Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment: A Randomized Clinical Trial

Enrique F Schisterman; Lindsey A Sjaarda; Traci Clemons; Douglas T Carrell; Neil J Perkins; Erica Johnstone; Denise Lamb; Kayla Chaney; Bradley J Van Voorhis; Ginny Ryan; Karen Summers; Jim Hotaling; Jared Robins; James L Mills; Pauline Mendola; Zhen Chen; Elizabeth A DeVilbiss; C Matthew Peterson; Sunni L Mumford

doi:10.1001/jama.2019.18714

Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment: A Randomized Clinical Trial

Schisterman EF, Sjaarda LA, Clemons T, Carrell DT, Perkins NJ, Johnstone E, Lamb D, Chaney K, Van Voorhis BJ, Ryan G, Summers K, Hotaling J, Robins J, Mills JL, Mendola P, Chen Z, DeVilbiss EA, Peterson CM, Mumford SL

Published January 7, 2020 JAMA, 323(1), 35-48

DOI 10.1001/jama.2019.18714 PMID 31910279 PMC PMC6990807

RRM Academy Synopsis

Folic acid and zinc for men did not improve semen or live birth

Folic acid and zinc did not improve semen quality or live birth in a randomized, placebo-controlled trial of 2370 couples seeking infertility treatment. Men taking the supplement had more stomach symptoms and higher DNA fragmentation on one test. Pregnancy detected by hCG occurred in about 4 out of 10 couples in each group.

Key Findings

The trial randomized 2370 couples: 1185 men received folic acid and zinc and 1185 received placebo. Live birth had a risk ratio of 0.98 (95% CI 0.88 to 1.09).
At 6 months, sperm concentration, motility, morphology and total motile sperm count showed no significant differences between the supplement and placebo groups.
In the supplement group versus placebo, DNA fragmentation was higher on COMET (adjusted difference 2.4, 95% CI 0.5 to 4.4) and not significantly different on SCSA (1.6, 95% CI -0.1 to 3.2).
Abdominal discomfort or pain affected 66 (5.57%) men on supplements versus 40 (3.38%) on placebo; nausea 50 (4.22%) versus 24 (2.03%); vomiting 32 (2.70%) versus 17 (1.43%).
Pregnancy detected by hCG occurred in 478 (40%) supplement couples and 485 (41%) placebo couples. Early pregnancy loss before 20 weeks occurred in 136 (11%) and 149 (13%).

Interpretation

The trial was double-blind, randomized and placebo-controlled. It enrolled couples seeking infertility treatment and excluded men with a genetic cause of infertility, vitamin B12 deficiency, anemia or a vegan diet. In total, 1773 men (74.8%) attended the 6-month visit. The authors reweighted for missed visits and report no change in the estimate. They conclude the findings do not support this supplement for male partners in a general population of couples seeking infertility treatment.

RRM Context

Male factor is a major contributor to couple infertility. RRM evaluates both partners and looks for the cause of an abnormal semen result before choosing a treatment. The trial tested one supplement in couples seeking infertility treatment, the setting its conclusion addresses.

Our editorial summary of this paper, not the article's abstract.

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 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.

Trial Registration

ClinicalTrials.gov Identifier: NCT01857310.

Topics

Male Fertility

Male Factor Treatment Medical Management

Male Fertility › Male Factor Treatment › Medical Management

Enrique F Schisterman, Lindsey A Sjaarda, Traci Clemons, Douglas T Carrell, Neil J Perkins, Erica Johnstone, Denise Lamb, Kayla Chaney, Bradley J Van Voorhis, Ginny Ryan, Karen Summers, Jim Hotaling, Jared Robins, James L Mills, Pauline Mendola, Zhen Chen, Elizabeth A DeVilbiss, C Matthew Peterson, Sunni L Mumford

E Schisterman, L Sjaarda, T Clemons, Doug Carrell, D Carrell, N Perkins, E Johnstone, D Lamb, K Chaney, B Voorhis, G Ryan, K Summers, James Hotaling, J Hotaling, J Robins, Jim Mills, Jimmy Mills, J Mills, P Mendola, Z Chen, Liz DeVilbiss, Beth DeVilbiss, Betsy DeVilbiss, E DeVilbiss, S Mumford

PMID 31910279 31910279 DOI 10.1001/jama.2019.18714 10.1001/jama.2019.18714 Schisterman et al. 2020, Schisterman 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

Folic acid and zinc for men did not improve semen or live birth

Key Findings

Interpretation

RRM Context

Abstract

Topics

By this author

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