BACKGROUND AND PURPOSE:

• Folic acid and zinc-based supplements are being marketed to improve male fertility based on limited data
• Schisterman et al. (JAMA, 2020) sought to examine whether these supplements can improve semen quality and live birth

METHODS:

• Multicenter randomized clinical trial (RCT)
  • 4 US sites (2013 to 2017)
• Participants
  • Couples: Men aged ≥18 years | Women aged 18 to 45 years
  • Planning fertility treatment
  • Exclusion: Planning use of donor sperm or a gestational surrogate | Were pregnant at enrollment | Presence of obstructive azoospermia or other male infertility causes that would not benefit from supplementation
• Interventions
  • 5 mg of folic acid and 30 mg of elemental zinc daily for 6 months
  • Placebo daily for 6 months
• Study design
  • Men were block randomized by study site and planned infertility treatment
  • 2310 couples (rounded to 2400) total were planned to provide 90% power to detect a risk difference of 7% in live birth
• Primary outcomes
  • Live birth
  • Semen quality parameters at 6 months after randomization
    • Sperm concentration | Motility | Morphology | Volume | DNA fragmentation | Total motile sperm count

RESULTS:

• 2,370 men were randomized | Mean age: 33 years
  • 75% attended the final 6-month study visit
  • 69% had semen available for analysis at 6 months after randomization
• Live birth: No significant differences were found
  • Folic acid and zinc group: 34%
  • Placebo: 35%
  • Risk difference: −0.9% (95% CI, −4.7% to 2.8%)
• Semen quality: No difference were found in the following parameters
  • Sperm concentration | Motility | Morphology | Volume | Total motile sperm count
• However, mean DNA fragmentation was increased folic acid and zinc supplementation
  • Folic acid and zinc group: 29.7%
  • Placebo: 27.2%
  • Mean difference: 2.4% (95% CI, 0.5% to 4.4%)
• Adverse events and side effects: GI symptoms were more common with folic acid and zinc supplementation
  • Abdominal discomfort or pain: 6%) vs 3%
  • Nausea: 4% vs 2%
  • Vomiting: 3% vs 1%

CONCLUSION:

• Authors acknowledge limitations, including the fact that participants were from the general infertility clinic population and not subfertile men specifically
• Male supplementation with zinc and folic acid did not significantly improve live birth rate or semen quality in couples seeking fertility treatment

Learn More – Primary Sources:

Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment: A Randomized Clinical Trial

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