Novel use of COMET parameters of sperm DNA damage may increase its utility to diagnose male infertility and predict live births following both IVF and ICSI

Abstract

STUDY QUESTION Do the Comet parameters of the proportions of sperm with low or high DNA damage improve the power of the test in the diagnosis of male infertility and/or prediction of IVF and ICSI live birth rates? SUMMARY ANSWER The mean Comet score and the scores for proportions of sperm with high or low DNA damage were useful in diagnosing male infertility and provided additional discriminatory information for the prediction of both IVF and ICSI live births. WHAT IS KNOWN ALREADY Sperm DNA damage impacts adversely on male fertility and IVF outcomes. STUDY DESIGN, SIZE, DURATION A retrospective study was performed involving a total of 457 participants (381 patients and 76 fertile donors). Data was collected from a fertility clinic between 2015 and 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS A total of 381 consecutive male partners of couples attending for ART and 76 fertile donors were included in the study. DNA fragmentation was measured by the alkaline Comet assay. Receiver operator characteristic curve analysis (area under the ROC curve (AUC)) was used to determine the value of average Comet score (ACS), low Comet score (LCS) and high Comet score (HCS) to diagnose male factor infertility. In total, 77 IVF and 226 ICSI cycles were included to determine thresholds for each parameter (AUC analysis) and to compare live birth rates (LBRs) following each ART. MAIN RESULTS AND THE ROLE OF CHANCE ACS, HCS and LCS were predictive of male infertility (AUC > 0.9, P < 0.0001). IVF LBRs declined once DNA damage exceeded the threshold levels. HCS showed the sharpest decline. Following ICSI, the highest LBRs were in men whose DNA damage levels approached the fertile range. Trends differed in IVF. LBRs decreased as damage increased whereas in ICSI the LBRs decreased but then remained stable. LIMITATIONS, REASONS FOR CAUTION Since this is the first study to show the impact of sperm DNA damage on ICSI live births, a prospective study should be performed (stratifying patients to IVF or ICSI based on these thresholds) to validate this study. WIDER IMPLICATIONS OF THE FINDINGS Our study presents novel information towards elucidating the genetic basis of male infertility and secondly on relevance of the extent of DNA damage as an impending factor in both IVF and ICSI success. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by Examenlab Ltd, The Lister Clinic, Cryos International and Imperial College London NHS Trust. No external funding was obtained for this study. SL and KL are employees of Examenlab Ltd, a university spin-out company with a commercial interest in sperm DNA damage. No other author has a conflict of interest to declare. TRIAL REGISTRATION NUMBER Non-applicable.

Normal sperm parameters per se do not reliably account for fertility: A case–control study in the real‐life setting

“…tT (Simoni et al, 2019). For instance, sperm DNA damage is more common in infertile than fertile men and it is also associated with impaired embryo development, miscarriage and recurrent pregnancy losses (Nicopoullos et al, 2019;Simoni et al, 2019). In this study, we showed that SDF index increased along with the increased number of sperm abnormalities in infertile men, with the highest values observed in men with 2-3 sperm abnormalities.…”

European Association of Urology Guidelines Panel on Male Sexual and Reproductive Health: A Clinical Consultation Guide on the Indications for Performing Sperm DNA Fragmentation Testing in Men with Infertility and Testicular Sperm Extraction in Nonazoospermic Men

“…Indeed, a recent study analysing the discriminatory value of COMET scores in ART outcomes observed that this test could be used in conjunction with female age to predict those who would benefit from ICSI rather than IVF [9]. This highlights a further clinical utility for SDF testing, and further prospective trials are needed to validate this indication.…”

“…This highlights a further clinical utility for SDF testing, and further prospective trials are needed to validate this indication. Furthermore, there is sufficient evidence to support SDF testing in couples who have failed ARTs, as it can be used to counsel the couple regarding the chances of future successful ART cycles or the use of donor sperm [9].…”

“…Within this context, the contribution of sperm DNA fragmentation (SDF) to male infertility has emerged. SDF has been advocated as a novel biomarker in the diagnostic work-up of male infertility and for stratifying success rates in patients undergoing ARTs [9].…”

When to pull the trigger in nonazoospermic infertile men undergoing intracytoplasmic sperm injection?

“…In fact, it has been suggested that this novel way of assessing sperm DNA damage might be the ideal method to identify men at risk of poor reproductive outcomes in ICSI. 13 Thus, the inclusion of approximately 30% of men with arguably high SDF values (SDF values between 15% and 30%) in the study by Alharbi et al . 8 might have diluted the positive effect of ICSI using testicular sperm (Testi-ICSI).…”