Effect of paternal age on outcomes in ART cycles: A systematic review and meta-analysis

Abstract Objective To investigate whether paternal age exerts an independent effect on the clinical outcomes of ART cycles. Evidence Review Observational studies were identified through a systematic search of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and NHS evidence. Data for women aged 39 years or under were extracted and analyzed. We included all studies, both autologous and donor oocyte, into separate analyses of the effect of paternal age on ART outcome. We excluded studies in azoospermic men, women aged 40 years and above, ART including preimplantation genetic testing (PGT) and studies involving donor sperm. The included studies scored well on the Newcastle-Ottawa Quality Assessment Scale for observational studies. The primary outcome was livebirth rate (LBR) and secondary outcome measures were clinical pregnancy rate (CPR) and miscarriage rate (MR). When pooling data, the random-effects model was used to counter the effect of heterogeneity in the studies. Result(s) Live birth rate was reported in three autologous oocyte studies (2926 cycles) and five donor oocyte studies (7648 cycles). Live birth rate was found to be significantly increased when male age was under 40 years in autologous oocyte studies (OR 2.37, [1.15 – 4.85]; p = 0.02) but no difference in live birth rate was found in donor oocyte studies (OR1.03, [0.80 – 1.32]; p = 0.84). Clinical pregnancy rates were found to be statistically higher when the paternal age was under 40 years in autologous oocyte studies (OR 1.68, [1.24 – 2.28]; p = 0.0009) however there was no difference in clinical pregnancy in the same age category when donor oocyte studies were analyzed (OR 0.95, [0.84 – 1.07]; p = 0.41). Miscarriage rate was reported in two autologous oocyte studies (970 cycles) and four donor oocyte studies (3741 cycles). Miscarriage was found to be more likely with male age over 40 years in autologous studies (OR 1.77, [1.30 – 2.40]; p = 0.0003). In donor oocyte studies, the miscarriage rate was not increased when male age was above 50 years (OR 1.41, [0.96 – 2.08]; p value = 0.08). All of the autologous oocyte studies reported a statically significant association between male age and female age. Conclusion(s) The findings of this review and meta-analysis, based on the donor oocyte model, suggests that advanced paternal age does not exert an independent effect on the outcome of ART cycles. Miscarriage rates do not appear to be increased even for men over the age of 50 following treatment with donor oocytes. The meta-analysis of autologous oocyte studies suggests that increasing male age may have a deleterious effect on the outcome of ART, however this may be confounded by the strong association with increasing maternal age.