In this issue of Fertility and Sterility, McCarter et al. (1McCarter K. Setton R. Chung A. An A. Rosenwaks Z. Spandorfer S. Is increasing paternal age negatively associated with donor oocyte recipient success? A paired analysis using sibling oocytes.) report on a retrospective, observational, single-center cohort study of shared egg donation cycles to investigate whether increasing paternal age, defined as ≥45 years, negatively impacts pregnancy outcomes compared with paternal age of Previous studies have demonstrated the adverse effects of increasing paternal age on embryo development and assisted reproductive technology outcomes in couples undergoing anonymous donor oocyte cycles (2Frattarelli J.L. Miller K.A. Miller B.T. Elkind-Hirsch K. Scott Jr., R.T. Male age negatively impacts embryo development and reproductive outcome in donor oocyte assisted reproductive technology cycles., 3Begueria R. Garcia D. Obradors A. Poisot F. Vassena R. Vernaeve V. Paternal age and assisted reproductive outcomes in ICSI donor oocytes: is there an effect of older fathers?.). In a retrospective cohort study analyzing 1,023 male partners participating in anonymous oocyte donation cycles, Frattarelli et al. (2Frattarelli J.L. Miller K.A. Miller B.T. Elkind-Hirsch K. Scott Jr., R.T. Male age negatively impacts embryo development and reproductive outcome in donor oocyte assisted reproductive technology cycles.) showed significantly higher pregnancy loss rates and lower blastocyst formation and live birth rates in men aged >50 years compared with men aged ≤50 years. By only including oocytes donated by women aged ≤35 years, Frattarelli et al. (2Frattarelli J.L. Miller K.A. Miller B.T. Elkind-Hirsch K. Scott Jr., R.T. Male age negatively impacts embryo development and reproductive outcome in donor oocyte assisted reproductive technology cycles.) eliminated the potential confounding effect of increasing maternal age on oocyte quality. The maternal genome controls early cleavage events, while development beyond the cleavage stage is regulated by the embryonic genome; consequently, Frattarelli et al. (2Frattarelli J.L. Miller K.A. Miller B.T. Elkind-Hirsch K. Scott Jr., R.T. Male age negatively impacts embryo development and reproductive outcome in donor oocyte assisted reproductive technology cycles.) attributed this decrease in embryonic developmental potential beyond the cleavage stage to the aging paternal gamete. The study by McCarter et al. (1McCarter K. Setton R. Chung A. An A. Rosenwaks Z. Spandorfer S. Is increasing paternal age negatively associated with donor oocyte recipient success? A paired analysis using sibling oocytes.) aimed to expand on this work by only including oocytes from a single controlled ovarian hyperstimulation cycle of an egg donor split between two recipients, categorized by paternal age. The use of sibling oocyte recipients perfectly controls for oocyte quality, eliminating the oocyte heterogeneity associated with different egg sources. In contrast to Frattarelli et al. (2Frattarelli J.L. Miller K.A. Miller B.T. Elkind-Hirsch K. Scott Jr., R.T. Male age negatively impacts embryo development and reproductive outcome in donor oocyte assisted reproductive technology cycles.), McCarter et al. (1McCarter K. Setton R. Chung A. An A. Rosenwaks Z. Spandorfer S. Is increasing paternal age negatively associated with donor oocyte recipient success? A paired analysis using sibling oocytes.) controlled for recipient age, eliminating the possible bias of an aging uterus. When stratified by paternal age, recipients with male partners aged ≥45 years had a higher pregnancy loss rate and lower implantation, pregnancy, and live birth rates compared with recipients with male partners aged It is significant to note that although the mixed-effects logistic regression analysis adjusted for the use of fresh vs. frozen sperm, the model did not control for semen parameters. In a retrospective observational study assessing 1,024 couples undergoing intracytoplasmic sperm injection (ICSI) with fresh spermatozoa, Ferreira et al. (4Ferreira R.C. Braga D.P. Bonetti T.C. Pasqualotto F.F. Iaconelli Jr., A. Borges Jr., E. Negative influence of paternal age on clinical intracytoplasmic sperm injection cycle outcomes in oligozoospermic patients.) evaluated the effect of paternal age on ICSI outcomes in normozoospermic and oligozoospermic patients. They demonstrated that paternal age negatively influences implantation and pregnancy rates in couples in which the sperm concentration was 6/mL: in these couples, the chance of pregnancy decreased 5% for each year of paternal age. In contrast, in normozoospermic patients, there was no influence of paternal age on implantation or pregnancy rates. Ferreira et al. (4Ferreira R.C. Braga D.P. Bonetti T.C. Pasqualotto F.F. Iaconelli Jr., A. Borges Jr., E. Negative influence of paternal age on clinical intracytoplasmic sperm injection cycle outcomes in oligozoospermic patients.) suggest that in patients in whom spermatogenesis is impaired, sperm factors critical for fertilization are further affected by increasing age. Thus, by failing to control for sperm concentration, the present study may overestimate the impact of paternal age on pregnancy outcomes.Furthermore, the study by McCarter et al. (1McCarter K. Setton R. Chung A. An A. Rosenwaks Z. Spandorfer S. Is increasing paternal age negatively associated with donor oocyte recipient success? A paired analysis using sibling oocytes.) did not assess embryo quality or aneuploidy rates between groups, although donor egg embryos typically have low rates of aneuploidy. Previous studies have attributed embryo aneuploidy to increasing paternal age, positing that defects in the paternally inherited centrioles may result in abnormal spindle formation and inappropriate chromosomal segregation (5García-Ferreyra J. Luna D. Villegas L. Romero R. Zavala P. Hilario R. et al.High aneuploidy rates observed in embryos derived from donated oocytes are related to male aging and high percentages of sperm DNA fragmentation.). In a study evaluating 286 embryos obtained from 32 in vitro fertilization (IVF)/ICSI cycles utilizing donor oocytes, García-Ferreyra et al. (5García-Ferreyra J. Luna D. Villegas L. Romero R. Zavala P. Hilario R. et al.High aneuploidy rates observed in embryos derived from donated oocytes are related to male aging and high percentages of sperm DNA fragmentation.) demonstrated significantly higher rates of deoxyribonucleic acid fragmentation and embryo aneuploidy in cycles with men aged >50 years compared with cycles with men aged ≤39 years. Although this study was limited by a small sample size, these results suggest that the lower implantation, pregnancy, and live birth rates seen in the older paternal age group in the McCarter et al. (1McCarter K. Setton R. Chung A. An A. Rosenwaks Z. Spandorfer S. Is increasing paternal age negatively associated with donor oocyte recipient success? A paired analysis using sibling oocytes.) study could be partially attributed to underlying embryo aneuploidy.

Despite these limitations, to our knowledge, this is the first study to evaluate the effect of paternal age on assisted reproductive technology outcomes using paired sibling oocyte recipients. Studies with larger sample sizes controlling for sperm concentration and embryo ploidy are needed to further elucidate the underlying mechanisms responsible for lower pregnancy, implantation, and live birth rates seen with increasing paternal age.

ReferencesMcCarter K. Setton R. Chung A. An A. Rosenwaks Z. Spandorfer S.

Is increasing paternal age negatively associated with donor oocyte recipient success? A paired analysis using sibling oocytes.

Fertil Steril. ()Frattarelli J.L. Miller K.A. Miller B.T. Elkind-Hirsch K. Scott Jr., R.T.

Male age negatively impacts embryo development and reproductive outcome in donor oocyte assisted reproductive technology cycles.

Fertil Steril. 90: 97-103Begueria R. Garcia D. Obradors A. Poisot F. Vassena R. Vernaeve V.

Paternal age and assisted reproductive outcomes in ICSI donor oocytes: is there an effect of older fathers?.

Hum Reprod. 29: 2114-2122Ferreira R.C. Braga D.P. Bonetti T.C. Pasqualotto F.F. Iaconelli Jr., A. Borges Jr., E.

Negative influence of paternal age on clinical intracytoplasmic sperm injection cycle outcomes in oligozoospermic patients.

Fertil Steril. 93: 1870-1874García-Ferreyra J. Luna D. Villegas L. Romero R. Zavala P. Hilario R. et al.

High aneuploidy rates observed in embryos derived from donated oocytes are related to male aging and high percentages of sperm DNA fragmentation.

Clin Med Insights Reprod Health. 9: 21-27Article InfoPublication History

Published online: July 09, 2021

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DOI: https://doi.org/10.1016/j.fertnstert.2021.06.031

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©2021 Published by Elsevier Inc. on behalf of the American Society for Reproductive Medicine

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