Controversy and Consensus on the Management of Elevated Sperm DNA Fragmentation in Male Infertility: A Global Survey, Current Guidelines, and Expert Recommendations

Abstract

Purpose: Sperm DNA fragmentation (SDF) has been associated with male infertility and poor outcomes of assisted reproductive technology (ART). The purpose of this study was to investigate global practices related to the management of elevated SDF in infertile men, summarize the relevant professional society recommendations, and provide expert recommendations for managing this condition.

Materials and methods: An online global survey on clinical practices related to SDF was disseminated to reproductive clinicians, according to the CHERRIES checklist criteria. Management protocols for various conditions associated with SDF were captured and compared to the relevant recommendations in professional society guidelines and the appropriate available evidence. Expert recommendations and consensus on the management of infertile men with elevated SDF were then formulated and adapted using the Delphi method.

Results: A total of 436 experts from 55 different countries submitted responses. As an initial approach, 79.1% of reproductive experts recommend lifestyle modifications for infertile men with elevated SDF, and 76.9% prescribe empiric antioxidants. Regarding antioxidant duration, 39.3% recommend 4-6 months and 38.1% recommend 3 months. For men with unexplained or idiopathic infertility, and couples experiencing recurrent miscarriages associated with elevated SDF, most respondents refer to ART 6 months after failure of conservative and empiric medical management. Infertile men with clinical varicocele, normal conventional semen parameters, and elevated SDF are offered varicocele repair immediately after diagnosis by 31.4%, and after failure of antioxidants and conservative measures by 40.9%. Sperm selection techniques and testicular sperm extraction are also management options for couples undergoing ART. For most questions, heterogenous practices were demonstrated.

Conclusions: This paper presents the results of a large global survey on the management of infertile men with elevated SDF and reveals a lack of consensus among clinicians. Furthermore, it demonstrates the scarcity of professional society guidelines in this regard and attempts to highlight the relevant evidence. Expert recommendations are proposed to help guide clinicians.

Keywords: DNA fragmentation; Delphi method; Disease management; Male infertility; Practice guideline; 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. General approach to managing elevated SDF in infertile men. 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=402). ART: assisted reproductive technology, ICSI: intracytoplasmic sperm injection, SDF: sperm DNA fragmentation.

Fig. 3. Ordering a repeat SDF test as confirmation for elevated SDF, with results stratified according to the cost of SDF testing. The majority do not order a confirmation test regardless of the cost of testing, as there is no significant difference when responses were compared between costs less than $100 and more than $100 (p=0.2). SDF: sperm DNA fragmentation.

Fig. 4. Duration of abstinence recommended by respondents as a means to lower SDF. ART: assisted reproductive technology, SDF: sperm DNA fragmentation.

Fig. 5. ART referral for men with unexplained infertility and elevated SDF. ART: assisted reproductive technology, SDF: sperm DNA fragmentation, UMI: unexplained male infertility.

Fig. 6. ART referral for men with idiopathic infertility and elevated SDF. ART: assisted reproductive technology, IMI: idiopathic male infertility, SDF: sperm DNA fragmentation.

Fig. 7. Management approach for those who have elevated SDF and are experiencing recurrent pregnancy loss after spontaneous conception. 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=402). ART: assisted reproductive technology, ICSI: intracytoplasmic sperm injection, RPL: recurrent pregnancy loss, SDF: sperm DNA fragmentation.

Fig. 8. ART referral for recurrent pregnancy loss and men with elevated SDF. ART: assisted reproductive technology, RPL: recurrent pregnancy loss, SDF: sperm DNA fragmentation.

Fig. 9. Management approach for infertile men who have a clinical varicocele, normal conventional semen parameters, and elevated SDF. 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=401). ART: assisted reproductive technology, SDF: sperm DNA fragmentation.

Fig. 10. Varicocele repair for infertile men who have a clinical varicocele, normal conventional semen parameters and elevated SDF. ART: assisted reproductive technology, SDF: sperm DNA fragmentation.

Fig. 11. ART referral for infertile men who have a clinical varicocele, normal conventional semen parameters, and elevated SDF. ART: assisted reproductive technology, SDF: sperm DNA fragmentation.

Fig. 12. Varicocele repair for infertile men who have subclinical varicocele and elevated SDF. ART: assisted reproductive technology, SDF: sperm DNA fragmentation.

Fig. 13. Prescribing antioxidants for infertile men with elevated SDF. SDF: sperm DNA fragmentation.

Fig. 14. Conditions associated with elevated SDF in infertile men, for which antioxidants are prescribed. 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=401). ART: assisted reproductive technology, IMI: idiopathic male infertility, RPL: recurrent pregnancy loss, SDF: sperm DNA fragmentation, UMI: unexplained male infertility.

Fig. 15. Recommended duration of treatment with antioxidants for infertile men with elevated SDF. SDF: sperm DNA fragmentation.

Fig. 16. Follow-up on the success of antioxidant therapy in the management of infertile men with elevated SDF. SDF: sperm DNA fragmentation.

Fig. 17. Prescribing hormones for infertile men with elevated SDF. SDF: sperm DNA fragmentation.

Fig. 18. Recommended duration of treatment with hormones for infertile men with elevated SDF. SDF: sperm DNA fragmentation.

Fig. 19. Approach to miscarriage after IVF or ICSI and elevated SDF in the male partner. ICSI: intracytoplasmic sperm injection, IVF: in vitro fertilization, SDF: sperm DNA fragmentation.

Fig. 20. Recommending sperm selection techniques for infertile men with elevated SDF. SDF: sperm DNA fragmentation.

Fig. 21. Sperm selection techniques recommended by the 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=401). SDF: sperm DNA fragmentation.

Fig. 22. Recommending testicular for infertile men with elevated SDF undergoing ICSI. ICSI: intracytoplasmic sperm injection, SDF: sperm DNA fragmentation.

Fig. 23. Responses to when experts would recommend testicular sperm if they do for infertile men with elevated SDF. ICSI: intracytoplasmic sperm injection, SDF: sperm DNA fragmentation.

Fig. 24. Reasons for recommending against the use of testicular sperm for infertile men with elevated SDF. Respondents were allowed to select more than one answer. The percentage for each answer is calculated by dividing the number of respondents who have selected it by the total number of respondents who have answered this question (n=341). SDF: sperm DNA fragmentation.

Fig. 25. Treatment strategies for infertile men with elevated SDF. ICSI: intracytoplasmic sperm injection, SDF: sperm DNA fragmentation.