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Should we be worried about advanced paternal age?

      In an era when childbearing is often being delayed, there has been great focus on the effects of advanced maternal age on pregnancy and beyond. The discussion of advanced paternal age, however, has taken a backseat. Advanced maternal age is often defined as a woman aged >35 years at delivery, when maternal and fetal risks increase. The rate of first births among women aged 35–39 years has increased sixfold over the past 5 decades and fourfold for those aged 40–45 years; women of advanced maternal age make up about 15% of those giving birth in the United States (
      • Stone J.
      Advanced maternal age and the risk of antepartum stillbirth.
      ). Delayed childbearing for women is accompanied by increased risk of aneuploidy, stillbirths, miscarriage, hypertensive disorders, diabetes, and cesarean delivery (
      • Sauer M.V.
      Reproduction at an advanced maternal age and maternal health.
      ).
      A woman’s biological fertility declines with age due to a constant and substantial decrease in number of oocytes, but men continue to produce sperm throughout their life span. Recently advanced paternal age has garnered some attention as well because this has also been shown to be a growing population. Should there be an age when prospective fathers need to be more cautious? Is there any evidence that advanced paternal age, often defined as >40 years, carries additional risk?
      In their eloquent retrospective cohort study, Dviri et al. (
      • Dviri M.
      • Madjunkova S.
      • Koziarz A.
      • Antes R.
      • Abramov R.
      • Mashiach J.
      • et al.
      Is there a correlation between paternal age and aneuploidy rate? An analysis of 3,118 embryos derived from young egg donors.
      ) evaluated over 3,000 embryos stratified by paternal age (
      • Dviri M.
      • Madjunkova S.
      • Koziarz A.
      • Antes R.
      • Abramov R.
      • Mashiach J.
      • et al.
      Is there a correlation between paternal age and aneuploidy rate? An analysis of 3,118 embryos derived from young egg donors.
      ). They grouped over 400 male patients by age (<39, 40–49, and >50 years) and investigated whether day-5 or day-6 trophectoderm biopsies examined by next-generation sequencing showed any correlation between chromosomal abnormalities and age. They found no differences among the paternal age groups when comparing rates of euploidy, aneuploidy, mosaicism, or blastocyst formation. Importantly, to control for the effect of maternal age, they only included cycles using donor oocytes from women aged ≤33 years and adjusted for other confounding factors related to cycle and donor parameters. They further excluded severe male factor infertility, and they used standard density gradient centrifugation to prepare all semen samples in an effort to decrease other possible causes of increased aneuploidy rate. It is interesting that they found that segmental aneuploidies were higher and fertilization rates were lower in the older versus younger paternal age groups. The difference in fertilization rate between the groups aged >50 and 40–49 years was only 76.35% versus 80.09%. The finding was statistically significant but may not be clinically relevant; however, the difference in segmental aneuploidy remains very intriguing.
      The clinical relevance of increased segmental aneuploidy in older males has yet to be explored. Sperm DNA fragmentation is more common in older men (
      • Wyrobek A.J.
      • Eskenazi B.
      • Young S.
      • Arnheim N.
      • Tiemann-Boege I.
      • Jabs E.W.
      • et al.
      Advancing age has differential effects on DNA damage, chromatin integrity, gene mutations, and aneuploidies in sperm.
      ), and it could potentially be an explanation for why segmental changes affect the paternal chromosomes at older ages. Further studies evaluating DNA fragmentation and paternal segmental aneuploidy would be worthwhile. Furthermore, therapeutic options such as antioxidants or testicular sperm extraction (if a couple is undergoing assisted reproduction) can be explored for these patients. Additionally, future studies with single nucleotide polymorphism array technology to try to establish haplotypes in segmental aneuploidies would be interesting to confirm that these findings are truly related to advanced paternal age and not to maternal chromosomes. This could further aid in patient counseling regarding whether donor eggs or donor sperm would be more appropriate after failed cycles in an otherwise healthy young female patient.
      This study is reassuring that our current belief is correct that aneuploidy rates increase with maternal but not paternal age. However, there are some important aspects that need to be discussed with patients of advanced paternal age that are not related to aneuploidy but to other health associations. Studies have shown that single-gene autosomal dominant disorders, such as Apert syndrome or achondroplasia, are more common in children with older fathers (
      • Wyrobek A.J.
      • Eskenazi B.
      • Young S.
      • Arnheim N.
      • Tiemann-Boege I.
      • Jabs E.W.
      • et al.
      Advancing age has differential effects on DNA damage, chromatin integrity, gene mutations, and aneuploidies in sperm.
      ). Further, more complex disorders have also been found to be increased, such as autism and schizophrenia, and there is a lack of consensus on the origins of this increased risk. Future research is needed to tease out whether these findings are related to inherited genetic factors, to a de novo paternal spermatogonial contribution as a result of aging, or to an effect of behavior traits associated with a delay in reproduction, such as social withdrawal (
      • Janecka M.
      • Mill J.
      • Basson M.A.
      • Goriely A.
      • Spiers H.
      • Reichenberg A.
      • et al.
      Advanced paternal age effects in neurodevelopmental disorders-review of potential underlying mechanisms.
      ). Furthermore, the psychological and ethical principles of advanced fatherhood need to be discussed just as they are with oocyte donation to women of advanced reproductive age.
      As we push the boundaries of reproduction, we should continuously consider how old is too old, and there should be some equitability between the sexes. The morbidity of carrying a pregnancy at an advanced age is clear, and now gestational carriers can bear the risk associated with the pregnancy; however, we also should discuss whether either parent has the physical capacity to meet the demands of parenting and surviving past their offspring’s childhood. There remain many unanswered questions, and research in the field of parenting in the later decades of life—especially for men—is sparse.

      References

        • Stone J.
        Advanced maternal age and the risk of antepartum stillbirth.
        Society for Maternal Fetal Medicine, Washington, DC2012
        • Sauer M.V.
        Reproduction at an advanced maternal age and maternal health.
        Fertil Steril. 2015; 103: 1136-1143
        • Dviri M.
        • Madjunkova S.
        • Koziarz A.
        • Antes R.
        • Abramov R.
        • Mashiach J.
        • et al.
        Is there a correlation between paternal age and aneuploidy rate? An analysis of 3,118 embryos derived from young egg donors.
        Fertil Steril. 2020; 114: 293-300
        • Wyrobek A.J.
        • Eskenazi B.
        • Young S.
        • Arnheim N.
        • Tiemann-Boege I.
        • Jabs E.W.
        • et al.
        Advancing age has differential effects on DNA damage, chromatin integrity, gene mutations, and aneuploidies in sperm.
        Proc Natl Acad Sci USA. 2006; 103: 9601-9606
        • Janecka M.
        • Mill J.
        • Basson M.A.
        • Goriely A.
        • Spiers H.
        • Reichenberg A.
        • et al.
        Advanced paternal age effects in neurodevelopmental disorders-review of potential underlying mechanisms.
        Transl Psychiatry. 2017; 7e1019

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