continuous and ongoing process throughout the reproductive lifetime, spermatozoa are prone to acquiring DNA mutations, particularly due to the oxidative stress in aging men.²⁸ This increased rate of mutation places the sperm of older men at risk of acquiring mutations that impact the health of their offspring. After the discovery of a link between APA and achondroplasia, an increasing number of disorders have been identified to be associated with increasing paternal age.²⁹ Of note, incidence of chromosomal aneuploidies-an abnormal number of chromosomes-increases with the age of the father.³⁰ When controlling for random variation, a study on genome-wide de novo single-nucleotide polymorphism (SNP) mutation rates in offspring similarly demonstrated two mutations per year of paternal age.³¹ In women aged 35 and greater, Fisch et al identified a two-fold increase in the rate of neonates with Trisomy 21 when the father was aged ≥ 40 compared with ≤ 24 years.³² Similarly, when controlling for maternal age, men aged ≥ 50 had a two-fold greater odds of a child with Down syndrome compared with men aged 25 to 29.³³ In addition, one case-control study indicated that a 10-year increase in paternal age increased the odds of Down syndrome by 11%. Conversely, two studies identified no association between paternal age and Trisomy 13 or Trisomy 18.^34,35 To investigate risk of sex chromosome anomalies compared to autosomal anomalies (adjusting for Down syndrome and paternal age), one study found that a 10-year increase in paternal age increased the odds of Klinefelter syndrome by 35%.³⁴ Overall, APA appears to account for a small proportion of chromosomal aneuploidies.

Much of the literature similarly supports a correlation between paternal age and risk of neurocognitive disorders. 

Four hypotheses have been suggested to explain this increased risk with APA: 

• Increased frequency of de novo mutations; 

• Age-related epigenetic alterations in sperm; 

• Selection into late fatherhood secondary to paternal psychiatric disorders or subclinical predisposition; and 

• Environmental characteristics.³⁶

A recent review suggests that these etiologies-both inherited predisposition and de novo events-may all contribute to the complex neurocognitive disorders associated with APA.³⁷ A large study of individuals born in Denmark over a 51-year span (n=2,894,688) identified a 34% increase in risk of any psychiatric diagnosis in offspring of fathers aged 45 or older compared with offspring of fathers aged 25 to 29.³⁸ A similar study composed of individuals born in Sweden over a 28-year span (n=2,615,081) compared siblings and identified an increased risk of autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder, psychosis, bipolar disorder, suicide attempts, substance abuse, failing a grade, and low education attainment in offspring born to fathers aged 45 or older compared with fathers aged 20 to 24.³⁹ Of note, risks for ADHD (hazard ratio [HR] 13.13, 95% CI 6.85-25.16) and bipolar disorder (HR 24.70, 95% CI 12.12-50.31) were particularly increased. A meta-analysis of 12 studies similarly found increased risk of schizophrenia associated with fatherhood at aged 30 or older compared to age 25 to 29, with the highest effect size in men aged 50 or older (RR 1.66, 95% CI 1.46-1.89).⁴⁰

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The literature most strongly supports a link between APA and ASD. D’Onofrio et al. (2014) identified a nearly 3.5 times higher risk of ASD in offspring born to fathers aged 45 or older.³⁹ A recent meta-analysis of 27 studies similarly found a 55% increased risk of ASD in the highest paternal age category; an increase of 10 years in paternal age was associated with a 21% increase in risk of ASD.⁴¹ This association has been supported by several other studies spanning a wide range of populations and databases.^42–45 The neurocognitive implications of APA, particularly increased risk of ASD, must be considered when counseling patients regarding APA.

In addition to neurocognitive disorders and chromosomal aneuploidies, APA has been associated with an increased risk of congenital anomalies and cancer in the offspring.³ These findings are summarized in Table 1.^{32-35, 41-50}

Conclusions

With a growing trend of delaying fatherhood, couples must be informed of the increased risks of producing abnormal offspring associated with APA. The ACMG currently recommends a prenatal counseling session regarding potential risks of APA such as Trisomy 21 and individualized genetic counseling for specific concerns. The process of conception in older men may be complicated by decreased libido or altered sperm characteristics. APA may or may not impair the outcomes of ART; some evidence suggests impaired ability to conceive and decreased rates of live birth in conceptions by older men, but any decreases in fertility attributed to APA are minor in comparison to those of advanced maternal age. The fetus may be at increased risk of spontaneous abortion and very preterm birth. Increased oxidative stress may be linked to higher rates of DNA fragmentation in older men, but data on the impact on reproductive outcomes remain inconclusive. 

Lastly, in the offspring of older men, certain medical comorbidities have also been identified, including ASD and acute lymphoblastic leukemia. Although the effect of APA on reproductive outcomes and medical comorbidities in the offspring remains an active area of research, we recommend that physicians discuss these risks-particularly Trisomy 21, psychiatric diagnoses, and ASD-with couples with male partners aged 40 or older. Studies differ in their definition of APA when assessing risk for chromosomal aneuploidies versus neurocognitive outcomes. Establishing a consensus definition of APA will help guide management and counseling of patients.

Disclosures:

The authors report no potential conflicts of interest with regard to this article.

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