Abstract
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.
Similar content being viewed by others
Data Availability
The data that support the findings of this study are available from the corresponding author, TF, upon reasonable request.
References
Khandwala YS, Zhang CA, Lu Y, Eisenberg ML. The age of fathers in the USA is rising: an analysis of 168 867 480 births from 1972 to 2015. Hum Reprod. 2017;32:2110–6.
Mills M, Rindfuss RR, McDonald P, te Velde E, ESHRE Reproduction and society task force. Why do people postpone parenthood? Reasons and social policy incentives. Hum Reprod Update. 2011;17:848–60.
Lean SC, Derricott H, Jones RL, Heazell AEP. Advanced maternal age and adverse pregnancy outcomes: a systematic review and meta-analysis. PLoS One. 2017;12: e0186287.
Baird DT, Collins J, Egozcue J, Evers LH, Gianaroli L, Leridon H, et al. Fertility and ageing. Hum Reprod Update. 2005;11:261–76.
Broekmans FJ, Knauff EAH, te Velde ER, Macklon NS, Fauser BC. Female reproductive ageing: current knowledge and future trends. Trends Endocrinol Metab. 2007;18:58–65.
Menken J, Trussell J, Larsen U. Age and infertility. Science. 1986;233:1389–94.
Centers for Disease Control and Prevention. 2019 Assisted reproductive technology fertility clinic and national summary report. 2021;112. Available at https://www.cdc.gov/art/reports/2019/pdf/2019-report-art-fertility-clinic-nationalsummary-h.pdf
Bergh C, Pinborg A, Wennerholm U-B. Parental age and child outcomes. Fertil Steril. 2019;111:1036–46.
Jolly M, Sebire N, Harris J, Robinson S, Regan L. The risks associated with pregnancy in women aged 35 years or older. Hum Reprod. 2000;15:2433–7.
Oldereid NB, Wennerholm U-B, Pinborg A, Loft A, Laivuori H, Petzold M, et al. The effect of paternal factors on perinatal and paediatric outcomes: a systematic review and meta-analysis. Hum Reprod Update. 2018;24:320–89.
Johnson SL, Dunleavy J, Gemmell NJ, Nakagawa S. Consistent age-dependent declines in human semen quality: a systematic review and meta-analysis. Ageing Res Rev. 2015;19:22–33.
du Fossé NA, van der Hoorn M-LP, van Lith JMM, le Cessie S, Lashley EELO. Advanced paternal age is associated with an increased risk of spontaneous miscarriage: a systematic review and meta-analysis. Hum Reprod Update. 2020;26:650–69.
Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010;25:603–5.
Sterne JA, Hernán MA, Reeves BC, Savović J, Berkman ND, Viswanathan M, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016;355: i4919.
Shim SR, Lee J. Dose-response meta-analysis: application and practice using the R software. Epidemiol Health. 2019;41: e2019006.
Higgins J, Thomas J, Chandler J, Cumpston M, Li T, Page M, et al. Cochrane Handbook for Systematic Reviews of Interventions [Internet]. version 6.2 (updated February 2021). Cochrane; 2021. Available from: www.training.cochrane.org/handbook.
Atkins D, Best D, Briss PA, Eccles M, Falck-Ytter Y, Flottorp S, et al. Grading quality of evidence and strength of recommendations. BMJ. 2004;328:1490.
Campos I, Gómez E, Fernández-Valencia AL, Landeras J, González R, Coy P, et al. Effects of men and recipients’ age on the reproductive outcome of an oocyte donation program. J Assist Reprod Genet. 2008;25:445–52.
Cito G, Picone R, Fucci R, Giachini C, Micelli E, Cocci A, et al. Sperm morphology: what implications on the assisted reproductive outcomes? Andrology. 2020;8:1867–74.
Hogan RG, Wang AY, Li Z, Hammarberg K, Johnson L, Mol BW, et al. Oocyte donor age has a significant impact on oocyte recipients’ cumulative live-birth rate: a population-based cohort study. Fertil Steril. 2019;112:724–30.
Legro RS, Wong IL, Paulson RJ, Lobo RA, Sauer MV. Recipient’s age does not adversely affect pregnancy outcome after oocyte donation. Am J Obstet Gynecol. 1995;172:96–100.
Peyser A, Brownridge S, Rausch M, Noyes N. The evolving landscape of donor egg treatment: success, women’s choice, and anonymity. J Assist Reprod Genet. 2021.
Paulson RJ, Milligan RC, Sokol RZ. The lack of influence of age on male fertility. Am J Obstet Gynecol. 2001;184:818–22 (discussion 822-824).
Gu L, Zhang H, Yin L, Bu Z, Zhu G. Effect of male age on the outcome of in vitro fertilization: oocyte donation as a model. J Assist Reprod Genet. 2012;29(4):331–334. https://doi.org/10.1007/s10815-012-9719-9.
Beguería R, García 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. 2014;29:2114–22.
Capelouto SM, Nagy ZP, Shapiro DB, Archer SR, Ellis DP, Smith AK, et al. Impact of male partner characteristics and semen parameters on in vitro fertilization and obstetric outcomes in a frozen oocyte donor model. Fertil Steril. 2018;110:859–69.
Cito G, Coccia ME, Picone R, Cocci A, Russo GI, Garaffa G, et al. Impact of advanced paternal age on the intracytoplasmic sperm injection (ICSI) outcomes in donor egg cycles. Transl Androl Urol. 2019;8:S22-30.
Setti AS, Braga DPAF, Iaconelli Junior A, Borges JE. Increasing paternal age and ejaculatory abstinence length negatively influence the intracytoplasmic sperm injection outcomes from egg-sharing donation cycles. Andrology. 2020;8:594–601.
McCarter 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. 2021;S0015–0282(21):00242–9.
Duran EH, Dowling-Lacey D, Bocca S, Stadtmauer L, Oehninger S. Impact of male age on the outcome of assisted reproductive technology cycles using donor oocytes. Reprod Biomed Online. 2010;20:848–56.
Frattarelli JL, Miller KA, Miller BT, Elkind-Hirsch K, Scott RT. Male age negatively impacts embryo development and reproductive outcome in donor oocyte assisted reproductive technology cycles. Fertil Steril. 2008;90:97–103.
Robertshaw I, Khoury J, Abdallah ME, Warikoo P, Hofmann GE. The effect of paternal age on outcome in assisted reproductive technology using the ovum donation model. Reprod Sci. 2014;21:590–3.
Whitcomb BW, Turzanski-Fortner R, Richter KS, Kipersztok S, Stillman RJ, Levy MJ, et al. Contribution of male age to outcomes in assisted reproductive technologies. Fertil Steril. 2011;95:147–51.
Sagi-Dain L, Sagi S, Dirnfeld M. Effect of paternal age on reproductive outcomes in oocyte donation model: a systematic review. Fertil Steril. 2015;104:857-865.e1.
Murugesu S, Kasaven LS, Petrie A, Vaseekaran A, Jones BP, Bracewell-Milnes T, et al. Does advanced paternal age affect outcomes following assisted reproductive technology? A systematic review and meta-analysis. Reprod Biomed Online. 2022;45:283–331.
Hanson BM, Kaser DJ, Franasiak JM. Male infertility and the future of in vitro fertilization. Urol Clin North Am. 2020;47:257–70.
Hanson BM, Kim JG, Osman EK, Tiegs AW, Lathi RB, Cheng PJ, et al. Impact of paternal age on embryology and pregnancy outcomes in the setting of a euploid single-embryo transfer with ejaculated sperm: retrospective cohort study. F S Rep. 2020;1:99–105.
Luna M, Finkler E, Barritt J, Bar-Chama N, Sandler B, Copperman AB, et al. Paternal age and assisted reproductive technology outcome in ovum recipients. Fertil Steril. 2009;92:1772–5.
Vogiatzi P, Pouliakis A, Sakellariou M, Athanasiou A, Athanasiou A, Colaghis A, et al. Male age and progressive sperm motility are critical factors affecting embryological and clinical outcomes in oocyte donor ICSI cycles. Reprod Sci. 2022;29:883–95.
Schmid TE, Grant PG, Marchetti F, Weldon RH, Eskenazi B, Wyrobek AJ. Elemental composition of human semen is associated with motility and genomic sperm defects among older men. Hum Reprod. 2013;28:274–82.
Wyrobek AJ, Eskenazi B, Young S, Arnheim N, Tiemann-Boege I, Jabs EW, et al. Advancing age has differential effects on DNA damage, chromatin integrity, gene mutations, and aneuploidies in sperm. Proc Natl Acad Sci U S A. 2006;103:9601–6.
Humm KC, Sakkas D. Role of increased male age in IVF and egg donation: is sperm DNA fragmentation responsible? Fertil Steril. 2013;99:30–6.
Nago M, Arichi A, Omura N, Iwashita Y, Kawamura T, Yumura Y. Aging increases oxidative stress in semen. Investig Clin Urol. 2021;62:233–8.
Van Opstal J, Fieuws S, Spiessens C, Soubry A. Male age interferes with embryo growth in IVF treatment. Hum Reprod. 2021;36:107–15.
Dviri M, Madjunkova S, Koziarz A, Madjunkov M, Mashiach J, Nekolaichuk E, et al. Is there an association between paternal age and aneuploidy? Evidence from young donor oocyte-derived embryos: a systematic review and individual patient data meta-analysis. Hum Reprod Update. 2021;27:486–500.
Newman H, Catt S, Vining B, Vollenhoven B, Horta F. DNA repair and response to sperm DNA damage in oocytes and embryos, and the potential consequences in ART: a systematic review. Mol Hum Reprod. 2022;28:gaab071.
Farhi J, Cohen K, Mizrachi Y, Weissman A, Raziel A, Orvieto R. Should ICSI be implemented during IVF to all advanced-age patients with non-male factor subfertility? Reprod Biol Endocrinol. 2019;17:30.
Salas-Huetos A, James ER, Broberg DS, Aston KI, Carrell DT, Jenkins TG. The combined effect of obesity and aging on human sperm DNA methylation signatures: inclusion of BMI in the paternal germ line age prediction model. Sci Rep. 2020;10:15409.
Shen X, Xie Y, Chen D, Guo W, Feng G, Jiang W, et al. Effect of female and male body mass index on cumulative live birth rates in the freeze-all strategy. J Clin Endocrinol Metab. 2021;dgab858.
Pennings G, Couture V, Ombelet W. Social sperm freezing. Hum Reprod. 2021;36:833–9.
Halvaei I, Litzky J, Esfandiari N. Advanced paternal age: effects on sperm parameters, assisted reproduction outcomes and offspring health. Reprod Biol Endocrinol. 2020;18:110. https://doi.org/10.1186/s12958-020-00668-y.
Sharma R, Agarwal A, Rohra VK, Assidi M, Abu-Elmagd M, Turki RF. Effects of increased paternal age on sperm quality, reproductive outcome and associated epigenetic risks to offspring. Reprod Biol Endocrinol. 2015;13:35.
Acknowledgements
We thank the Interuniversity Library of Medicine (BIUM) of Paris for methodological support. We thank Dr. John Frattarelli, Dr. Hakan Duran, and Dr. Amanda Setti for providing us with detailed data on LBR according to paternal age for their studies. We thank Pr. Brian Whitcomb and Dr. Richard Paulson for answering our queries regarding their studies.
Funding
This work was sponsored by an unrestricted grant from Gedeon Richter France. The sponsor participated in the supervision and revision of the manuscript.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests..
Additional information
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Supplementary Fig. 1
Risk of bias assessment for the included studies (PNG 16 kb)
Supplementary Fig. 2
Primary outcome after meta-analysis and exclusion of the outlier study (PNG 83 kb)
Supplementary Fig. 3
(a) Line chart of a secondary outcome (CPR) for each study available, using raw data, (b) Linear and nonlinear models of a secondary outcome (CPR) after meta-analysis (PNG 156 kb)
Supplementary Fig. 4
Line chart of a secondary outcome (early pregnancy loss) for each study available, using raw data (PNG 115 kb)
ESM 1
(DOCX 15 kb)
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Begon, E., Lefebvre, T., Arbo, E. et al. Does paternal age affect the live birth rate in donor oocyte cycles? A systematic review and meta-analysis. J Assist Reprod Genet 40, 617–626 (2023). https://doi.org/10.1007/s10815-023-02714-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10815-023-02714-1