SMAD4 mutations causing Myhre syndrome are under positive selection in the male germline.

While it is widely thought that de novo mutations (DNMs) occur randomly, we previously showed that some DNMs are enriched because they are positively selected in the testes of aging men. These "selfish" mutations cause disorders with a shared presentation of features, including exclusive paternal origin, significant increase of the father's age, and high apparent germline mutation rate. To date, all known selfish mutations cluster within the components of the RTK-RAS-MAPK signaling pathway, a critical modulator of testicular homeostasis. Here, we demonstrate the selfish nature of the SMAD4 DNMs causing Myhre syndrome (MYHRS). By analyzing 16 informative trios, we show that MYHRS-causing DNMs originated on the paternally derived allele in all cases. We document a statistically significant epidemiological paternal age effect of 6.3 years excess for fathers of MYHRS probands. We developed an ultra-sensitive assay to quantify spontaneous MYHRS-causing SMAD4 variants in sperm and show that pathogenic variants at codon 500 are found at elevated level in sperm of most men and exhibit a strong positive correlation with donor's age, indicative of a high apparent germline mutation rate. Finally, we performed in vitro assays to validate the peculiar functional behavior of the clonally selected DNMs and explored the basis of the pathophysiology of the different SMAD4 sperm-enriched variants. Taken together, these data provide compelling evidence that SMAD4, a gene operating outside the canonical RAS-MAPK signaling pathway, is associated with selfish spermatogonial selection and raises the possibility that other genes/pathways are under positive selection in the aging human testis.

Paternal aging impacts expression and epigenetic markers as early as the first embryonic tissue lineage differentiation.

BACKGROUND: Advanced paternal age (APA) is associated with adverse outcomes to offspring health, including increased risk for neurodevelopmental disorders. The aim of this study was to investigate the methylome and transcriptome of the first two early embryonic tissue lineages, the inner cell mass (ICM) and the trophectoderm (TE), from human blastocysts in association with paternal age and disease risk. High quality human blastocysts were donated with patient consent from donor oocyte IVF cycles from either APA (≥ 50 years) or young fathers. Blastocysts were mechanically separated into ICM and TE lineage samples for both methylome and transcriptome analyses. RESULTS: Significant differential methylation and transcription was observed concurrently in ICM and TE lineages of APA-derived blastocysts compared to those from young fathers. The methylome revealed significant enrichment for neuronal signaling pathways, as well as an association with neurodevelopmental disorders and imprinted genes, largely overlapping within both the ICM and TE lineages. Significant enrichment of neurodevelopmental signaling pathways was also observed for differentially expressed genes, but only in the ICM. In stark contrast, no significant signaling pathways or gene ontology terms were identified in the trophectoderm. Despite normal semen parameters in aged fathers, these significant molecular alterations can adversely contribute to downstream impacts on offspring health, in particular neurodevelopmental disorders like autism spectrum disorder and schizophrenia. CONCLUSIONS: An increased risk for neurodevelopmental disorders is well described in children conceived by aged fathers. Using blastocysts derived from donor oocyte IVF cycles to strategically control for maternal age, our data reveals evidence of methylation dysregulation in both tissue lineages, as well as transcription dysregulation in neurodevelopmental signaling pathways associated with APA fathers. This data also reveals that embryos derived from APA fathers do not appear to be compromised for initial implantation potential with no significant pathway signaling disruption in trophectoderm transcription. Collectively, our work provides insights into the complex molecular mechanisms that occur upon paternal aging during the first lineage differentiation in the preimplantation embryo. Early expression and epigenetic markers of APA-derived preimplantation embryos highlight the susceptibility of the future fetus to adverse health outcomes.

Sperm mosaicism: implications for genomic diversity and disease.

While sperm mosaicism has few consequences for men, the offspring and future generations are unwitting recipients of gonadal cell mutations, often yielding severe disease. Recent studies, fueled by emergent technologies, show that sperm mosaicism is a common source of de novo mutations (DNMs) that underlie severe pediatric disease as well as human genetic diversity. Sperm mosaicism can be divided into three types: Type I arises during sperm meiosis and is non-age dependent; Type II arises in spermatogonia and increases as men age; and Type III arises during paternal embryogenesis, spreads throughout the body, and contributes stably to sperm throughout life. Where Types I and II confer little risk of recurrence, Type III may confer identifiable risk to future offspring. These mutations are likely to be the single largest contributor to human genetic diversity. New sequencing approaches may leverage this framework to evaluate and reduce disease risk for future generations.

The current 'dramatically' high paternal ages at childbirth are not unprecedented.

There is strong individual-level evidence that late fatherhood is related to a wide range of health disorders and conditions in offspring. Over the last decades, mean paternal ages at childbirth have risen drastically. This has alarmed researchers from a wide range of fields. However, existing studies have an important shortcoming in that they lack a long-term perspective. This article is a step change in providing such a long-term perspective. We unveil that in many countries the current mean paternal ages at childbirth and proportions of fathers of advanced age at childbirth are not unprecedented. Taking the detected U-shaped trend pattern into account, we discuss individual- and population-level implications of the recent increases in paternal ages at childbirth and highlight important knowledge gaps. At the individual level, some of the biological mechanisms that are responsible for the paternal age-related health risk might, at least to some degree, be counterbalanced by various social factors. Further, how these individual-level effects are linked to population health and human cognitive development might be influenced by various factors, including technical advances and regulations in prenatal diagnostics.

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.

Age related semen parameters and ICSI pregnancy outcomes of 8046 men in Turkey over a 9-year period.

The effect of paternal age on fertility remains unclear. This retrospective study aims to examine the impact of male age on semen parameters and the reproductive outcomes of men admitted to an infertility center over a 9-year period. A total of 8046 patients were included in the study. Men were divided into four age groups. The groups were evaluated for semen parameters and reproductive outcome. The 21-30 year group presented lower sperm concentrations in comparison to those aged 31-40 and 41-50, yet shared a similar concentration to those over 50 years of age. Moreover, grades A and B decreased significantly in men aged over 50 years. The highest progressive motility and normozoospermia were observed in the age group 31-40 years while men over 50 years of age had the highest rates of asthenozoospermia and oligoasthenozoospermia. Furthermore, live birth results were reported in 5583 of the patients who underwent intracytoplasmic sperm injection (ICSI) and were found highest between 31-40 years of age. To our knowledge, this is the largest study in Turkey focusing on male age-related semen parameters and ICSI pregnancy outcomes. The study demonstrates that age is a significant factor for semen quality and live birth.

Does the Fraternal Birth Order Effect Influence Handedness?

The fraternal birth order effect (FBOE) is the phenomenon whereby the probability that a man has a same-sex sexual orientation in adulthood increases with each biological older brother. Several studies have found evidence that the FBOE is limited to right-handed men, and left-handed men do not show an FBOE. Recent debates about the appropriate methods for quantifying the FBOE center on distinguishing the FBOE from other effects, such as the female fecundity effect (FFE), whereby mothers more prone to bearing gay sons are also more fecund. The FBOE and FFE are confounded in that a real FFE will result in data consistent with the FBOE under some analyses. Here, we applied some recent proposed analytic methods for the FBOE to the property of handedness. A straightforward application of Khovanova's technique to the binary trait of handedness yielded support for a fraternal birth order effect consistent with the maternal immune hypothesis, in that the ratios of handedness differed between men with one older brother only, and men with one younger brother only, while no such effect was seen in women. This effect was not seen, however, when the confounding effects of parental age were controlled for. Models including factors to simultaneously test multiple posited effects find significant female fecundity effects, as well as paternal age and birth order effects on handedness in men, but no FBOE. The effects seen in women were different, with no fecundity or parental age effects, but birth order and sex of older siblings had effects. We conclude, based on this evidence, that many of the factors thought to contribute to sexual orientation in men may also have an influence on handedness, and further note that parental age is a potential confound which may be overlooked by some analyses of the FBOE.

Limiting access to assisted reproductive technologies for males of advanced age-Pros and cons from a Nordic perspective.

It is not controversial to state that parental age is increasing in several countries. But how to deal with this increase might be. Some Nordic countries have set an upper age limit for females seeking assisted reproduction in their national legislation, but none have done so for males. There are also recommendations in place that restrict access to publicly funded assisted reproduction for both females and males of advanced age in some Nordic countries. As recent data now show somatic and psychiatric health risks related to advanced paternal age, we ask if the time has come for countries to set an upper age limit for males seeking assisted reproduction like there already is for females, and summarize some of the risks and rewards involved in treating couples with advanced age in fertility clinics.

Li-Fraumeni syndrome presenting with de novo TP53 mutation, severe phenotype and advanced paternal age: a case report.

BACKGROUND: Li-Fraumeni syndrome (LFS) is an autosomal dominant hereditary cancer syndrome caused by pathogenic variants in the gene TP53. This gene codes for the P53 protein, a crucial player in genomic stability, which functions as a tumor suppressor gene. Individuals with LFS frequently develop multiple primary tumors at a young age, such as soft tissue sarcomas, breast cancer, and brain tumors. CASE PRESENTATION: A 38 years-old female with a history of femur osteosarcoma, ductal carcinoma of the breast, high-grade breast sarcoma, pleomorphic sarcoma of the left upper limb, infiltrating lobular carcinoma of the breast, gastric adenocarcinoma, leiomyosarcoma of the right upper limb, and high-grade pleomorphic renal sarcoma. Complete molecular sequencing of the TP53 gene showed c.586 C > T (p.R196X) in exon 6, which is a nonsense mutation that produces a shorter and malfunctioning P53. Family history includes advanced father's age at the time of conception (75 years), which has been associated with an increased risk of de novo germline mutations. The patient had seven paternal half-siblings with no cancer history. The patient received multiple treatments including surgery, systemic therapy, and radiotherapy, but died at the age of 38. CONCLUSIONS: Advanced paternal age is a risk factor to consider when hereditary cancer syndrome is suspected. Early detection of hereditary cancer syndromes and their multi-disciplinary surveillance and treatment is important to improve clinical outcomes for these patients. Further investigation of the relationship between the pathogenic variant of TP53 and its phenotype may guide the stratification of surveillance and treatment.

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.

Predictors of age at diagnosis in autism spectrum disorders: the use of multiple regression analyses and a classification tree on a clinical sample.

The increasing prevalence of autism spectrum disorders (ASD) has led to worldwide interest in factors influencing the age of ASD diagnosis. Parents or caregivers of 237 ASD children (193 boys, 44 girls) diagnosed using the Autism Diagnostic Observation Schedule (ADOS) completed a simple descriptive questionnaire. The data were analyzed using the variable-centered multiple regression analysis and the person-centered classification tree method. We believed that the concurrent use of these two methods could produce robust results. The mean age at diagnosis was 5.8 ± 2.2 years (median 5.3 years). Younger ages for ASD diagnosis were predicted (using multiple regression analysis) by higher scores in the ADOS social domain, higher scores in ADOS restrictive and repetitive behaviors and interest domain, higher maternal education, and the shared household of parents. Using the classification tree method, the subgroup with the lowest mean age at diagnosis were children, in whom the summation of ADOS communication and social domain scores was ≥ 17, and paternal age at the delivery was ≥ 29 years. In contrast, the subgroup with the oldest mean age at diagnosis included children with summed ADOS communication and social domain scores < 17 and maternal education at the elementary school level. The severity of autism and maternal education played a significant role in both types of data analysis focused on age at diagnosis.

Relationship between degree of methylation of sperm long interspersed nuclear element-1 (LINE-1) gene and alteration of sperm parameters and age: a meta-regression analysis.

INTRODUCTION: The long interspersed nuclear element-1 (LINE1) gene is a retrotransposon whose methylation status appears to play a role in spermatogenesis, the outcome of assisted reproductive techniques (ART), and even in recurrent pregnancy loss (RPL). Advanced paternal age appears associated with altered sperm parameters, RPL, poor ART outcomes, and compromised offspring health. The methylation status of LINE1 has been reported to be affected by age. The latest meta-analysis on the LINE1 methylation pattern in spermatozoa found no significant differences in methylation levels between infertile patients and fertile controls. However, to the best of our knowledge, no updated meta-analysis on this topic has been published recently. Furthermore, no comprehensive meta-regression analysis was performed to investigate the association between sperm LINE1 methylation pattern and age. OBJECTIVES: To provide an updated and comprehensive systematic review and meta-analysis on sperm LINE1 gene methylation degree in patients with abnormal sperm parameters compared to men with normal sperm parameters and to probe the association between sperm LINE1 methylation status and age and/or sperm concentration. METHODS: This meta-analysis was registered in PROSPERO (registration n. CRD42023397056). It was performed according to the MOOSE guidelines for Meta-analyses and Systematic Reviews of Observational Studies and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P). Only original articles evaluating LINE1 gene methylation in spermatozoa from patients with infertility or abnormalities in one or more sperm parameters compared to fertile or normozoospermic men were included. RESULTS: Of 192 abstracts evaluated for eligibility, only 5 studies were included in the quantitative synthesis, involving a total of 340 patients and 150 controls. Our analysis showed no significant difference in LINE1 gene methylation degree in patients with infertility and/or abnormal sperm parameters compared to fertile controls and/or men with normal sperm parameters, although there was significant heterogeneity across studies. No significant evidence of publication bias was found, and no study was sensitive enough to alter the results. In meta-regression analysis, we found that the results were independent of both ages and sperm concentration. A sub-analysis examining patients and controls separately was also conducted and we found a trend for a positive correlation between LINE1 methylation and sperm concentration in the control group only. CONCLUSIONS: The results of this systematic review and meta-analysis do not suggest a determining role of sperm LINE1 gene methylation degree in patients with infertility and/or abnormal sperm parameters. Therefore, we do not suggest including LINE1 in the genetic panel of prospective studies aimed at identifying the most representative and cost-effective genes to be analyzed in couples undergoing ART cycles.

Change in the perceived reproductive age window and delayed fertility in Europe.

While extensive literature documents the massive fertility delay of recent decades, knowledge about whether and how attitudes towards the timing of births have changed in Europe remains limited. Using data from two rounds of the European Social Survey, we investigate these changes and their association with macro-level fertility indicators in 21 countries. Between 2006-07 and 2018-19, societal consensus regarding the existence of optimal childbearing ages remained strong and became more in favour of later parenthood. Decomposition analyses show that these shifts were driven only partially by changes in population composition, supporting the idea that a general attitudinal change in favour of later childbearing is underway. We also find a trend towards gender convergence in upper age limits driven by the increasing social recognition of an age deadline for men's childbearing. Although shifts in perceived reproductive age windows occurred during periods of birth postponement, they corresponded only loosely to country-level changes in fertility.

Against age limits for men in reproductive care.

Almost all countries and fertility clinics impose age limits on women who want to become pregnant through Assisted Reproductive Technologies (ART). Age limits for aspiring fathers, however, are much less common and remain a topic of debate. This article departs from the principle of reproductive autonomy and a conditional positive right to receive ART, and asks whether there are convincing arguments to also impose age limits on aspiring fathers. After considering three consequentialist approaches to justifying age limits for aspiring fathers, we take in a concrete normative stance by concluding that those are not strong enough to justify such cut-offs. We reinforce our position by drawing a comparison between the case of a 39-year-old woman who wants to become a single mother via a sperm donor on the one hand, and on the other hand the same woman who wants to have a child with a 64-year-old man who she loves and who is willing to care for the child as long as he is able to. We conclude that, as long as appropriate precautions are taken to protect the welfare of the future child, couples who want to receive fertility treatment should never be limited on the basis of the age of the (male) partner. An absence of age limits for men would respect the reproductive autonomy of both the man and the woman.

Parental Age and Childhood Risk for Cerebral Palsy in California.

OBJECTIVE: To investigate the associations between maternal or paternal age at the time of delivery and offspring's risk for cerebral palsy (CP) in California. STUDY DESIGN: We conducted a population-based, case-control study that included 8736 singleton CP cases and 90 250 singleton controls, matched by sex and birth year, selected from California birth certificate records from 1994 to 2010. We estimated OR and 95% CIs for CP diagnosis according to maternal and paternal age recorded on the birth certificates. Causal mediation analysis was performed to estimate direct and indirect effects of parental ages on CP with preterm delivery as a potential mediator. RESULTS: Children born to younger mothers (≤19 years) or older mothers (35-39 years; ≥40 years) had a greater risk of CP compared with children of mothers aged 25-29 years (ORs ranging from 1.13 to 1.59). Compared with paternal age 25-29 years, older paternal age (40-44 years; ≥45 years) also was associated with an increased risk for CP independent of maternal age. When analyzing jointly using both parents of ages 20-34 years as the reference, the greatest risk was estimated for older parents (≥35 years). Preterm birth was estimated to mediate 19%-34% of the total effects between maternal or paternal age and offspring CP risk. CONCLUSIONS: Young maternal age and an older age in either or both parents were associated with a greater risk of CP in their children. Although preterm birth was a mediator, additional factors related to parental age need further exploration to explain risk of CP.

The psychosocial outcomes of older parenthood in early to mid-childhood: a mini-review.

Recent decades have seen a global trend towards delaying parenthood, referred to as the 'postponement transition'. Whilst there is plentiful research regarding obstetric and paediatric outcomes related to delayed parenthood, relatively little is known about the psychosocial outcomes associated with advanced parental age during early and middle childhood. This mini-review examines the current literature regarding the psychosocial functioning of families headed by older parents. First, we give an overview of the literature that examines the psychological wellbeing of older first-time parents. We then review the literature regarding the quality of the parent-child relationship in older parent families. Finally, we discuss the psychosocial adjustment and cognitive development of children of older parents. We conclude with suggestions for future research avenues.

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.

Defects in sperm capacitation/fertilizing ability are equally prevalent across ages in men seeking fertility assistance.

RESEARCH QUESTION: How do capacitation ability, measured by Cap-Score™, and traditional semen analysis measures (volume, concentration, motility) change with age in men questioning their fertility (MQF)? DESIGN: Cap-Score and semen analysis measures were obtained from MQF (n = 2652; multicentric design: 35 reproductive endocrinologist prescribers, n = 16 clinics). Morphology was not included due to differences among clinics. A Mann-Whitney test was used to compare Cap-Scores between MQF and men with known recent paternity (n = 76). The following age groups were constructed for MQF: 20-24, 25-29, 30-34, 35-39, 40-44, 45-49 and 50+. Associations between semen analysis, Cap-Score and age groups were evaluated using mixed-model analysis of variance to identify possible influence of Cap-Score collection kit type (n = 763 collected at home; n = 1889 collected at clinics). RESULTS: MQF had reduced capacitation ability (mean ± SE; 29.25 ± 0.15 versus 35.34 ± 0.88; P < 0.001). No change in Cap-Score (P = 0.916) or concentration (P = 0.926) was detected with age group. In contrast, both volume (P = 0.008) and % motility (P < 0.001) declined with age. CONCLUSIONS: Men presenting because of difficulties in generating pregnancy showed equivalent reductions in capacitation ability regardless of age. In contrast, motility and volume declined with age. These data suggest that capacitation ability is a more sensitive indicator of male fertility across age groups than traditional semen analysis and should not be reserved for older men. Importantly, these data do not address whether sperm fertilizing ability declines in the general population as men age. Instead, they indicate that if men are having difficulty conceiving, no matter what their age, then defects in sperm fertilizing ability are equally likely to be the cause.

Impact of male age on paternal aneuploidy: single-nucleotide polymorphism microarray outcomes following blastocyst biopsy.

RESEARCH QUESTION: Does advanced paternal age (APA; ≥40 years) contribute to a higher incidence of paternal origin aneuploidy in preimplantation embryos? DESIGN: This was a multicentre retrospective study of single-nucleotide polymorphism (SNP) microarray (Natera and Karyomapping) preimplantation genetic testing (PGT) outcomes of blastocyst-stage embryos. Whole-chromosome aneuploidy analysis was performed on 2409 embryos from 389 male patients undertaking 681 assisted reproductive technology (ART) cycles between 2012-2021. Segmental aneuploidy analysis was performed on 867 embryos from 140 men undertaking 242 ART cycles between 2016-2021. Embryos were grouped based on paternal age at sperm collection: <35, 35-39 and ≥40 years. Paternal and maternal origin aneuploidy rates were compared between groups using chi-squared and/or Fisher's exact tests. RESULTS: There was no significant difference across groups in paternal origin whole-chromosome aneuploidy rate, overall (P=0.7561) or when segregated by type (trisomy and monosomy: P=0.2235 and 0.8156) or complexity (single versus 2, 3 or ≥4 aneuploidies: P=0.9733, 0.7517, 0.669 and 0.1481). Conversely, maternal origin whole-chromosome aneuploidy rate differed across groups (P<0.0001) in alignment with differing mean maternal age (P<0.001). Paternal origin deletions were 2.9-fold higher than maternal origin deletions (P=0.0084), independent of age stratification. No significant difference in paternal origin deletions was observed with APA ≥40 compared with the younger age groups (4.8% versus 2.5% and 2.8%, P=0.5292). Individual chromosome aneuploidy rates were too low to perform statistical comparisons. CONCLUSIONS: No significant association was found between APA and the incidence of paternal origin aneuploidy in preimplantation embryos, irrespective of type or complexity. Thus, APA may not be an indication for PGT.

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.