Paternal Age Amplifies Cryopreservation-Induced Stress in Human Spermatozoa.

The global fall in male fertility is a complicated process driven by a variety of factors, including environmental exposure, lifestyle, obesity, stress, and aging. The availability of assisted reproductive technology (ART) has allowed older couples to conceive, increasing the average paternal age at first childbirth. Advanced paternal age (APA), most often considered male age ≥40, has been described to impact several aspects of male reproductive physiology. In this prospective cohort study including 200 normozoospermic patients, 105 of whom were ≤35 years (non-APA), and 95 of whom were ≥42 years (APA), we assessed the impact of paternal age on different endpoints representative of sperm quality and cryopreservation tolerance. Non-APA patients had superior fresh semen quality; DNA fragmentation was notably increased in APA as compared to non-APA individuals (21.7% vs. 15.4%). Cryopreservation further increased the DNA fragmentation index in APA (26.7%) but not in non-APA patients. Additionally, APA was associated with increased mtDNAcn in both fresh and frozen/thawed sperm, which is indicative of poorer mitochondrial quality. Cryopreservation negatively impacted acrosome integrity in both age groups, as indicated by reduced incidences of unreacted acrosome in relation to fresh counterparts in non-APA (from 71.5% to 57.7%) and APA patients (from 75% to 63%). Finally, cryopreservation significantly reduced the phosphorylation status of proteins containing tyrosine residues in sperm from young males. Therefore, the present findings shed light on the effects of paternal age and cryopreservation on sperm quality and serve as valuable new parameters to improve our understanding of the mechanisms underlying sperm developmental competence that are under threat in current ART practice.

Reproductive Ageing: Current insights and a potential role of NAD in the reproductive health of aging fathers and their children.

In brief: In light of the increasing age of first-time fathers, this article summarizes the current scientific knowledge base on reproductive aging in the male, including sperm quality and health impacts for the offspring. The emerging role of NAD decline in reproductive aging is highlighted. Abstract: Over the past decades, the age of first-time fathers has been steadily increasing due to socio-economic pressures. While general mechanisms of aging are subject to intensive research, male reproductive aging has remained an understudied area, and the effects of increased age on the male reproductive system are still only poorly understood, despite new insights into the potential dire consequences of advanced paternal age for the health of their progeny. There is also growing evidence that reproductive aging is linked to overall health in men, but this review mainly focuses on pathophysiological consequences of old age in men, such as low sperm count and diminished sperm genetic integrity, with an emphasis on mechanisms underlying reproductive aging. The steady decline of NAD levels observed in aging men represents one of the emerging concepts in that regard. Because it offers some mechanistic rationale explaining the effects of old age on the male reproductive system, some of the NAD-dependent functions in male reproduction are briefly outlined in this review. The overview also provides many questions that remain open about the basic science of male reproductive aging.

Paternal age and first trimester placental size and growth: The Rotterdam Periconceptional Cohort.

INTRODUCTION: Despite a noticeable trend of delayed fatherhood, less is known about the impact of paternal age on the paternally programmed placenta. We hypothesize that paternal aging affects seminal quality and as such induces ageing-related epigenetic alterations that influence placental growth. Our main aim is to investigate associations between paternal age and first trimester (vascular) placental growth trajectories. METHODS: Pregnant women were enrolled before 10 weeks of gestation in the Rotterdam Periconceptional Cohort (Predict study). Placental volumes (PV) and utero-placental vascular volumes (uPVV) were measured at 7, 9, and 11 weeks gestation. Associations between paternal age and PV and uPVV were investigated using linear mixed models and the maximum likelihood ratio test to test non-linear relationships. We adjusted for gestational age, fetal sex, parental smoking and maternal age, BMI, education and parity, and stratified for conception mode. RESULTS: From 808 pregnancies we obtained 1313 PV and from 183 pregnancies 345 uPVV measurements. We show no associations between paternal age and PV (p = 0.934) and uPVV (p = 0.489) in our total population or in pregnancies conceived naturally (PV p = 0.166; uPVV p = 0.446) and after IVF/ICSI (PV p = 0.909; uPVV p = 0.749). For example, PV was 0.9% smaller (95% CI -5.7%-7.1%) in fathers aged 40 compared to 30 years old at 9 weeks gestation in the total study population. DISCUSSION: We are not demonstrating a significant impact of paternal age on first trimester placental growth in a tertiary care population. Given the trend of increasing paternal age, our study should be repeated in the general population.

Exploring FGFR3 Mutations in the Male Germline: Implications for Clonal Germline Expansions and Paternal Age-Related Dysplasias.

Delayed fatherhood results in a higher risk of inheriting a new germline mutation that might result in a congenital disorder in the offspring. In particular, some FGFR3 mutations increase in frequency with age, but there are still a large number of uncharacterized FGFR3 mutations that could be expanding in the male germline with potentially early- or late-onset effects in the offspring. Here, we used digital polymerase chain reaction to assess the frequency and spatial distribution of 10 different FGFR3 missense substitutions in the sexually mature male germline. Our functional assessment of the receptor signaling of the variants with biophysical methods showed that 9 of these variants resulted in a higher activation of the receptor´s downstream signaling, resulting in 2 different expansion behaviors. Variants that form larger subclonal expansions in a dissected postmortem testis also showed a positive correlation of the substitution frequency with the sperm donor's age, and a high and ligand-independent FGFR3 activation. In contrast, variants that measured high FGFR3 signaling and elevated substitution frequencies independent of the donor's age did not result in measurable subclonal expansions in the testis. This suggests that promiscuous signal activation might also result in an accumulation of mutations before the sexual maturation of the male gonad with clones staying relatively constant in size throughout time. Collectively, these results provide novel insights into our understanding of the mutagenesis of driver mutations and their resulting mosaicism in the male germline with important consequences for the transmission and recurrence of associated disorders.

Association of Paternal Age Alone and Combined with Maternal Age with Perinatal Outcomes: A Prospective Multicenter Cohort Study in China.

Maternal and paternal age at birth is increasing globally. Maternal age may affect perinatal outcomes, but the effect of paternal age and its joint effect with maternal age are not well established. This prospective, multicenter, cohort analysis used data from the University Hospital Advanced Age Pregnant Cohort Study in China from 2016 to 2021, to investigate the separate association of paternal age and joint association of paternal and maternal age with adverse perinatal outcomes. Of 16,114 singleton deliveries, mean paternal and maternal age (± SD) was 38.0 ± 5.3 years and 36.0 ± 4.1 years. In unadjusted analyses, older paternal age was associated with increased risks of gestational diabetes mellitus (GDM), hypertensive disorders of pregnancy, preeclampsia, placenta accreta spectrum disorders, placenta previa, cesarean delivery (CD), and postpartum hemorrhage, preterm birth (PTB), large-for-gestational-age, macrosomia, and congenital anomaly, except for small-for-gestational-age. In multivariable analyses, the associations turned to null for most outcomes, and attenuated but still significant for GDM, CD, PTB, and macrosomia. As compare to paternal age of < 30 years, the risks in older paternal age groups increased by 31-45% for GDM, 17-33% for CD, 32-36% for PTB, and 28-31% for macrosomia. The predicted probabilities of GDM, placenta previa, and CD increased rapidly with paternal age up to thresholds of 36.4-40.3 years, and then plateaued or decelerated. The risks of GDM, CD, and PTB were much greater for pregnancies with younger paternal and older maternal age, despite no statistical interaction between the associations related to paternal and maternal age. Our findings support the advocation that paternal age, besides maternal age, should be considered during preconception counseling.Trial Registration NCT03220750, Registered July 18, 2017-Retrospectively registered, https://classic.clinicaltrials.gov/ct2/show/NCT03220750 .

Familial factors rather than paternal age contribute to the aetiology of epilepsy.

BACKGROUND: Whether paternal age associated with offspring's epilepsy risk is a cause of de novo mutation as men age, or just an association due to confounding factors, is still unclear. METHODS: We performed a population-based, multi-generation and sibling comparison study in Taiwan, which included 2 751 232 singletons born in 2001-17 who were followed until 2020. Of these, 819 371/826 087 with information on paternal/maternal grandparents were selected for multi-generation analyses and 1 748 382 with sibling(s) were selected for sibling comparison. Cox proportional hazard regression was used to estimate the hazard ratio (HR) and 95% confidence interval (CI). RESULTS: In the total cohort, there was an increased risk of epilepsy in individuals with advanced paternal age, e.g. the HR for paternal age ≥50 was1.36 (95% CI: 1.15-1.61) compared with paternal age 25-29, and fathers older than mothers, e.g. the HR for parental age difference ≥15 years was 1.29 (95% CI: 1.16-1.43). When accounting for parental age difference, the association between paternal age and epilepsy in offspring was attenuated (HR for paternal age ≥50 was 1.11, 95% CI: 0.93-1.34). Multi-generation analyses did not support the association of advanced grand-paternal age at childbirth of the parent with offspring's risk of epilepsy. Sibling comparison analyses did not support the association of older paternal age with increased risk of epilepsy (HR was 0.96 for per year increase in paternal age, 95% CI: 0.96-0.97). CONCLUSIONS: These results do not support the hypothesis that advanced paternal age is associated with epilepsy in offspring. Instead, familial factors may explain the observed paternal age association with the offspring's risk of epilepsy.

Paternal age does not jeopardize the live birth rate and perinatal outcomes after in vitro fertilization: an analysis based on 56,113 frozen embryo transfer cycles.

BACKGROUND: The global trend of delaying childbearing has led to an increasing number of couples seeking in vitro fertilization. The adverse effects of advanced maternal age on pregnancy and perinatal outcomes are well documented, regardless of the conception method. In addition, advanced paternal age may contribute to poor reproductive potential because of high levels of sperm DNA fragmentation. However, it remains challenging to guide older men regarding the effect of paternal age on pregnancy and birth outcomes in the field of assisted reproduction. OBJECTIVE: This study aimed to investigate the association of paternal age with live birth and perinatal outcomes following in vitro fertilization-frozen embryo transfer. STUDY DESIGN: A retrospective study was performed at a university-affiliated fertility center, involving women who were younger than 36 years and had undergone frozen embryo transfer from January 2011 to June 2021. Subjects were categorized into 6 groups based on paternal age: <25, 25 to 29, 30 to 34, 35 to 39, 40 to 44, and ≥45 years. A generalized estimating equation logistic regression model was used to account for the clustered nature of data and to adjust for confounders. Paternal age between 25 and 29 years served as the reference group in the logistic regression models. RESULTS: A total of 56,113 cycles who met the inclusion criteria were included in the final analysis. On unadjusted analyses, the reproductive outcome parameters showed a considerable decline with increasing male age. The live birth rate decreased from 47.9% for men aged 25 to 29 years to 40.3% among men aged ≥40 years. Similarly, the clinical pregnancy rate decreased from 54.4% in the reference group to 47.8% in the ≥40 years age group. Conversely, the miscarriage rate increased as male age increased, from 10.2% among men aged 25 to 29 years to 13.5% among men aged ≥45 years. However, the differences in the reproductive outcomes mentioned above were no longer significant in the multivariable models. Compared with the younger controls, advanced paternal age was not associated with a lower chance of live birth (males aged 40-44 years: adjusted odds ratio, 0.94; 95% confidence interval, 0.85-1.04; males aged ≥45 years: adjusted odds ratio, 0.93; 95% confidence interval, 0.79-1.10). In addition, the rates of clinical pregnancy (males aged 40-44 years: adjusted odds ratio, 0.95; 95% confidence interval, 0.85-1.05; males aged ≥45 years: adjusted odds ratio, 0.94; 95% confidence interval, 0.79-1.12) and miscarriage (males aged 40-44 years: adjusted odds ratio, 1.05; 95% confidence interval, 0.85-1.31; males aged ≥45 years: adjusted odds ratio, 1.07; 95% confidence interval, 0.77-1.50) were comparable between the reference and advanced paternal age groups. Furthermore, men in the youngest age group (<25 years) did not have worse pregnancy outcomes than those in the reference group. Regarding perinatal outcomes, there was no difference among the study cohorts in terms of preterm birth, low birthweight, macrosomia, small for gestational age, and large for gestational age, both in the unadjusted and confounder-adjusted models. CONCLUSION: This study did not demonstrate a significant association between paternal age and live birth and perinatal outcomes after in vitro fertilization-frozen embryo transfer when the female partners were younger than 36 years. With the global trend toward delaying childbirth, our findings provide useful information for counseling patients that increasing paternal age may not adversely affect pregnancy and perinatal outcomes in assisted reproduction.

Paternal age and perinatal outcomes: an observational study.

OBJECTIVES: The study's primary aim was to examine the relationship between paternal age and perinatal outcomes. METHODS: This study used data from two hospital birth registries to examine the association between paternal age and adverse perinatal outcomes. The sample included all live singleton births between 2010 and 2022. The primary exposure was paternal age, and the following perinatal outcomes were considered: mode of conception, mode of delivery, pregnancy complications, and neonatal outcomes. RESULTS: A total of 15,232 pregnant women were considered. Maternal and paternal ages were 31.9 ± 5.3 and 36.5 ± 6.5 years, respectively. Independent of maternal, paternal age was associated with lower odds of spontaneous conceptions (OR 0.930, 95 % CI 0.968/0.993; p=0.003) and higher odds of intracytoplasmatic sperm injection (OR 1.054, 95 % CI 1.045/1.062; p=0.0001), respectively. In contrast to maternal age, paternal age decreased the odds of any (OR 0.922, 95 % CI 0.985/0.999; p=0.032) and urgent/emergent (OR 0.984, 95 % CI 0.975/0.993; p=0.0001) cesarean delivery. Paternal age did not affect the gestation length, placental or neonatal weight, blood loss during delivery, and neonatal 5th-minute Apgar score. CONCLUSIONS: Paternal age is associated with perinatal outcomes. These findings suggest that advanced paternal age may have implications for reproductive counseling and prenatal care.

Paternal age and risk for selected birth defects in a large South American sample.

BACKGROUND: The relationship between maternal age (MA) and birth defects (BD) has been extensively studied while much less research, mostly with discordant results, has focused on the risk of paternal age (PA) for BD. Furthermore, no consensus has been reached on the best way to control the association of PA with MA. OBJECTIVES: The aim of the study was to evaluate the risk of PA increase, at 1-year intervals, for selected BD, especially controlling for the confounding effect of MA. METHODS: The sample comprised of 27,944 liveborns presenting 1 of 18 selected isolated BD. Conditional logistic regressions were applied to evaluate the risk of advanced PA and its yearly increase, adjusting by MA and other variables. RESULTS: Of the 18 analyzed BD, only the risk for preaxial polydactyly (PreP) showed a significant association with increasing PA, while advanced MA was of low risk. For esophageal and anal atresia, associations with both PA and MA increases were observed. CONCLUSIONS: Results support the hypothesis of advanced PA as a risk factor for PreP and helps clarify the so far unexplained nonrandom association between this defect and Down syndrome.

Impact of increased paternal age on neonatal outcomes in very-low-birth-weight infants.

OBJECTIVE: Despite the trend of increasing paternal age, its impact on neonatal outcomes, particularly in preterm infants, has not been thoroughly investigated. We aimed to evaluate the perinatal characteristics and neonatal outcomes associated with paternal age. METHODS: Electronic medical records of very low-birthweight infants admitted to our unit from July 2013 to March 2022 were reviewed. Infants grouped according to paternal age (<35 years, 35-39 years, and ≥40 years) were analyzed for differences in perinatal findings and neonatal outcomes. RESULTS: A total of 637 infants were included (194, 294, and 149 in the <35, 35-39, and ≥40 years groups, respectively). The increase in paternal age paralleled the increase in maternal age. The Z-score of head circumference at birth was significantly different between the groups, showing the lowest median value in the ≥40 years group. Small-for-gestational age (Odds ratio 71.074, p < .001, 95% confidence interval 19.337 - 261.236) and male sex (Odds ratio 3.309, p < .034, 95% confidence interval 1.089 - 8.425), but not paternal or maternal age groups were significant factors associated with head circumference Z-scores less than -2 standard deviation based on the multivariable logistic regression analysis. Infants affected by chromosomal or genetic anomaly were more frequently identified (3.4 vs 0.0 vs 0.5%) in the ≥40 years group than in the other two groups. When infants with anomalies or critical illnesses were excluded, overall neonatal outcomes did not statistically differ according to paternal age. CONCLUSION: Although increased paternal age ≥40 years may be associated with relatively smaller head circumferences, the impact on fetal head growth does not imply a definite risk for microcephaly. Nonetheless, based on the possible negative impact on chromosomal/genetic anomaly, increased paternal age warrants attention, even though neonatal outcomes concerning prematurity were not significantly affected. A large-scale longitudinal study is needed to further elucidate the impact of advanced paternal age in preterm infants and provide guidelines for appropriate antenatal counseling and surveillance.

Paternal age, risk of congenital anomalies, and birth outcomes: a population-based cohort study.

The objective of the study was to explore the impact of paternal age on the risk of congenital anomalies and birth outcomes in infants born in the USA between 2016 and 2021. This retrospective cohort study used data from the National Vital Statistics System (NVSS) database, a data set containing information on live birth in the USA between 2016 and 2021. Newborns were divided into four groups based on their paternal age (< 25, 25-34, 35-44, and > 44 years) and using the 25-34 age group as a reference. The primary outcomes were congenital anomalies involving structural anomalies and chromosome anomalies. Secondary outcomes were preterm birth, low birth weight, severe neonatal perinatal asphyxia, and admission to neonatal intensive care units (NICU). A multivariable logistic regression model was used to analyze the association between paternal age and outcomes. Overall, 17,764,695 live births were included in the final analyses. After adjusting confounding factors, advanced paternal age > 44 years was associated with increased odds of congenital anomalies (adjusted odds ratio (aOR) = 1.17, 95%CI 1.12-1.21) compared with the 25-34 age group, mainly for the chromosomal anomalies (aOR = 1.59, 95%CI 1.40-1.78) but not the structure anomalies (aOR = 1.03, 95%CI 0.97-1.09). The risk of preterm delivery, low birth weight, and NICU hospitalization in their infants was increased by advanced parental age as well.  Conclusion: Advanced paternal age increases the risk of congenital anomalies, especially chromosomal anomalies in their offspring, implying prenatal genetic counseling is required. What is Known: • There's a rising trend of advanced paternal age, which is associated with an increased likelihood of premature birth and low birth weight in their offspring. However, the exploration between paternal age and congenital abnormalities in offspring was limited and contradictory. What is New: • Infants with a paternal age > 44 years were more likely to be born with congenital anomalies, especially chromosomal anomalies.

Semen parameters' mediation effect on the association between advanced paternal age and IVF clinical outcomes: A 10-year retrospective cohort study.

OBJECTIVE: To explore the mediation between advanced paternal age and the outcomes of in vitro fertilization (IVF) in a female-adjusted cohort. METHODS: The study retrospectively included couples undergoing IVF cycles between 2011 and 2020, and whose female partner was free of medical conditions that would significantly worsen clinical outcomes. Data on patient medical conditions, clinical data, and follow-up information were collected. Causal mediation effect analysis adopting both linear/logistic regression and mixed-effects models was carried out to evaluate the effect of paternal age on the outcomes. RESULTS: 21,959 IVF cycles were included in the study. Semen volume, sperm motility and sperm morphology were significantly associated (P value <0.05) with paternal age. A lower fertilization rate was associated with increased paternal age after adjustment for maternal age (adjusted OR = 0.800; 95 % CI, 0.678, 0.943; P value = 0.008). Mediation analysis revealed that A-level sperm rate and progressive rate respectively mediated 37.0 % and 41.0 % of the association between paternal age and fertilization rate. CONCLUSION: Sperm motility rate, especially A-level sperm rate and rapid progressive rate, mediated the association between advanced paternal age and lower fertilization rate in the cycles.

Advanced Paternal Age Affects the Sperm DNA Fragmentation Index and May Lead to Lower Good-quality Blastocysts.

Several studies show reductions in some seminal parameters in aged men and describe them as a consequence of many age-dependent changes in male organisms. This study aims to evaluate the impact of age on seminal parameters, particularly the DNA fragmentation index (DFI), and outcomes after in vitro fertilization (IVF) cycles. This is a retrospective study that includes 367 patients who underwent sperm chromatin structure assay testing between 2016 and 2021. The participants were split into three groups according to age: < 35 years (younger group, n = 63), 35-45 years (intermediate group, n = 227), and ≥ 45 years (older group, n = 77). The mean DFI (%) was compared. Among all patients, 255 received IVF cycles after DFI evaluation. For these patients, the sperm concentration, motility, and volume, as well as the fertilization rate, mean oocyte age, and good-quality blastocyst formation rate, were analyzed. One-way ANOVA was applied. The older group showed a significantly higher sperm than did the younger group (28.6% vs. 20.8% p = 0.0135). Despite not presenting a significant difference, the DFI level tends to be inversely related to good-quality blastocyst formation since the oocyte age was similar between the groups (32.0 v.s 33.6 vs. 32.3 years, respectively, p = 0.1183). Among aged men, the sperm DFI level is increased but other seminal parameters are not modified. Considering that men with a high sperm DFI can present some degree of infertility due to high sperm chromatin damage, male age should also be considered a limiting factor of IVF.

Sex-specific paternal age effects on offspring quality in Drosophila melanogaster.

Advanced paternal age has been repeatedly shown to modulate offspring quality via male- and/or female-driven processes, and there are theoretical reasons to expect that some of these effects can be sex-specific. For example, sex allocation theory predicts that, when mated with low-condition males, mothers should invest more in their daughters compared to their sons. This is because male fitness is generally more condition-dependent and more variable than female fitness, which makes it less risky to invest in female offspring. Here, we explore whether paternal age can affect the quality and quantity of offspring in a sex-specific way using Drosophila melanogaster as a model organism. In order to understand the contribution of male-driven processes on paternal age effects, we also measured the seminal vesicle size of young and older males and explored its relationship with reproductive success and offspring quality. Older males had lower competitive reproductive success, as expected, but there was no difference between the offspring sex ratio of young and older males. However, we found that paternal age caused an increase in offspring quality (i.e., offspring weight), and that this increase was more marked in daughters than sons. We discuss different male- and female-driven processes that may explain such sex-specific paternal age effects.

Impact of Advanced Paternal Age on Fertility and Risks of Genetic Disorders in Offspring.

The average age of fathers at first pregnancy has risen significantly over the last decade owing to various variables, including a longer life expectancy, more access to contraception, later marriage, and other factors. As has been proven in several studies, women over 35 years of age have an increased risk of infertility, pregnancy problems, spontaneous abortion, congenital malformations, and postnatal issues. There are varying opinions on whether a father's age affects the quality of his sperm or his ability to father a child. First, there is no single accepted definition of old age in a father. Second, much research has reported contradictory findings in the literature, particularly concerning the most frequently examined criteria. Increasing evidence suggests that the father's age contributes to his offspring's higher vulnerability to inheritable diseases. Our comprehensive literature evaluation shows a direct correlation between paternal age and decreased sperm quality and testicular function. Genetic abnormalities, such as DNA mutations and chromosomal aneuploidies, and epigenetic modifications, such as the silencing of essential genes, have all been linked to the father's advancing years. Paternal age has been shown to affect reproductive and fertility outcomes, such as the success rate of in vitro fertilisation (IVF), intracytoplasmic sperm injection (ICSI), and premature birth rate. Several diseases, including autism, schizophrenia, bipolar disorders, and paediatric leukaemia, have been linked to the father's advanced years. Therefore, informing infertile couples of the alarming correlations between older fathers and a rise in their offspring's diseases is crucial, so that they can be effectively guided through their reproductive years.

Does paternal age affect the live birth rate in donor oocyte cycles? A systematic review and meta-analysis.

PURPOSE: While delayed parenthood is increasing worldwide, the effect of paternal age on in vitro fertilization (IVF) outcomes remains unclear. The egg donation model appears to be relevant to studying the independent impact of paternal age on clinical outcome, but the available studies are heterogeneous and contradictory. This systematic review and meta-analysis aimed to assess the relationship between paternal age and live birth rate (LBR) in egg donation cycles. METHODS: A systematic search of the literature was conducted in PubMed, Embase, and the Cochrane Library from inception to June 30, 2021. All studies on egg donation cycles where LBR is reported according to male age were included. Study selection, bias assessment, and data extraction were performed by two independent reviewers according to the Cochrane methods. RESULTS: Eleven studies involving 10,527 egg donation cycles were finally included. The meta-analysis showed a slight but significant and linear decrease in LBR with increasing paternal age (estimate - 0.0055; 95% CI (- 0.0093; - 0.0016), p = 0.006), with low heterogeneity (I2 = 25%). No specific threshold was identified. A similar trend toward decreased clinical pregnancy rate with advancing paternal age was found but did not reach statistical significance (p = 0.07). CONCLUSION: This meta-analysis demonstrates that increasing paternal age is associated with a slight but significant and linear decrease in the live birth rate in egg donation cycles, with no apparent threshold effect. Although this requires further confirmation, this information is important for counseling men who are considering delayed childbearing.

Impact of paternal age on assisted reproductive technology outcomes and offspring health: a systematic review.

BACKGROUND: The increase in paternal age and the percentage of births after assisted reproductive technologies (ART) may have consequences on offspring and society's position regarding access to ART must be questioned. Most countries recommend limiting ART to men under 60 years. What is the rationale for this threshold? OBJECTIVE: This systematic review assesses scientific arguments to establish links between paternal age, male fertility, and offspring health. MATERIAL AND METHODS: Using the PRISMA guidelines, this systematic review of the literature analyzed 111 articles selected after screening PubMed, ScienceDirect, and Web of Science for articles published between January 1, 1995 and December 31, 2021. RESULTS: A strong correlation was highlighted between advanced paternal age and a decrease of some sperm parameters (semen volume and sperm motility) and infant morbidity (exponentially increased incidence of achondroplasia and Apert syndrome, and more moderately increased incidence of autism and schizophrenia). The impact of paternal age on pregnancy and fetal aneuploidy rates is more controversial. No association was found with spontaneous abortion rates. DISCUSSION AND CONCLUSION: The scientific parameters should be explained to older parents undergoing ART. And for countries that discuss a limit on paternal age for access to ART, the debate requires consideration of social and ethical arguments.

IVF outcomes following ICSI cycles using testicular sperm in obstructive (OA) vs. non-obstructive azoospermia (NOA) and the impact of maternal and paternal age: a SART CORS data registry.

PURPOSE: To assess the differences in IVF outcomes between couples with obstructive azoospermia (OA), non-obstructive azoospermia (NOA), and male factor (MF). METHODS: Using the SART CORS data from 2016 to 2017, we included all initial autologous cycles with a diagnosis of male factor with ejaculated and surgically obtained sperm. We analyzed 71,121 cycles, including 3467 with a diagnosis of azoospermia and 67,654 with other non-azoospermic MF. Using a multivariate binomial regression, we estimated adjusted risk ratios comparing outcomes for ICSI cycles using surgically acquired (OA and NOA) versus ejaculated sperm (MF). Outcomes reported per initial cycle included clinical pregnancy, live birth, biochemical pregnancy, and miscarriage. Outcomes reported per singleton pregnancy included full-term delivery (≥ 37 weeks), normal birth weight (≥ 2500 g), and delivery method. RESULTS: After frozen embryo transfers (FET), patients with NOA had 7% higher odds of live birth compared to MF (aOR 1.23 (0.94-1.74)), and those with OA had 2.6% lower chance of live birth compared to MF (aOR 0.73 (95%CI 0.5-1.05)). After fresh ET, patients with NOA had 5% higher chance of live birth (aOR 1.11 (0.9-1.36)), and those with OA had a 2.5% higher chance of live birth (aOR 1.10 (95%CI 0.89-1.34)) compared to MF. All three subgroups had lower fresh live birth rates (LBR) compared to FETs. CONCLUSION: Couples with either NOA or OA have overall comparable ART and perinatal outcomes to couples with MF, and their success is primarily dependent on both patient's and partner's age.

The effect of advanced paternal age on the lifespan of male offspring in an ancient Chinese genealogical data set.

BACKGROUND: Advanced paternal age has been reported to be associated with a variety of short-term outcomes in offspring, but long-term effects are rarely examined. The present study evaluated the impact of advanced paternal age on offspring's longevity. METHODS: We studied the effect of paternal reproductive age on the lifespan of male offspring using a Chinese genealogy data set that spans 226 years of the Qing Dynasty (1683-1909). Multivariable-adjusted Cox regression analyses of 1274 men with survival data were used to calculate hazard ratios (HRs) of advanced parental age at reproduction. We also evaluated whether the lifespan of brothers differed when they were born to the same parents at different ages. RESULTS: In models adjusted for maternal age, advanced paternal age was negatively associated with the lifespan of male offspring. Individuals born to fathers aged >40 years had a 32 % higher HR of a lifespan shorter than those born to fathers aged 25-29 years (adjusted HR 1.320, 95 % CI: 1.066-1.634). The adjusted HR for offspring born to fathers aged 35-39 years was 1.232 (95 % CI: 1.013-1.500). Older brothers born to fathers aged 20-34 years had a significantly lower risk of a reduced lifespan compared with their younger brothers with fathers aged ≥35 years at reproduction (P < 0.01). CONCLUSION: Advanced paternal age at reproduction is a negative factor for male offspring's life expectancy. With the sustained increase in paternal age over the past generation, further investigation is warranted into the impact on birth outcomes and public health.

Effect of paternal age on assisted reproductive outcomes in ICSI donor cycles.

BACKGROUND: Despite growing evidence suggesting age-related molecular changes in gametes, the impact of paternal age on clinical outcomes during infertility treatments has not been adequately assessed. OBJECTIVES: This study aims to assess the correlation of paternal age to clinical pregnancy and live birth rates in egg donation cycles undergoing intracytoplasmic sperm injection. MATERIALS AND METHODS: This retrospective cohort study includes 4930 fresh oocyte donation cycles from 3995 couples between April 2005 and February 2020 in a private IVF hospital. Clinical pregnancy and live birth rates were the primary outcome measures. The results were also assessed according to the paternal age groups, donor characteristics, semen parameters, fertilization rate, and quality of the transferred embryos. RESULTS: The age and body mass index of the donors, oocyte maturation, fertilization rates, and the mean number of transferred embryo quality were comparable on day-3 but not on day-5 embryo transfers between paternal age groups (p > 0.05). Paternal age was found to be negatively correlated to the number of oocytes utilized, normal semen parameters, fertilization, clinical pregnancy, and live birth rates (p < 0.05). In day-5 embryo transfer cycles, only the rate of cycles with normal spermatozoa, number of allocated oocytes, and pregnancy were found to be statistically significant. DISCUSSION AND CONCLUSION: Paternal age may influence reproductive outcomes and should be considered during infertility evaluations in intracytoplasmic sperm injection donor cycles. Further research is needed to confirm these findings.