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

Abstract

BACKGROUND Delayed parenthood, by both women and men, has become more common in developed countries. The adverse effect of advanced maternal age on embryo aneuploidy and reproductive outcomes is well known. However, whether there is an association between paternal age (PA) and embryonic chromosomal aberrations remains controversial. Oocyte donation (OD) is often utilized to minimize maternal age effects on oocyte and embryo aneuploidy, thus providing an optimal model to assess the effect of PA. Several studies have revealed a higher than expected rate of aneuploidy in embryos derived from young oocyte donors, which warrants examination as to whether this may be attributed to advanced PA (APA). OBJECTIVE AND RATIONALE The objective of this systematic review and individual patient data (IPD) meta-analysis is to evaluate existing evidence regarding an association between PA and chromosomal aberrations in an OD model. SEARCH METHODS This review was conducted according to PRISMA guidelines for systematic reviews and meta-analyses. Medline, Embase and Cochrane databases were searched from inception through March 2020 using the (MeSH) terms: chromosome aberrations, preimplantation genetic screening and IVF. Original research articles, reporting on the types and/or frequency of chromosomal aberrations in embryos derived from donor oocytes, including data regarding PA, were included. Studies reporting results of IVF cycles using only autologous oocytes were excluded. Quality appraisal of included studies was conducted independently by two reviewers using a modified Newcastle-Ottawa Assessment Scale. A one-stage IPD meta-analysis was performed to evaluate whether an association exists between PA and aneuploidy. Meta-analysis was performed using a generalized linear mixed model to account for clustering of embryos within patients and clustering of patients within studies. OUTCOMES The search identified 13 032 references, independently screened by 2 reviewers, yielding 6 studies encompassing a total of 2637 IVF-OD cycles (n = 20 024 embryos). Two ‘low’ quality studies using FISH to screen 12 chromosomes on Day 3 embryos (n = 649) reported higher total aneuploidy rates and specifically higher rates of trisomy 21, 18 and 13 in men ≥50 years. One ‘moderate’ and three ‘high’ quality studies, which used 24-chromosome screening, found no association between PA and aneuploidy in Day 5/6 embryos (n = 12 559). The IPD meta-analysis, which included three ‘high’ quality studies (n = 10 830 Day 5/6 embryos), found no significant effect of PA on the rate of aneuploidy (odds ratio (OR) 0.97 per decade of age, 95% CI 0.91–1.03), which was robust to sensitivity analyses. There was no association between PA and individual chromosome aneuploidy or segmental aberrations, including for chromosomes X and Y (OR 1.06 per decade of age, 95% CI 0.92–1.21). Monosomy was most frequent for chromosome 16 (217/10802, 2.01%, 95% CI 1.76–2.29%) and trisomy was also most frequent for chromosome 16 (194/10802, 1.80%, 95% CI 1.56–2.06%). WIDER IMPLICATIONS We conclude, based on the available evidence, that APA is not associated with higher rates of aneuploidy in embryos derived from OD. These results will help fertility practitioners when providing preconception counselling, particularly to older men who desire to have a child.

Blastocyst Morphology Based on Uniform Time-Point Assessments is Correlated With Mosaic Levels in Embryos

“…Notably, the present study showed that male factors, that is, male age and semen quality, were not significantly related to mosaic levels. These results are supported by the findings of a previous study that used young donor oocytes for analysis, which revealed that advanced paternal age was not associated with higher aneuploidy rates ( Dviri et al, 2021 ). Moreover, as per blastocysts obtained, sperm factors did not exert significant effects on the euploidy rate, although using poor-quality sperm for insemination appears to reduce fertilization and blastocyst formation rates ( Mazzilli et al, 2017 ).…”

Risk assessment of assisted reproductive technology and parental ages at childbirth for the development of uniparental disomy-mediated imprinting disorders caused by aneuploid gametes

“…Therefore, we suggest that advanced paternal age does not likely contribute to the development of sperm aneuploidy leading to UPDs. Consistent with this, previous systematic reviews focusing on embryos derived from young oocyte donors concluded that advanced paternal age was not associated with aneuploidy rates [18,19].…”

Risk assessment of assisted reproductive technology and parental age at childbirth for the development of uniparental disomy-mediated imprinting disorders caused by aneuploid gametes

“…Therefore, we suggest that advanced paternal age does not likely contribute to the development of sperm aneuploidy leading to UPDs. Consistent with this, previous systematic reviews focusing on embryos derived from young oocyte donors concluded that advanced paternal age was not associated with aneuploidy rates [ 20 , 21 ].…”

“… UPD, uniparental disomy; IDs, imprinting disorders; UPD-IDs, uniparental disomy-mediated imprinting disorders; Hetero, heterodisomy; Iso, isodisomy; UPD(6)mat, maternal uniparental disomy of chromosome 6; UPD(6)pat, paternal uniparental disomy of chromosome 6; UPD(7)mat, maternal uniparental disomy of chromosome 7; UPD(7)pat, paternal uniparental disomy of chromosome 7; UPD(14)mat, maternal uniparental disomy of chromosome 14; UPD(14)pat, paternal uniparental disomy of chromosome 14; UPD(15)mat, maternal uniparental disomy of chromosome 15; UPD(15)pat, paternal uniparental disomy of chromosome 15; UPD(20)mat, maternal uniparental disomy of chromosome 20; UPD(20)pat, paternal uniparental disomy of chromosome 20 a 9 out of 25 UPD(7)mat patients were reported by Fuke et al [ 20 ] b 17 out of 18 UPD(14)mat patients were reported by Kagami et al [ 22 ] c 19 out of 27 UPD(14)pat patients were reported by Kagami et al [ 21 ] d 27 out of 48 UPD(15)mat patients were reported by Matsubara et al [ 17 ] e 5 out of 6 UPD(20)mat patients were reported by Kawashima et al [ 23 ] …”