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Sperm DNA fragmentation (SDF) is a molecular marker of sperm chromatin health. Elevated SDF is associated with male infertility, recurrent pregnancy loss, and failure of assisted reproductive technologies (ART). In 2021, the sixth edition of the World Health Organization (WHO) Manual for the Laboratory Examination and Processing of Human Semen has listed SDF as an extended test of semen that can be ordered under certain circumstances. However, the manual neither explained the indications for testing nor provided clear guidance on diagnostic thresholds. This article summarizes the current body of knowledge regarding clinical applications of SDF, including the appropriate population to test, methods of testing, and management strategies. Several etiologic factors and pathophysiologic mechanisms for SDF have been described including poor lifestyle habits, noxious exposures, and varicocele. Four SDF assays are included in the WHO manual and may be utilized based on resources and expertise. Strategies to lower SDF levels in infertile men include addressing underlying causes, supplementation with antioxidants, shorter abstinence periods, and use of testicular sperm for intracytoplasmic sperm injection. SDF testing can be implemented in the evaluation of infertile men and couples experiencing ART failure and appropriate management strategies can be offered to improve reproductive outcomes. There is vast potential for future research regarding the clinical utility of SDF in the evaluation and treatment of infertile couples.

Sperm DNA fragmentation in male infertility: From bench to bedside