Study Objective
The primary objective of the FAZST study is to assess the efficacy in males of folic acid and zinc supplementation on semen quality and live birth rate) among couples seeking fertility treatment.
Background
Infertility affects 10 to 15% of couples attempting to conceive. Male factor subfertility plays a role in about 50% of subfertile couples, with largely unknown etiology. An intervention with even a small absolute effect on any component of male factor infertility has implications at the population level because of the large potential attributable benefit. Two micronutrients fundamental to the process of spermatogenesis, folic acid and zinc, are of particular interest as they are low cost and widely available. Though the evidence has been inconsistent, small, randomized trials and observational studies show that folate and zinc have biologically plausible effects on spermatogenesis and improved semen parameters. These results suggest that supplementation with folate and zinc may improve semen quality and assisted reproductive technology outcomes. While dietary supplements marketed for male fertility commonly contain folic acid and zinc based on limited prior evidence for improving semen quality, no large-scale trial has examined the efficacy of this therapy for improving semen quality or live birth.
Study Design & Progress
FAZST, as detailed in the baseline publication,2 is a multi-center, double-blind, block-randomized, and placebo-controlled trial designed to determine whether folic acid and zinc supplementation in men improves semen quality and increases live birth rate among couples planning infertility treatment. Eligible men were 18 years or older with female partners between the ages of 18 and 45. Overall, 2,370 men were randomized between June 2013 and December 2017 at 4 U.S. reproductive and infertility care study centers. Men were block-randomized by study center and planned infertility treatment (in vitro fertilization, other treatment at a study site, and other treatment at an outside clinic), to receive either 5 mg of folic acid and 30 mg of elemental zinc (n = 1185) or matching placebo (n = 1185) daily for 6 months.
Study visits were completed by men at baseline, 2, 4, and 6 months, and female partners were passively followed for a minimum of 9 months. Women who conceived were followed throughout pregnancy. The trial completed recruitment in December 2017, the last 6-month study visit for semen collection occurred in August 2018, and chart abstraction of live birth and pregnancy information was completed in April 2019. The co-primary outcomes were live birth (resulting from pregnancies occurring within 9 months of randomization) and semen quality parameters (sperm concentration, motility, morphology, volume, DNA fragmentation, and total motile sperm count) at 6 months after randomization.
As reported in the FAZST baseline paper,2 male participants had a mean age of 33 years and body mass index (weight (kg)/height (m)2) of 29.8. Most participants were white (82%), well educated (83% with some college), and employed (72%). Participant characteristics were balanced across intervention arms. Study visits were completed by 89%, 77%, and 75% of men at months 2, 4, and 6, respectively. Live birth outcomes were available for all couples, and 1,629 men (69%) had semen available for analysis at 6 months after randomization. Main findings for the trial were accepted in the Journal of the American Medical Association on January 7, 2020.3
Broadly, among a general population of couples seeking infertility treatment, the use of folic acid and zinc supplementation by male partners, compared with placebo, did not significantly improve semen quality or couples’ live birth rates. However, men randomized to folic acid and zinc had significantly higher sperm DNA fragmentation at 6 months and reported gastrointestinal symptoms more frequently than men randomized to placebo.
NCT Clinical Trials.gov Number: NCT01857310
Principal Investigator
EB Collaborators
- Elizabeth A. DeVilbiss, M.S., M.P.H., Ph.D.
- James Mills, M.D., M.S.
Selected Publications
- DeVilbiss, E. A., Sjaarda, L. A., Peterson, C. M., Hotaling, J. M., Mills, J. L., Mendola, P., Carrell, D. T., Johnstone, E., Chen, Z., Perkins, N. J., Ryan, G., Schisterman, E. F., & Mumford, S. L. (2022). Longitudinal semen parameter assessments and live birth: Variability and implications for treatment strategies. Fertility and Sterility, 118(5), 852–863. PMID: 36192231
- Schisterman, E. F., Clemons, T., Peterson, C. M., Johnstone, E., Hammoud, A. O., Lamb, D., Carrell, D. T., … Mumford, S. L. (2020). A randomized trial to evaluate the effects of folic acid and zinc supplementation on male fertility and livebirth: Design and baseline characteristics. American Journal of Epidemiology, 189(1), 8-26. PMID: 31712803
- Schisterman, E. F., Sjaarda, L. A., Perkins, N. J., Mills, J. L., Mendola, P., Devilbiss, E. A., Mumford, S. L., ... Chen, Z. (2020). 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-Journal of the American Medical Association 323(12), 35-48. PMID: 31910279
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