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Advanced Paternal Age Does Not Affect Embryo Aneuploidy Following Blastocyst Biopsy in Egg Donor Cycles

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Advanced Paternal Age Does Not Affect Embryo Aneuploidy Following Blastocyst Biopsy in Egg Donor Cycles Journal of Assisted Reproduction and Genetics (2019) 36:2039–2045 https://doi.org/10.1007/s10815-019-01549-z ASSISTED REPRODUCTION TECHNOLOGIES Advanced paternal age does not affect embryo aneuploidy following blastocyst biopsy in egg donor cycles Robert J. Carrasquillo1,2 & Taylor P. Kohn3 & Cengiz Cinnioglu4 & Carmen Rubio2 & Carlos Simon2 & Ranjith Ramasamy5 & Nasser Al-Asmar2 Received: 28 January 2019 /Accepted: 26 July 2019 /Published online: 5 August 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019 Abstract Purpose To study the impact of advanced paternal age on embryo aneuploidy. Methods This is a multicenter international retrospective case series of couples undergoing assisted reproduction via in vitro fertilization using donor eggs to control for maternal factors and preimplantation genetic testing for aneuploidy via next- generation sequencing at Igenomix reproductive testing centers. The main outcome measure was the prevalence of embryo aneuploidy in egg donor cycles. Semen analysis data was retrieved for a small subset of the male patients. Results Data from 1202 IVF/ICSI egg donor cycles using ejaculated sperm (total 6934 embryos) evaluated using PGT-A between January 2016 and April 2018 in a global population across all Igenomix centers were included. No significant associ- ation was identified between advancing paternal age and the prevalence of embryo aneuploidy overall and when analyzing for each chromosome. There was also no significant association between advancing paternal age and specific aneuploid conditions (monosomy, trisomy, partial deletion/duplication) for all chromosomes in the genome. Conclusions This is the largest study of its kind in an international patient population to evaluate the impact of advancing paternal age on embryo aneuploidy. We conclude there is no specific effect of paternal age on the prevalence of embryo aneuploidy in the context of embryo biopsies from egg donor cycles. Keywords Advanced paternal age . Advanced maternal age . Aneuploidy . In vitro fertilization . Egg donor Introduction potential, reproductive success, and the health of offspring. This is of particular relevance as the age at which men and In recent years, there has been growing interest in the study of women choose to start families has become increasingly later advanced paternal age (APA) and its impact on male fertility than their parents due to a variety of sociocultural factors including increasing life expectancy, changing roles for wom- en, advanced age at time of marriage, and improving access to Electronic supplementary material The online version of this article assisted reproductive technologies (ART). Recent epidemio- (https://doi.org/10.1007/s10815-019-01549-z) contains supplementary material, which is available to authorized users. logic data in the USA published by Khandwala et al. demon- strated that the mean paternal age increased from 27.4 to * Robert J. Carrasquillo 30.9 years on a review of more than 168 million live births [email protected] between 1972 and 2016 [1]. While the impact of advanced maternal age on reproductive success is well understood, only 1 Division of Urology, Beth Israel Deaconess Medical Center, 145 more recently has the consequence of advanced paternal age Rosemary Street, C-1, Needham, MA 02494, USA become more tangible. McPherson et al. published retrospec- 2 Igenomix, Valencia, Spain tive data in 2018 on 4057 in vitro fertilization (IVF) cycles confirming that there is an additive negative effect of ad- 3 Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA vanced age in both parents on pregnancy and live birth rate [2]. With regard to male reproductive health specifically, ad- 4 Igenomix USA, Los Angeles, CA, USA vanced age has demonstrated negative consequences for tes- 5 Department of Urology, University of Miami Health System, ticular function [3], the male reproductive endocrine axis [4], Miami, FL, USA 2040 J Assist Reprod Genet (2019) 36:2039–2045 semen parameters [5–8], and the integrity of the sperm ge- shown to result in high implantation rates, high pregnancy nome and epigenome [9–12]. Associations between APA rates, and good obstetric outcomes [38–40]. We hypothesized and morbidity in offspring have been documented since the advancing paternal age would be associated with increased 1980s, including increased risk of fetal demise [13]; congen- embryo aneuploidy, and the aim of this study was to investi- ital anomalies [14]; single genetic disorders [15–19]; malig- gate the impact of advanced paternal age on the prevalence of nancies of the breast, central nervous system, and hematopoi- embryo aneuploidy in IVF cycles using egg donors as a con- etic system [20–22]; and neurocognitive disorders such as trol for maternal factors by means of preimplantation genetic autism, bipolar affective disorder, and schizophrenia [23–28]. testing for aneuploidy (PGT-A) and next-generation sequenc- Single-gene mutations appear to be the mode of disease ing (NGS). inheritance most strongly associated with APA with parent- offspring trio studies demonstrating an average de novo mu- tation rate of + 2 point mutations per year of advancing pater- Materials and methods nal age and a doubling of paternally inherited mutations every 16.5 years [29]; however, paternally linked aneuploid condi- This is a retrospective non-randomized study on data obtained tions have also been reported, but the evidence remains con- from sperm injection (ICSI) cycles with donated oocytes in troversial. Aneuploidy, a condition of abnormal chromosome conjunction with preimplantation genetic testing for aneuploi- number, is a result of non-disjunction during meiosis with dy (PGT-A) using next-generation sequencing (NGS) across trisomy being the most common class of aneuploidy. Studies Igenomix testing centers in Spain, USA (Florida, California, on human sperm, specifically, have shown that all chromo- and New York), Canada, Brazil, Mexico, India, and the United somes are susceptible to non-disjunction with chromosomes Arab Emirates between January 2016 and April 2018. This 21, 22, and the sex chromosomes having an increased fre- study received an Institutional Review Board waiver from the quency of aneuploidy [30]. While most embryo aneuploidies University of Miami Health System as all patient data was de- are a result of maternally inherited aberrations, with preva- identified. lence increasing from 30% in women in their early 30s to Semen analysis and semen collection, donor oocyte selection nearly 90% for women > 44 years of age [31], there is some and harvest, and intracytoplasmic sperm injection were per- data to suggest an age-related paternal contribution. For ex- formed at each respective referring IVF center according to indi- ample, there is a known paternal contribution to trisomy 21 vidual protocol. All donated oocytes were from females aged (Down syndrome) in 10% of cases and work by Zaragoza 35 years or younger with proven fertility or otherwise normal et al. reported an additive effect of APA on the increased physical and gynecologic examinations. Trophectoderm biopsy prevalence of trisomy 21 when maternal age is also advanced was performed at days 5/6 blastocyst and a standardized protocol >35years[32]. Conversely, others have found no association was employed for processing of biopsy specimens and transport between APA and the prevalence of trisomy 21 [33]. As most to Igenomix testing centers. At the time of biopsy, samples were autosomal aneuploidies are non-viable, sex chromosome an- successively washed in washing buffer and ultimately placed into euploidies are more commonly seen in live births. sterile 200-μl PCR tubes aliquoted with 2.5 μl of buffer prior to Approximately 55% of sex chromosome aneuploidies are of transport at room temperature. paternal origin, including 80% of Turner syndrome 45,X0, 6% The NGS platform used in the current study was IonChef™ of 47,XXX, 100% of 47,XYY, and 50% of Klinefelter syn- and S5 sequencer from ThermoFisher Scientific. Ion drome 47,XXY [34]. Despite the obvious importance of pa- Reproseq™ PGS Kit was used to lyse the samples, amplify ternal contribution to sex chromosome aneuploidy, there has DNA, and generate DNA fragment libraries. The template and been no demonstrated effect of APA on the prevalence of loading of the libraries was carried out automatically by the these conditions in offspring [33, 35, 36]. A study of 7549 IonChef™ equipment. We used Ion 520 and Ion 530 chips blastocysts during 2826 cycles with preimplantation genetic with capacity for 24 and 96 embryo samples, respectively. testing specifically examined the prevalence of 47,XXY kar- Once a run was sequenced, the quality parameters of the se- yotypes and found a significant association with advancing quencing were examined, and if quality measures were met, maternal age but not advancing paternal age. The authors con- they were used for the following analyses. Those samples that cluded that a meiotic missegregation specifically in oogenesis did not meet minimum quality values were discarded from the was implicated [37]. study. Once sequencing analysis was performed, raw data was To best approach the question of how paternal age affects transferred to Torrent Suite Software v5.4 and Ion Reporter the prevalence of aneuploidy, it is essential to control for ma- Software for translation of raw sequence data into the embryo ternal factors. Oocyte donation for use in IVF represents
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