Folic Acid and Zinc Supplementation Trial

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Infertility affects 10 to 15% of couples attempting to conceive. Male factor subfertility plays a role in about 50% of sub-fertile couples, with largely unknown etiology. An intervention with even a small absolute effect on any component of male factor infertility has tremendous 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 offer a potential low cost and widely available treatment. While 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 perhaps, assisted reproductive technology (ART) 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. The Folic Acid and Zinc Supplementation Trial (FAZST) is a multi-center, double-blind, block-randomized 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 aged 18 years or older with female partners aged 18-45 years. Overall, 2,370 men were randomized between June 2013 and December 2017 at 4 US 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. 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 1629 men (69%) had semen available for analysis at 6 months after randomization. The primary findings for the trial were accepted for publication in the Journal of the American Medical Association (JAMA) in 2019 and published in the January 2020 issue of JAMA. 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.