January 7, 2020
A Randomized Clinical Trial
Enrique F. Schisterman, PhD1; Lindsey A. Sjaarda, PhD1; Traci Clemons, PhD2; et alDouglas T. Carrell, PhD3; Neil J. Perkins, PhD1; Erica Johnstone, MD4; Denise Lamb, BSN4; Kayla Chaney, BA2; Bradley J. Van Voorhis, MD5; Ginny Ryan, MD5; Karen Summers, MPH5; Jim Hotaling, MD6; Jared Robins, MD7; James L. Mills, MD1; Pauline Mendola, PhD1; Zhen Chen, PhD8; Elizabeth A. DeVilbiss, PhD1; C. Matthew Peterson, MD4; Sunni L. Mumford, PhD1
Author Affiliations Article Information
JAMA. 2020;323(1):35-48. doi:10.1001/jama.2019.18714
Key Points
Question What is the effect of folic acid and zinc supplementation in men on semen quality and live birth among couples planning infertility treatment?
Findings In this randomized clinical trial that included 2370 couples, the use of folic acid and zinc supplementation by male partners, compared with placebo, did not significantly improve couples’ live birth rates (34% vs 35%, respectively) or semen quality measured 6 months after randomization.
Meaning These findings do not support the use of folic acid and zinc supplementation by male partners for the treatment of infertility.
Importance Dietary supplements marketed for male fertility commonly contain folic acid and zinc based on limited prior evidence for improving semen quality. However, no large-scale trial has examined the efficacy of this therapy for improving semen quality or live birth.
Objective To determine the effect of daily folic acid and zinc supplementation on semen quality and live birth.
Design, Setting, and Participants The Folic Acid and Zinc Supplementation Trial was a multicenter randomized clinical trial. Couples (n = 2370; men aged ≥18 years and women aged 18-45 years) planning infertility treatment were enrolled at 4 US reproductive endocrinology and infertility care study centers between June 2013 and December 2017. The last 6-month study visit for semen collection occurred during August 2018, with chart abstraction of live birth and pregnancy information completed during April 2019.
Interventions 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 placebo (n = 1185) daily for 6 months.
Main Outcomes and Measures 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.
Results Among 2370 men who were randomized (mean age, 33 years), 1773 (75%) attended the final 6-month study visit. Live birth outcomes were available for all couples, and 1629 men (69%) had semen available for analysis at 6 months after randomization. Live birth was not significantly different between treatment groups (404 [34%] in the folic acid and zinc group and 416 [35%] in the placebo group; risk difference, −0.9% [95% CI, −4.7% to 2.8%]). Most of the semen quality parameters (sperm concentration, motility, morphology, volume, and total motile sperm count) were not significantly different between treatment groups at 6 months after randomization. A statistically significant increase in DNA fragmentation was observed with folic acid and zinc supplementation (mean of 29.7% for percentage of DNA fragmentation in the folic acid and zinc group and 27.2% in the placebo group; mean difference, 2.4% [95% CI, 0.5% to 4.4%]). Gastrointestinal symptoms were more common with folic acid and zinc supplementation compared with placebo (abdominal discomfort or pain: 66 [6%] vs 40 [3%], respectively; nausea: 50 [4%] vs 24 [2%]; and vomiting: 32 [3%] vs 17 [1%]).
Conclusions and Relevance 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. These findings do not support the use of folic acid and zinc supplementation by male partners in the treatment of infertility.