Controversy and Consensus on Indications for Sperm DNA Fragmentation Testing in Male Infertility: A Global Survey, Current Guidelines, and Expert Recommendations

Abstract

Purpose: Sperm DNA fragmentation (SDF) testing was recently added to the sixth edition of the World Health Organization laboratory manual for the examination and processing of human semen. Many conditions and risk factors have been associated with elevated SDF; therefore, it is important to identify the population of infertile men who might benefit from this test. The purpose of this study was to investigate global practices related to indications for SDF testing, compare the relevant professional society guideline recommendations, and provide expert recommendations.

Materials and methods: Clinicians managing male infertility were invited to take part in a global online survey on SDF clinical practices. This was conducted following the CHERRIES checklist criteria. The responses were compared to professional society guideline recommendations related to SDF and the appropriate available evidence. Expert recommendations on indications for SDF testing were then formulated, and the Delphi method was used to reach consensus.

Results: The survey was completed by 436 experts from 55 countries. Almost 75% of respondents test for SDF in all or some men with unexplained or idiopathic infertility, 39% order it routinely in the work-up of recurrent pregnancy loss (RPL), and 62.2% investigate SDF in smokers. While 47% of reproductive urologists test SDF to support the decision for varicocele repair surgery when conventional semen parameters are normal, significantly fewer general urologists (23%; p=0.008) do the same. Nearly 70% would assess SDF before assisted reproductive technologies (ART), either always or for certain conditions. Recurrent ART failure is a common indication for SDF testing. Very few society recommendations were found regarding SDF testing.

Conclusions: This article presents the largest global survey on the indications for SDF testing in infertile men, and demonstrates diverse practices. Furthermore, it highlights the paucity of professional society guideline recommendations. Expert recommendations are proposed to help guide clinicians.

Keywords: DNA fragmentation; Delphi method; Male infertility; Practice guidelines; Sperm; Survey.

Fig. 1. Complete survey methodology. The complete survey consisted of 64 questions on SDF clinical practices divided into five sections: demographics, indications for SDF testing, technical aspects of SDF testing, management of elevated SDF, and barriers in incorporating SDF into clinical practice. A total of 18 recommendations were made as follows: seven for indications for SDF testing, ten for management of infertile men with elevated SDF, and one for technical aspects of SDF testing. Passing criteria for the Delphi method was set at >80% scoring the recommendation ≥7 in agreement. GAF: Global Andrology Forum, SDF: sperm DNA fragmentation.

Fig. 2. Geographical distribution of respondents. The number of respondents is shown in brackets after the name of each country. The purple color indicates the country with the greatest number of respondents (Italy; n=57), the blue color indicates the countries with the second and third highest responses (n=40 or above), the pink color indicates countries with responses between 20 and 30, the orange color represents those countries with 5–19 responses, while the yellow color indicates countries with less than 5 respondents.

Fig. 3. Specialties of the survey respondents. ART: assisted reproductive technologies.

Fig. 4. Cost of sperm DNA fragmentation (SDF) testing.

Fig. 5. Sperm DNA fragmentation (SDF) testing in couples with unexplained infertility.

Fig. 6. Timing of sperm DNA fragmentation (SDF) testing in unexplained male infertility (UMI). Respondents were allowed to select more than one answer. The percentage for each answer was calculated by dividing the number of respondents who had selected it by the total number of respondents who had answered this question (n=436). ART: assisted reproductive technologies.

Fig. 7. Sperm DNA fragmentation (SDF) testing in idiopathic male infertility (IMI).

Fig. 8. Timing of sperm DNA fragmentation (SDF) testing in idiopathic male infertility (IMI). Respondents were allowed to select more than one answer. The percentage for each answer was calculated by dividing the number of respondents who had selected it by the total number of respondents who had answered this question (n=435). ART: assisted reproductive technologies.

Fig. 9. Sperm DNA fragmentation (SDF) testing after recurrent pregnancy loss (RPL). Respondents were allowed to select more than one answer. The percentage for each answer was calculated by dividing the number of respondents who had selected it by the total number of respondents who had answered this question (n=436). ART: assisted reproductive technologies.

Fig. 10. Sperm DNA fragmentation (SDF) testing in men with risk factors and exposures. Respondents were allowed to select more than one answer. The percentage for each answer was calculated by dividing the number of respondents who had selected it by the total number of respondents who had answered this question (n=436). BMI: body mass index.

Fig. 11. Ordering sperm DNA fragmentation (SDF) testing for infertile men with clinical varicocele and normal conventional semen parameters. Respondents were allowed to select more than one answer. The percentage for each answer was calculated by dividing the number of respondents who had selected it by the total number of respondents who had answered this question (n=434). ART: assisted reproductive technologies.

Fig. 12. Ordering sperm DNA fragmentation (SDF) testing for infertile men with clinical varicocele and normal conventional semen parameters. ART: assisted reproductive technologies.

Fig. 13. Ordering sperm DNA fragmentation (SDF) testing for infertile men with clinical varicocele and normal conventional semen parameters, with responses stratified according to the level of training among urologists. Fellowship-trained reproductive urologists tend to order more SDF testing in this population of men to justify varicocele surgery compared to general urologists who are more inclined to refuse SDF testing. The differences between the practices of both groups are significant (p=0.008). ART: assisted reproductive technologies.

Fig. 14. Ordering sperm DNA fragmentation (SDF) testing for infertile men with subclinical varicocele and abnormal conventional semen parameters. ART: assisted reproductive technologies.

Fig. 15. Ordering sperm DNA fragmentation (SDF) testing for infertile men with subclinical varicocele and normal conventional semen parameters. ART: assisted reproductive technologies.

Fig. 16. Sperm DNA fragmentation (SDF) testing for infertile men before assisted reproductive technologies (ART).

Fig. 17. Conditions before ART for which sperm DNA fragmentation (SDF) testing is ordered by respondents. Respondents were allowed to select more than one answer. The percentage for each answer was calculated by dividing the number of respondents who had selected it by the total number of respondents who had answered this question (n=434). ART: assisted reproductive technologies, IMI: idiopathic male infertility, UMI: unexplained male infertility.

Fig. 18. Sperm DNA fragmentation (SDF) testing before sperm cryopreservation.

Fig. 19. Approach if elevated sperm DNA fragmentation (SDF) is found prior to cryopreservation. Respondents were allowed to select more than one answer. The percentage for each answer was calculated by dividing the number of respondents who had selected it by the total number of respondents who had answered this question (n=428). ICSI: intracytoplasmic sperm injection.

Fig. 20. Indications for sperm DNA fragmentation testing.