Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment

Abstract

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 PARTICIPANTSThe Folic Acid and Zinc Supplementation Trial was a multicenter randomized clinical trial. Couples (n = 2370; men aged Ն18 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 MEASURESThe 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.

Dietary supplementation with a novel l‐carnitine multi‐micronutrient in idiopathic male subfertility involving oligo‐, astheno‐, teratozoospermia: A randomized clinical study

“…No stimulation on the progressive sperm motility was found in the small sample size studies with co‐enzyme Q10, folic acid, zinc, or combination of zinc and folic acid 20‐22 . In a recent large‐scale randomized multi‐center trial exploring the role of 6‐month folic acid (5 mg/daily) and zinc (30 mg/daily) supplementation in infertility couples, authors demonstrated no effects on any standard spermiogram parameters, including progressive sperm motility 23 . The doses of folic acid and zinc varied around recommended daily allowance and were times lesser in our study than in the referenced one.…”

“…Some of the components in the TDS may have improved sperm morphology. Zinc sulfate in a dose of 66 mg taken together with folic acid 5 mg a day for 26 weeks by the subfertile patients after varicocelectomy has been shown to significantly increase the percentage of spermatozoa with normal morphology at months 3 and 6 23 . Zinc sulfate administered as solution 5 mg × 3 times daily (15 mg) for 3 months has been shown to very slightly increase the percentage of sperm cells with normal morphology, 32 but much higher daily dose of zinc (220 mg for 4 months) with 5 mg folate showed no benefits 33 .…”

“…Further controlled trials were inconsistently conclusive with a systematic meta‐analysis of 247 cases suggesting that carnitines improve sperm concentration 14 . Co‐enzyme Q10, folic acid, and selenium did not affect sperm density being administered as a single formulation, 21‐23,28 while zinc with or without folic exerted a positive action on this parameter 23,34 . Multi‐component antioxidant formulation, consisting of the listed components and carnitines, increased sperm concentration by 158% as compared with 64% increment, when carnitines were taken alone 12 .…”

“…Indeed, progressive motility and morphology are among primary predictors of male fertility 39 . Better pregnancy outcomes were reported for the prescribed separately zinc‐, but not for folate‐ or co‐enzyme Q 10 ‐based supplements 7,23,40 . The cumulative data from 8 randomized clinical trials showed that carnitines increase proportion of pregnancies (OR = 4.10, P < .001) 41 .…”

Genes and Diet in the Prevention of Chronic Diseases in Future Generations

“…Inconsistencies in the reported effect of different foods were analyzed by Gaskins and Chavarro [8], who demonstrated that the role played by some elements in human fertility, such as vitamin D, antioxidants, long chain omega 3, fatty acid and dairy products is not yet clear. Moreover, very recent studies on folic acid and zinc supplementation in male partners did not show an improvement in semen quality or live birth rates in couples undergoing infertility treatment [9]. A possible explanation for these discrepancies is that people are not genetically identical and the presence of specific genetic variants can influence metabolism, therefore, the effect of diet may be variable.…”