PATERNAL AGE

Aneuploidy in embryos found unaffected by increasing paternal age

Published 26 August 2020

A study testing aneuploidy in more than 3000 embryos derived from young egg donors and male partners whose ages extended beyond 50 years has failed to find any correlation between the prevalence of aneuploidy and paternal age.

The age of fathers to newborns, like that of mothers, continues to rise. In the USA the number of first births to women over 35 has risen by about 2% annually since the 1970s, while the percentage of births to fathers over 40 has doubled - to 9% over the same period. In the UK the average age of all fathers of babies born (in England and Wales) in 2017 was 33.4 years, up slightly from 2016 and continuing a small but steady annual rise.

Despite the dominant effect of female age on the chance of conception and healthy live birth, recent studies increasingly warn of the neonatal and infant risks associated with an ageing paternal population, with a stark reminder not to forget the father. A 2015 review on the ‘male biological clock’ concluded that advancing paternal age presents no barrier to conception but ‘the medical community must do a better job of communicating to couples the current understanding of the risks of conception’.(1) The danger, explained the review, lay in the chances of introducing genetic abnormalities associated with serious diseases or birth defects.

Now, raising further question marks over such warnings, a new study has failed to find any correlation between paternal age and the rate of aneuploidy in more than 3000 embryos derived from young egg donors.(2) In fact, while the consistently young age of the egg donors (all under 33 years) was intended as a control in the study design, the only independent effect of paternal age on euploidy rates was found with an older oocyte donor.

The 407 male partners were allocated to three age groups: group A, <39 years (n = 203); group B, 40–49 years (n = 161); and group C, >50 years (n = 43). The primary endpoints of the study were aneuploidy, euploidy, mosaicism, and blastocyst formation rates; and analysis (by next generation sequencing) first found no significant differences among the three paternal age groups in euploidy rates (69.2%, 70.6%, 71.4%, respectively), aneuploidy rates (14.7%, 12.8%, 13.9%) or mosaicism rates (16.1%, 16.6%, 13.6%) – nor in the blastocyst formation rate. Only an advanced paternal age over 50 was associated with a lower fertilisation rate and increased rate of segmental aberrations than found in the younger age groups – this latter effect speculatively attributed by the authors to an increasing incidence of sperm DNA fragmentation with age, which appear to affect paternal chromosomes more frequently.

The authors acknowledge that a few earlier studies have found contradictory results, but these, they write, were of small sample size and used FISH as their PGT-A technology. Otherwise, they add, results from similar studies seem consistent with theirs, citing a large multicentre study from Spain which, after analysing almost 7000 embryos from egg donation cycles, similarly found no specific effect of paternal age on the prevalence of aneuploidy.(3)

What seems in less doubt is the deterioration in sperm quality (and numbers) with advancing age. Sperm DNA fragmentation, for example, has been shown consistently to have adverse effects on fertilisation and embryo development, an age-related effect reportedly linked to increasing oxidative stress. While ICSI, in cases where such sperm abnormalities have been detected, has eliminated some of these reproductive risks, an older paternal age nevertheless remains strongly associated with adverse perinatal outcomes. An analysis of almost 19,000 IVF cycles performed in Boston between 2000 and 2014 found that, while the age of the female partner had as expected the greatest effect on live birth, cumulative live birth rate was also significantly affected by male partner age and was found to decline as the man grew older. Similarly, another widely reported US study analysing data from more than 40 million documented live births between 2007 and 2016 found that men aged 45 or older had a small but greater chance of fathering infants born premature, of low birth weight, and with a lower Apgar score than their younger counterparts.(4)

Such perinatal risks now appear little associated with an effect (if any) of paternal age on embryonic aneuploidy rates; however, the study did find that fertilisation rates declined with increasing paternal age (76% in the over 50s group and 80% below) – although the blastocyst formation rate remained comparable between all three groups. Moreover, the decline in sperm quality and quantity that accompanies male ageing is a consistent finding and explanation for the falling fertilisation potential found in IVF, donor insemination and IUI, a reason why many countries have now set a limit on the age of their sperm donors.

 

1. Ramasamy R, Chiba K, Butler P, Lamb DJ. Male biological clock: a critical analysis of advanced paternal age. Fertil Steril 2015; 103: 1402-1406.
2. Dviri M, Madjunkova S, Koziarz A, 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.
doi.org/10.1016/j.fertnstert.2020.03.034
3. Carrasquillo RJ, Kohn TP, Cinnioglu C, et al. Advanced paternal age does not affect embryo aneuploidy following blastocyst biopsy in egg donor cycles. J Assist Reprod Genet 2019; 36: 2039–2045. doi.org/10.1007/s10815-019-01549-z
4. Khandwala YS, Baker VL, Shaw GM, et al. Association of paternal age with perinatal outcomes between 2007 and 2016 in the United States: population based cohort study. BMJ 2018; 363: k4372

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