Folic acid and zinc supplementation have been suggested to be beneficial to male fertility, according to a meta-analysis published in 2017.1 However, large-scale trials are needed to confirm this benefit. In a randomized clinical trial, folic acid and zinc supplementation did not improve either semen quality or live birth rates in couples seeking fertility treatment, according to study results published in JAMA.2
The antioxidant effects of folic acid and zinc have been hypothesized to synergistically improve spermatogenesis. The randomized double-blind placebo-controlled clinical trial examined the effects of daily folic acid and zinc supplementation on live birth and semen quality, assessed by parameters including volume; total motile sperm count; and sperm motility, morphology, and DNA fragmentation. Study participants consisted of 2370 adult male partners seeking infertility treatment. Participants were randomly assigned in a 1:1 ratio to either a daily dosage of 5 mg of folic acid and 30 mg elemental zinc or placebo for 6 months.
Live birth was assessed for all participants, but 31% of semen quality measures were missing due to lost follow-up or absence of samples. The researchers reported that live birth did not significantly differ in the folic acid and zinc-supplemented group (34%) vs placebo (35% [adjusted risk difference, -0.9%; 95% CI, -4.7 to 2.8]). Semen quality measures of sperm concentration, motility, morphology, volume, and total motile sperm count did not differ between the supplemented and placebo groups after 6 months. The percentage of DNA fragmentation in sperm was significantly increased in the folic acid and zinc-supplemented group (29.7%) vs placebo group (27.2%) with a mean difference of 2.4% (95% CI, 0.5-4.4).
The researchers reported several limitations, including limited generalizability to only men seeking infertility treatment rather than subfertile men. Other limitations included the possibility that couples may have conceived before the trial, fewer recorded cycles of infertility treatment than predicted, and passive assessment of live birth. Furthermore, the potential for a type I error due to multiple comparisons limited the clinical relevance of any statistical differences, which should be considered exploratory.
“This report addresses the long-standing need for a rigorous large-scale trial to examine the effects of folic acid and zinc supplementation on semen quality,” noted the researchers. “[However], these findings disagree with the conclusion of [the] recent meta-analysis.”2
1. Irani M, Amirian M, Sadeghi R, Lez JL, Latifnejad Roudsari R. The effect of folate and folate plus zinc supplementation on endocrine parameters and sperm characteristics in sub-fertile men: a systematic review and meta-analysis. Urol J. 2017;14(5):4069-4078.
2. Schisterman EF, Sjaarda LA, Clemons T, et al. Effect of folic acid and zinc supplementation in men on semen quality and live birth among couples undergoing infertility treatment: a randomized clinical trial. JAMA. 2020;323(1):35-48.