Warfarin Effects on Male Fertility After Cardiac Surgery

Condition(s) studied

Investigational drug(s) / intervention(s)

Semen analysis, sperm DNA fragmentation and hormonal evaluation: Participants undergo standardized study assessments including semen analysis according to WHO criteria, sperm DNA fragmentation assessment, hormonal blood tests, andrological ultrasound, and exploratory molecular analyses of spermatozoa (mitochondrial function, oxidative stress markers, inflammatory mediators, and protein expression). All assessments are performed for observational and research purposes only and do not guide or modify clinical treatment.

Study summary

Young male patients undergoing cardiac surgery may require oral anticoagulation with warfarin either lifelong, such as after mechanical valve replacement, or for a limited postoperative period, for example following valve repair or bioprosthetic valve implantation. Although the teratogenic effects of warfarin during pregnancy are well established, prospective clinical data on the potential impact of warfarin therapy on male reproductive health are scarce. This gap is particularly relevant for patients of reproductive age who may have a present or future desire for fatherhood.

Warfarin acts as a vitamin K antagonist by inhibiting the vitamin K epoxide reductase complex, thereby reducing the availability of functional vitamin K. Beyond its role in coagulation, vitamin K is increasingly recognized as an important regulator of spermatogenesis, mitochondrial function, oxidative balance, and steroid hormone synthesis. Experimental and translational evidence suggests that disruption of vitamin K-dependent pathways may impair sperm quality, DNA integrity, mitochondrial bioenergetics, and reproductive hormone homeostasis. In addition, warfarin exposure has been associated with increased oxidative stress and inflammatory responses, both of which are known contributors to male infertility.

Despite these biologically plausible mechanisms, no prospective observational studies have systematically evaluated semen parameters, sperm DNA fragmentation, hormonal profiles, inflammatory markers, and advanced molecular sperm alterations in men exposed to warfarin after cardiac surgery. Consequently, structured andrological assessment is rarely incorporated into routine preoperative counseling or postoperative follow-up in this population.

This prospective pilot observational study aims to investigate the association between warfarin therapy and male reproductive health in patients undergoing elective cardiac surgery. Male patients aged 18 to 50 years will be enrolled and observed in three cohorts based on clinical indication for anticoagulation: (1) long-term warfarin therapy following mechanical valve replacement; (2) short-term warfarin therapy (approximately three months) after selected cardiac procedures; and (3) a control cohort undergoing cardiac surgery without an indication for long-term oral anticoagulation beyond standard perioperative prophylaxis.

Participants will undergo comprehensive andrological assessments at baseline and during follow-up up to 12 months after surgery. Evaluations will include semen analysis according to World Health Organization guidelines, assessment of sperm DNA fragmentation, reproductive hormonal profiles, and seminal inflammatory markers. Exploratory analyses will assess mitochondrial function, oxidative stress, and molecular alterations in spermatozoa. Detailed warfarin exposure data, including dose, cumulative exposure, international normalized ratio values, and time in therapeutic range, will be collected to explore potential exposure-response relationships.

As a pilot study, the primary aims are to assess feasibility and generate preliminary clinical evidence to inform future larger studies. The findings may contribute to improved clinical counseling, fertility preservation strategies, and integration of reproductive health considerations into the multidisciplinary management of young male cardiac surgery patients.

Eligibility

Primary outcome measure(s)

• Change in sperm concentration over time — Baseline (T0) to 6 months (T2) and 12 months (T3)
  Change in sperm concentration expressed as millions of spermatozoa per milliliter (millions/mL), assessed by standard semen analysis performed according to World Health Organization (WHO) guidelines. Correlation between warfarin exposure status (long-term exposure, short-term exposure, or no exposure) and changes in sperm concentration over time will be evaluated.
• Change in progressive sperm motility over time — Baseline (T0) to 6 months (T2) and 12 months (T3)
  Change in progressive sperm motility expressed as percentage (%), assessed by standard semen analysis according to World Health Organization (WHO) guidelines. Correlation between warfarin exposure status (long-term exposure, short-term exposure, or no exposure) and changes in progressive sperm motility over time will be evaluated.
• Change in sperm morphology over time — Baseline (T0) to 6 months (T2) and 12 months (T3)
  Change in the percentage (%) of spermatozoa with normal morphology, assessed using strict criteria as part of standard semen analysis according to World Health Organization (WHO) guidelines. Correlation between warfarin exposure status (long-term exposure, short-term exposure, or no exposure) and changes in sperm morphology over time will be evaluated.

Trial sites (1)

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