INTRODUCTION — While the impact of increasing maternal age has received a great deal of attention, the impact of advanced paternal age on reproduction has been less well studied. However, as both males and females are now delaying childbearing until later than ever before, questions about the impact of advanced paternal age on reproduction are becoming more common.
This topic will review the available data regarding the impact of advanced paternal age on fertility, subsequent pregnancy, and the offspring. Topics related to male infertility and advanced maternal age are presented separately:
●(See "Causes of male infertility".)
●(See "Approach to the male with infertility".)
●(See "Treatments for male infertility".)
●(See "Effects of advanced maternal age on pregnancy".)
In this topic, when discussing study results, we will use the terms "woman/en," "man/en," or "patient(s)" as they are used in the studies presented. However, we recognize that not all genetic females identify as women nor all genetic males identify as men, and we encourage the reader to consider the specific counseling and treatment needs of transgender and gender diverse individuals.
DEFINITION — There is no evidence-based definition of advanced paternal age . While some studies use a specific age cut-off at the time of conception, others treat age as a continuous variable or group patients by age brackets . Any one cut-off may be misleading because, while male fertility decreases with increasing age, the process is gradual and many of the associated risks continue to rise with increasing age. Lastly, the process of aging and associated diseases impacts each person differently. Thus, the definition of advanced paternal age is somewhat arbitrary and based on studies of age-related changes in spermatogenesis and fertility. That said, in studies that use a discrete age threshold, age >40 is a common choice . (See 'Impact of age on fertility' below.)
EPIDEMIOLOGY AND LIFE EXPECTANCY — Similar to trends seen for females, males are fathering children at older ages. In one study from the United Kingdom, the percentage of live births attributed to men aged 35 to 54 years old increased 15 percent (from 25 to 40 percent) in a 10-year period . In the United States, the birth rate for fathers less than 30 years of age declined 27 percent from 1980 to 2014 (123.1 to 89.7 births per 1000 men) . A different study that reviewed over 160 million births reported that the mean paternal age in the United States rose from 27.4 to 30.9 during the time period 1972 to 2015 .
Some potential older fathers ask about their risk of dying while a child is still young. When counseling males who are considering fatherhood at older ages, it can be helpful to refer to life-expectancy or actuarial tables to help them understand the impact of their current habits and health conditions on their risk of death. As an example, a male who smokes has a risk of death similar to a nonsmoking male who is 5 to 10 years older . Such data also vary by race, ethnicity, and geography. One such table is published by the United States Social Security Administration. Such counseling provides an opportunity to make positive health interventions, such as smoking cessation.
IMPACT OF AGE ON FERTILITY — Multiple factors impact male fertility, of which age is one. In addition to the baseline biologic changes associated with increasing age, rising age also allows for greater duration of exposure to disease, stress (physiologic and psychologic), negative lifestyle choices (eg, smoking), and genetic changes (figure 1).
Decreased fertility — Studies have consistently reported that increasing male age is associated with an increased time to pregnancy and decreased pregnancy rates [7-10]. However, only a few studies have examined these outcomes adjusted for female age.
●A large population-based study conducted in the United Kingdom used self-reported surveys from 8559 pregnancies to determine the effect of age on time to pregnancy . After adjusting for female age, conception during a 12-month period was more than 30 percent less likely for males over 40 years of age as compared with males younger than 30 years of age.
●A self-report survey study of 1976 British women that controlled for multiple potential confounders (eg, female age, coital frequency) found a fivefold increase in time to pregnancy in men 45 years of age and older compared with men less than 25 years of age . Men 45 years of age and older were also 4.6 and 12.5 times more likely to have a time to pregnancy greater than one and two years, respectively. These increases in time to pregnancy were similar even when restricting the analysis to men who were conceiving with women less than 25 years of age.
●A French study examined 901 cycles of intrauterine insemination and found that the age of the husband was the most significant factor contributing to a decreased probability of a pregnancy . After six cycles, the pregnancy rate of partners of men 35 years of age and older was half that of men less than 35 years of age (25 versus 51.7 percent).
Few studies have assessed the impact of paternal age outcome of assisted reproduction. Reviews of these mostly retrospective studies did not observe an unfavorable effect, but there was considerable clinical and methodological heterogeneity [13,14].
The effect of the male's age is best evaluated by studying pregnancy outcome in couples using oocyte donation, thus allowing male age to be the dependent variable (most oocyte donor programs seek 18 to 34 year old females, often with proven fertility). These studies are often confounded by the use of intracytoplasmic sperm injection (ICSI) and have reported discordant results; some [15-17] but not all [18-22] show a trend towards a negative impact of advanced male age on fertilization and implantation rates, suggesting that if an effect exists, it is weak. There is more consistent evidence regarding increased miscarriage rates in partners of older males. (See 'Miscarriage' below.)
Semen quality — We request a semen analysis for nearly all males undergoing a fertility evaluation. The rationale includes that 25 percent of infertility is associated with male factor and even males with a history of paternity can have severe semen abnormalities . While these factors are true for males of all ages, males of advanced paternal age are more likely to have abnormal semen parameters and thus more likely to benefit from a semen evaluation . Exceptions include couples who are being evaluated for recurrent pregnancy loss (for which male factor relates only to possible translocations and not abnormalities in semen parameters) and couples for whom there is obvious ovulatory dysfunction which responds to oral treatments for controlled ovarian hyperstimulation.
It is important to note that there are no standardized guidelines for semen analysis based solely on male age and, while a normal semen analysis is generally considered a proxy for male fertility, standard sperm parameters do not correlate perfectly with oocyte fertilization and pregnancy. While earlier studies reported conflicting data on the impact of increasing age on semen analysis parameters, the studies were limited because they mainly included males who were being evaluated at infertility clinics [25-27]. In a meta-analysis of 90 studies including nearly 94,000 men that took the indication for evaluation into account (infertility versus volunteer donor), increasing male age negatively impacted semen volume, sperm concentration, total sperm count, sperm motility, progressive motility, normal morphology, and percentage of unfragmented cells (ie, increased in DNA fragmentation was reported) . While sperm concentration was not altered by increasing age, this finding was likely a result of decline in semen volume that left the concentration unchanged. The greatest declines were reported in the parameters of progressive motility and unfragmented DNA. The American Urological Association states an infertility work-up, including semen analysis, should be initiated for couples who have not conceived after 12 months of unprotected intercourse or in patients with additional infertility risk factors (eg, history of mumps infection) . A detailed discussion of semen analysis parameters is presented separately. (See "Approach to the male with infertility", section on 'Semen analysis'.)
Sexual function and coital frequency — In addition to female age, sexual functioning and coital frequency are variables that affect time to conception and pregnancy rates . Decreased coital frequency with age is due, in part, to diminished sexual functioning (age-related erectile dysfunction ); however, sexual dysfunction itself does not affect germ cells and its impact on infertility can be overcome by assisted reproductive technology . Failure to control for coital frequency may introduce a significant confounder when assessing time to pregnancy and pregnancy rates in partners of older males.
The impact of age on sexual function and coital frequency was illustrated in a study of 1290 men enrolled in the Massachusetts Male Aging Study (MMAS) . The probability of having complete erectile dysfunction increased threefold (from 5 to 15 percent) between ages 40 and 70 and the probability of moderate erectile dysfunction increased twofold (from 17 to 34 percent). Secondary data analysis of this same cohort observed that men engaged in sexual activity an average of 6.5 times per month prior to age 40; this frequency decreased by less than once per month after age 40, by one to two times per month after age 50, and by another one to two times per month after age 60 .
Genetic alterations and fetal disease — Older males can generally be reassured that any excess risk of disease in their offspring related to paternal age is very small, but not zero.
Potential mechanisms — Increasing paternal age is associated with changes in sperm DNA integrity, point mutations, telomere length, de novo mutation rate, chromosomal structure, apoptosis, and epigenetic factors [24,34-40]. In contrast to oogenesis, which is limited to 23 cell divisions from zygote to mature egg, spermatogenesis continues throughout a male's lifetime. One study estimated that the sperm of a 70-year-old male have undergone approximately 1300 mitotic divisions (assuming puberty at age 15) .
Since the adult male's germ cells have passed through more mitotic replications than the adult female's germ cells, there is a greater opportunity for error. Additional possible causes of genetic error include reduced activity of antioxidant enzymes in the seminal plasma and spermatozoa, thus making the spermatozoa more vulnerable to mutational changes, and spermatids and immature and mature spermatozoa of older males do not have a DNA repair system . Chromosomal aberrations, but not aneuploidy, also appear to be more common in males over age 45 to 59 years [42,43]. A list of genetic conditions that may be related to advancing paternal age is presented in the table (table 1). (See "Male reproductive physiology".)
Additionally, with increasing age there is an increased exposure to environmental and other toxins, like cadmium and lead, as well as both ionizing and nonionizing radiation. Multiple studies have reported the direct and indirect impacts of these exposures on decreasing testicular health and function .
Autosomal dominant — Advanced paternal age is associated with an increase in new autosomal dominant mutations (eg, achondroplasia; Apert, Waardenburg, Crouzon, Pfeiffer, and Marfan syndromes) that may result in congenital anomalies in progeny [45,46]. Although the collective increase in risk of progeny with autosomal dominant disease rises exponentially with advancing paternal age, the actual risk of any specific disease is small because of the rarity of autosomal dominant inherited disorders. One author calculated the overall frequency of offspring with autosomal dominant disease from fathers of various ages . The estimated frequency of any autosomal dominant disease due to a new mutation in offspring of fathers 40 years of age or older was 0.3 to 0.5 percent. This risk is similar in magnitude to the risk of Down syndrome in offspring of mothers age 35 to 40 years (table 2), but was based upon several assumptions for which there are scant data.
There is no method available to screen for sporadic new autosomal dominant disease. Fetal karyotype analysis assesses the number and overall structure of chromosomes and would not be expected to detect single gene defects. Prenatal ultrasonography may detect some abnormalities suggestive of such disease, but there are no data regarding the efficacy of this approach. Likewise, while microarray analysis of fetal DNA will afford a more detailed analysis for microdeletions and duplications, such disorders per se have not been noted to be increased in the offspring conceived by fathers of advanced paternal age. (See 'Preconception counseling' below.)
X-linked — Spontaneous germline mutations in X-linked genes may also be more common with advancing paternal age . These mutations would be transmitted from carrier daughters to affected grandsons and have thus been called the "grandfather effect." Examples of such diseases include hemophilia A and Duchenne muscular dystrophy. (See "Genetics of hemophilia A and B" and "Duchenne and Becker muscular dystrophy: Clinical features and diagnosis" and "Overview of the hereditary ataxias", section on 'X-linked ataxias'.)
Aneuploidy — The bulk of evidence suggests that the risk of fetal autosomal aneuploidy does increase with increasing paternal age, but the degree of increase is not nearly as great as that seen with increasing maternal age [48-55]. In a DNA study of 200 families, each with a single child with trisomy 21, approximately 5 percent of trisomies were paternal in origin . In a subsequent study of embryos conceived with donor oocytes, and thus partly controlling for maternal age and fertility, embryos of men ages ≥50 years had more sperm with damaged DNA, higher rates of failed blastocyst development, and higher aneuploidy rates compared with men ages ≤39 years or men ages 40 to 49 years .
Direct studies of paternal gametes have also suggested an increase in sex chromosome aneuploidy with advancing paternal age, which could lead to sex chromosome aneuploidies in the offspring . However, the data are conflicting. While one case-control study observed a higher risk of 47 XXY (Klinefelter syndrome) and 47 XYY with advancing paternal age, a different review of males with Klinefelter syndrome reported no association with advancing paternal age [54,57]. Although a small increase in risk of aneuploidy cannot be definitively excluded, there is insufficient evidence to determine a specific cut-off level for screening for fetal aneuploidy in the progeny of older males.
Congenital anomalies and diseases — Several studies reported an increase in some congenital anomalies (eg, neural tube defects, cardiac defects, limb defects) and diseases (eg, Wilms tumor) associated with advanced paternal age and suggested de novo mutations might be the cause [58-63]. As an example, a population-based retrospective cohort study including over five million births observed 1.5 percent had a congenital anomaly . When stratified by paternal age, the adjusted odds ratios for any congenital anomaly among infants born to fathers ages 30 to 35, 40 to 44, 45 to 49, and over 50 years compared with fathers ages 25 to 29 years were 1.04, 1.08, 1.08, and 1.15, respectively. These data suggest infants born to older fathers have slightly increased risk of congenital anomalies; however, the association is weak; thus, paternal age likely plays no more than a small role in the etiology of congenital anomalies. (See "Birth defects: Causes" and "Birth defects: Epidemiology, types, and patterns".)
IMPACT ON PREGNANCY — Although studies suggest that advancing paternal age may impact pregnancy outcomes, the impacts appear to be small and thus should not impact most couples' decisions to proceed with pregnancy or fertility therapy.
Preconception counseling — The risks associated with advanced paternal age warrant the same level of preconception counseling and discussion as is offered for advanced maternal age. Patients with pregnancies affected by advanced paternal age should be offered routine screening for aneuploidy. For couples using assisted reproductive technology (in vitro fertilization and intracytoplasmic sperm injection) to conceive, we discuss, and offer, preimplantation genetic screening (PGS) to all . That said, we do not use advancing male age as a specific indication for PGS because the overwhelming majority of aneuploidies are maternally derived . Additionally, although there is a correlation between male age and de novo single gene defects, preimplantation genetic diagnosis (PGD) is only useful for known gene targets and is therefore not performed for risk reduction in males of advanced paternal age . Additionally, we inform patients that traditional G-band karyotype or microarray testing cannot identify autosomal dominant or recessive disorders and there is no genetic test for identifying autism spectrum disorders (ASDs) antenatally.
Detailed discussions regarding options for routine aneuploidy screening in pregnancy and preimplantation testing are presented elsewhere:
●(See "First-trimester combined test and integrated tests for screening for Down syndrome and trisomy 18".)
●(See "Prenatal screening for common aneuploidies using cell-free DNA".)
●(See "Preimplantation genetic testing".)
Miscarriage — While older females experience an increase in both trisomic and euploid losses largely due to a decline in oocyte quality, the association between advancing paternal age and miscarriage risk is less clear. Advanced paternal age appears to be associated with a modest increase in the risk of miscarriage, but this risk is much lower than that observed with advanced maternal age and seems to occur at an older age than in females (over age 40 in males versus over age 30 in females), but there is no age threshold after which males cannot father offspring . These conclusions, however, are based upon small studies of various designs and therefore should be interpreted cautiously.
As examples, studies attempting to assess the impact of advanced paternal age on miscarriage risk have reported no association between paternal age and miscarriage risk [66,67], increased risk of miscarriage only for females <25 years whose partner was 35 years or older , and increased risk of miscarriage with advanced paternal age [69-71]. However, these studies were confounded in some degree by maternal age. In attempt to distinguish the respective maternal and paternal components of miscarriage risk, studies have been performed in oocyte donor pregnancies, which control for the age of the oocyte, oocyte quality, and endometrial receptivity. However, results of oocyte donation studies are also conflicted. Two oocyte donor studies reported no association between male age and live birth rate [18,72] while another observed an association between advancing paternal age and miscarriage . A third study (the largest, retrospective design) reported no significant association between male age and fertilization rate, embryo development through the cleavage stage, implantation rate, or pregnancy rate . However, male age over 50 years was associated with fewer live births, suggesting that advanced male age affected late, but not early, embryonic development.
Fetal growth restriction, preterm birth, and stillbirth — As with miscarriage risk, it is difficult to distinguish between the maternal and paternal effects on obstetric outcomes, and the available data conflict. There is no agreed-upon effect of advanced paternal age on the risk of fetal growth restriction [74,75], preterm birth , stillbirth [70,77-81], or adverse birth outcome , although larger studies suggest a negative impact for preterm birth. For example, in a cohort study of over 40 million live births in the United States from 2007 and 2016 that controlled for maternal age, infants born to fathers aged 45 years or older had 14 percent higher odds of premature birth that was independent of gestational age . In a retrospective cohort study, including over 750,000 births in Missouri from 1989 to 2005, that assessed risk by age groups, paternal age >45 years was associated with increased risk for low birth weight, preterm birth, and very preterm birth . A national cohort study of over 944,000 births from Denmark also analyzed risk by age cohort and reported that the relative risk of stillbirth was highest for fathers older than 40 years, with an approximately 50 percent increase in risk . By contrast, a retrospective review of over 830,000 births in Ohio (United States) reported no increased risk for preterm birth or growth restriction after controlling for maternal age and other confounding factors . In counseling patients about the risk of paternal age on birth outcomes, we review that the absolute risk of stillbirth in an in vitro fertilization pregnancy is approximately 0.6 percent . Therefore, while advancing paternal age may impact birth outcomes such as stillbirth, the overall risk is thought to be small.
IMPACT ON OFFSPRING — While studies suggest that advancing paternal age is associated with various concerning developmental outcomes in the offspring, the overall magnitude of risk appears to range from small to negligible.
Cognitive ability — There is limited information on the relationship between advanced paternal age neurocognitive ability in offspring, and the available data conflict, which makes counseling patients challenging. In a study of over 33,000 children from the United States Collaborative Perinatal Project, advanced paternal age was associated with modest negative effects on neurocognitive function, as assessed by Bayley scales (except the Bayley Motor score), Stanford Binet Intelligence Scale, Graham-Ernhart Block Sort Test, Wechsler Intelligence Scale for Children, and Wide Range Achievement Test . In the same study, advanced maternal age was generally associated with better scores on these tests. Of note, these tests were administered to children at ages eight months, four years, and seven years. In contrast, a population-based study of over 565,000 Swedish brothers whose IQ was measured during conscription examinations (ages 17 to 20), advanced paternal age did not impact offspring IQ, but advanced maternal age was associated with a slight worsening of IQ . For specific learning differences, one report linked advanced paternal age and dyslexia in male offspring . Further studies using consistent methodologies and neurocognitive tests are needed to address this issue.
Schizophrenia — Multiple studies have reported an increased risk of schizophrenia in children conceived by fathers of advanced paternal age [46,91-94]. Older paternal age has also been associated with younger age of symptom onset in affected children [95,96]. The risk appears to be transcultural . The causal mechanism is hypothesized to involve mutational errors during spermatogenesis . However, the overall incidence of schizophrenia is low, at approximately 1.5 per 10,000 people . Thus, even in families with a family history of psychiatric disorder, the overall increased risk from advanced paternal age is negligible.
In one study, the relative risk of schizophrenia in children of older fathers compared with those younger than age 25 increased in each five-year age group, reaching 2.02 (95% CI 1.17-3.51) and 2.96 (95% CI 1.60-5.47) in offspring of males ages 45 to 49 and ≥50 years, respectively . The actual incidence of schizophrenia in offspring at age 21 according to the fathers' age at their birth was: age <25 years (2.5 per 1000), 25 to 29 (3.5 per 1000), 30 to 34 (3.7 per 1000), 35 to 39 (4.4 per 1000), 40 to 44 (4.6 per 1000), 45 to 49 (5 per 1000), and ≥50 years (11.4 per 1000). For comparison, the baseline incidence of schizophrenia ranges from 10.2 to 22 per 100,000 people per year . In another series, the overall hazard ratio for each 10-year increase in paternal age was 1.47 (95% CI 1.23-1.76) .
Autism spectrum disorder — A small but statistically significant association between advancing paternal age and risk of autism spectrum disorder (ASD) has also been observed [101-106]. As an example, a dose-response meta-analysis of 27 observational studies reported that a 10-year increase in paternal age resulted in a 21 percent increased risk of autism in the child . A study of over 14,000 Dutch patients reported that, compared with fathers under age 20, males over age 40 who father children were 3.3 times as likely to have a child affected with ASD . Another study in Israel, which drew data from over 130,000 couples, reported that, compared with fathers under age 30, males over the age of 40 were 5.75 times as likely to have an offspring with ASD . This may be related to de novo spontaneous mutations and/or alterations in genetic imprinting.
Although not proven as an independent risk factor for autism, paternal age warrants examination in large, prospective population-based birth cohorts that carefully examine potential confounders. Until prospective data are available, we counsel patients that the incidence of autism is 1 to 2 per 1000, and the absolute increased risk related to advanced paternal age should not discourage a couple from proceeding with procreative efforts or fertility treatments .
Attention-deficit/hyperactivity disorder — Although there has been increasing attention paid to possible links between parental age and attention-deficit/hyperactivity disorder (ADHD) or autism spectrum disorder (ASD), evidence from a study of 10,000 Finnish children suggests that there is a decreased incidence with increasing maternal age but that paternal age plays no significant role [110,111].
Psychological development — There are limited data on the impacts of paternal age on psychological development in offspring. While there is evidence that advanced paternal age is associated with higher rates of bipolar disorder, this effect was only noted in new fathers over age 55 as compared with new fathers in their 20s . Interestingly, an examination of the Wisconsin Longitudinal Study suggested that increased paternal age was associated with a lower chance of ever being married and a higher probability of childlessness in offspring . The clinical significance of these findings is not known.
Cancer — As with the other offspring outcomes reviewed above, the increased risk of cancer in the offspring of males of advanced paternal age is negligible, increasing from a rate of 1 in 25,000 for the population at large to 1 in 21,930 for children fathered by males greater than 40 years . This equates to an impact of one additional case for every 220,000 people, which is of little clinical concern. Similarly, a population-based study that evaluated 4.3 million children (up to 14 years of age) and their parents observed paternal age was associated with a statistically significant increased risk of leukemia and central nervous system cancers, both of which had previously been reported, but the absolute risk was small [114-116].
Risk of death — It appears that children born to males ages ≥40 years have an increased risk of death before the age of 5, mainly due to the increased risk of congenital anomalies. In a Danish national cohort study of over 1.5 million live births, children born to males age 45 and greater had a more than 50 percent increased risk of death by age 5 compared with children born to males age 30 to 34 years . Of note, the study controlled for maternal age, parity, maternal and paternal education levels, and year of birth.
ROLE OF SPERM BANKING — Given the relatively low risks associated with increased male age, we do not recommend that otherwise healthy males bank sperm for future use in order to reduce the risk of potential complications in their offspring. The use of frozen and thawed sperm is not itself without potential risk, and the use of this sperm requires some level of assisted reproductive technology and generates increased cost . Additionally, frozen sperm samples are likely less efficient at achieving pregnancy as compared with freshly ejaculated samples. Given the overall risk-benefit profile, we do not recommend that males freeze sperm samples, even as they approach their 40s or 50s.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: General prenatal care".)
SUMMARY AND RECOMMENDATIONS
●There is no evidence-based definition of advanced paternal age. While some studies use a specific age cut-off at the time of conception, others treat age as a continuous variable or group patients by age brackets. That said, in studies that use a discrete age threshold, age >40 is a common choice. (See 'Definition' above.)
●Births attributed to males age 35 and older are increasing. When counseling males who are considering fatherhood at older ages, it can be helpful to refer to life-expectancy or actuarial tables to help them understand the impact of their current habits and health conditions on their risk of death (eg, United States Social Security Administration). Such counseling provides an opportunity to make positive health interventions, such as smoking cessation. (See 'Epidemiology and life expectancy' above.)
●Multiple factors impact male fertility, of which age is one part. In addition to the baseline biologic changes associated with increasing age, rising age also allows for greater duration of exposure to disease, stress (physiologic and psychologic), negative lifestyle choices (eg, smoking), and genetic changes (figure 1). (See 'Impact of age on fertility' above.)
•Studies have consistently reported that increasing male age is associated with an increased time to pregnancy and decreased pregnancy rates. The effect of the male's age is best evaluated by studying pregnancy outcome in couples using oocyte donation, thus allowing male age to be the dependent variable. However, these studies are often confounded by the use of intracytoplasmic sperm injection (ICSI) and have reported discordant results. (See 'Decreased fertility' above.)
•Increasing paternal age is associated with changes in sperm DNA integrity, point mutations, telomere length, de novo mutation rate, chromosomal structure, apoptosis, and epigenetic factors, with a resultant increase in autosomal dominant mutations. (See 'Potential mechanisms' above.)
•Although the collective increase in risk of progeny with autosomal dominant disease rises exponentially with advancing paternal age, the actual risk of any specific disease is small because of the rarity of autosomal dominant inherited disorders. The best estimate of risk of autosomal dominant disease in progeny is ≤0.5 percent. (See 'Autosomal dominant' above.)
•The bulk of evidence suggests that the risk of fetal autosomal aneuploidy does increase with increasing paternal age, but the degree of increase is not nearly as great as that seen with increasing maternal age. (See 'Aneuploidy' above.)
Advanced paternal age is associated with an increase in new autosomal dominant mutations. The best estimate of risk of autosomal dominant disease in progeny is ≤0.5 percent. (See 'Autosomal dominant' above.)
●Although studies suggest that advancing paternal age may impact pregnancy outcomes, the impacts appear to be small and thus should not impact most couples' decisions to proceed with pregnancy or fertility therapy. (See 'Impact on pregnancy' above.)
•The risks associated with advanced paternal age warrant the same level of preconception counseling and discussion as is offered for advanced maternal age. Patients with pregnancies affected by advanced paternal age should be offered routine screening for aneuploidy. For couples using assisted reproductive technology (in vitro fertilization and ICSI) to conceive, we discuss, and offer, preimplantation genetic testing to all. (See 'Preconception counseling' above.)
•Advanced paternal age appears to be associated with a small increase in the risk of miscarriage and other poor birth outcomes, but this risk is much lower than that observed with advanced maternal age. (See 'Miscarriage' above and 'Fetal growth restriction, preterm birth, and stillbirth' above.)
●While studies suggest that advancing paternal age is associated with various concerning developmental outcomes in the offspring, the overall magnitude of risk appears to range from small to negligible. (See 'Impact on offspring' above.)
●Given the overall profile and risks and benefits, we do not recommend that males freeze sperm samples, even as they approach their 40s or 50s. (See 'Impact on offspring' above and 'Role of sperm banking' above.)
6 : The risk of death by age, sex, and smoking status in the United States: putting health risks in context.
7 : Effect of male age on fertility: evidence for the decline in male fertility with increasing age.
8 : The effect of advancing paternal age on pregnancy and live birth rates in couples undergoing in vitro fertilization or gamete intrafallopian transfer.
10 : Fathers over 40 and increased failure to conceive: the lessons of in vitro fertilization in France.
11 : Increasing paternal age is associated with delayed conception in a large population of fertile couples: evidence for declining fecundity in older men. The ALSPAC Study Team (Avon Longitudinal Study of Pregnancy and Childhood).
12 : Cumulative conception rate following intrauterine artificial insemination with husband's spermatozoa: influence of husband's age.
15 : Male age negatively impacts embryo development and reproductive outcome in donor oocyte assisted reproductive technology cycles.
17 : Paternal Age Is Not Associated With Pregnancy Outcomes After Single Thawed Euploid Blastocyst Transfer.
21 : Paternal age and assisted reproductive outcomes in ICSI donor oocytes: is there an effect of older fathers?
24 : Consistent age-dependent declines in human semen quality: a systematic review and meta-analysis.
27 : Association between socio-psycho-behavioral factors and male semen quality: systematic review and meta-analyses.
28 : Association between socio-psycho-behavioral factors and male semen quality: systematic review and meta-analyses.
32 : Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study.
33 : Changes in sexual function in middle-aged and older men: longitudinal data from the Massachusetts Male Aging Study.
35 : The paternal-age effect in Apert syndrome is due, in part, to the increased frequency of mutations in sperm.
36 : Age-related decline in sperm deoxyribonucleic acid integrity in patients evaluated for male infertility.
37 : Meta-analysis of telomere length in 19,713 subjects reveals high heritability, stronger maternal inheritance and a paternal age effect.
44 : Environmental Factors-Induced Oxidative Stress: Hormonal and Molecular Pathway Disruptions in Hypogonadism and Erectile Dysfunction.
46 : Effects of increased paternal age on sperm quality, reproductive outcome and associated epigenetic risks to offspring.
52 : A search for a paternal-age effect upon cases of 47, +21 in which the extra chromosome is of paternal origin.
53 : Effects of male age on the frequencies of germinal and heritable chromosomal abnormalities in humans and rodents.
55 : High Aneuploidy Rates Observed in Embryos Derived from Donated Oocytes are Related to Male Aging and High Percentages of Sperm DNA Fragmentation.
56 : Parental origin of the extra chromosome in trisomy 21 as indicated by analysis of DNA polymorphisms. Down Syndrome Collaborative Group.
67 : Paternal age and maternal age are risk factors for miscarriage; results of a multicentre European study.
68 : Does male age affect the risk of spontaneous abortion? An approach using semiparametric regression.
71 : Effect of maternal and paternal age on pregnancy and miscarriage rates after intrauterine insemination.
74 : Intrauterine growth retardation as an endpoint in mutation epidemiology: an evaluation based on paternal age.
75 : The influence of male age on treatment outcomes and neonatal birthweight following assisted reproduction technology involving intracytoplasmic sperm injection (ICSI) cycles.
76 : Paternal factors and low birthweight, preterm, and small for gestational age births: a systematic review.
83 : Association of paternal age with perinatal outcomes between 2007 and 2016 in the United States: population based cohort study.
85 : Advanced paternal age and stillbirth rate: a nationwide register-based cohort study of 944,031 pregnancies in Denmark.
88 : Advanced paternal age is associated with impaired neurocognitive outcomes during infancy and childhood.
89 : Is later better or worse? Association of advanced parental age with offspring cognitive ability among half a million young Swedish men.
93 : Modifiable risk factors for schizophrenia and autism--shared risk factors impacting on brain development.
95 : Association of older paternal age with earlier onset among co-affected schizophrenia sib-pairs.
96 : Advanced paternal age is associated with earlier schizophrenia onset in offspring. Results from the national multicentric FACE-SZ cohort.
97 : Advanced paternal age associated with an elevated risk for schizophrenia in offspring in a Japanese population.
98 : Aberrant epigenetic regulation could explain the relationship of paternal age to schizophrenia.
105 : Effects of familial risk factors and place of birth on the risk of autism: a nationwide register-based study.
110 : Parental age and the risk of attention-deficit/hyperactivity disorder: a nationwide, population-based cohort study.
115 : Association of early life factors and acute lymphoblastic leukaemia in childhood: historical cohort study.
116 : Parental age and risk of sporadic and familial cancer in offspring: implications for germ cell mutagenesis.
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