Sperm aneuploidy and DNA fragmentation in unexplained recurrent pregnancy loss: a multicenter case-control study

Abstract

BackgroundRecurrent pregnancy loss (RPL) is defined as the loss of at least three pregnancies in the first trimester. Although the most common cause is embryo aneuploidy, and despite female checkup and couple karyotyping, in about 50% of cases RPL remain unexplained. Male implication has little been investigated and results are discordant. In this context, we conducted a multi-center prospective case-control study to investigate male gamete implication in unexplained RPL.MethodsA total of 33 cases and 27 controls were included from three university hospitals. We investigated environmental and family factors with a detailed questionnaire and andrological examination, sperm characteristics, sperm DNA/chromatin status using the sperm chromatin structure assay (SCSA) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and sperm aneuploidy using fluorescence in situ hybridization (FISH). The Mann-Whitney test and the Wilcoxon or Fisher exact tests were used. A non-parametric Spearman correlation was performed in order to analyze the relationship between various sperm parameters and FISH and sperm DNA fragmentation results.ResultsWe found significant differences between cases and controls in time to conceive, body mass index (BMI), family history of infertility and living environment. In cases, total sperm motility and the percentage of morphologically normal spermatozoa were significantly decreased. No difference was found between cases and controls in sperm DNA fragmentation or chromatin integrity. In cases, spermatozoa with aneuploidy, hyperhaploidy and chromosome 18 disomy were significantly increased.ConclusionsThis prospective case-control study is one of the largest to examine environmental factors, sperm characteristics, sperm DNA fragmentation and chromatin, and chromosome anomalies in spermatozoa in relation to unexplained recurrent pregnancy loss. The originality of our study lies in the comprehensive andrological examination and search for risk factors and fertility history. Further studies are needed to confirm the links between unexplained RPL and a male family history of infertility or miscarriages. The increased sperm aneuploidy observed in unexplained RPL supports a male etiology. These data pave the way for further studies to demonstrate the value of preimplantation genetic screening in men with increased sperm aneuploidy whose partners experience unexplained RPL.

Meiotic nondisjunction and sperm aneuploidy in humans

“…In recent years, the paternal contribution to RPL and RIF beyond semen parameters and karyotyping is being increasingly examined. Multiple studies suggest that increased levels of sperm aneuploidy may be a significant contributory factor in RPL and/or RIF (Rubio et al 2001, Carrell et al 2003, Bernardini et al 2004, Collodel et al 2009, Rubio et al 2009, Neusser et al 2015, Ramasamy et al 2015, Zidi-Jrah et al 2016, Esquerre-Lamare et al 2018. These studies have reported a two-to seven-fold increase in sperm aneuploidy for the investigated chromosomes in these patients (Fig.…”

“…These studies have reported a two-to seven-fold increase in sperm aneuploidy for the investigated chromosomes in these patients (Fig. 3) (Collodel et al 2009, Kohn et al 2016, Zidi-Jrah et al 2016, Esquerre-Lamare et al 2018. The majority of the aforementioned studies have focused on males with reduced semen parameters; however, a large study reported that up to 40% of male partners of RPL with normal semen parameters also had significantly increased sperm aneuploidy levels (Ramasamy et al 2015).…”

Effects of the normal sperm morphology rate on the clinical and neonatal outcomes of conventional IVF cycles

“…The rates of abnormal sperm morphology and sperm DNA fragmentation have been reported to be significantly increased in patients with repeated abortions compared with those of fertile men without ART treatments (Esquerré‐Lamare et al, 2018; Kamkar, Ramezanali, & Sabbaghian, 2018; Zidi‐Jrah et al, 2016). A meta‐analysis review showed that the NSMR was decreased among men with unexplained repeated abortions compared with the control group (Cao et al, 2017).…”

Male Infertility is a Women’s Health Issue—Research and Clinical Evaluation of Male Infertility Is Needed

“…For example, some studies report that up to 40% of men from couples with recurrent pregnancy loss had normal sperm density and motility, but had sperm aneuploidy [17]. While the role and degree of sperm DNA defects are controversial [18], there are examples where, even with normal semen analysis, men can have sperm with abnormal components.…”