Cited by 180Sperm and Testicular FunctionReproductive Health and TechnologiesMale Reproductive Health Studies

The DOI matches its Crossref record; 41 of the 42 references it cites were found in a registry or an index; none of the 19 sources its claims cite is checked for support yet.

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

Open access

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.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

In a multicenter randomized trial of 2370 couples seeking infertility treatment, daily folic acid (5 mg) and zinc (30 mg) supplementation in men did not improve live birth or most semen quality parameters compared with placebo. Supplementation was associated with a small increase in sperm DNA fragmentation and more gastrointestinal adverse effects.

Key findings

  • Live birth did not differ significantly between groups: 404/1185 (34%) with folic acid and zinc vs 416/1185 (35%) with placebo; adjusted risk difference, −0.9% (95% CI, −4.7% to 2.8%).
  • Most semen quality parameters at 6 months were not significantly different, but DNA fragmentation index was higher with supplementation: mean 29.7% vs 27.2%; mean difference, 2.4% (95% CI, 0.5% to 4.4%).
  • The permutation test across sperm concentration, motility, morphology, and DNA fragmentation indicated lower overall semen quality in the folic acid and zinc group (t sum4 = −6.06; P = .03), largely driven by DNA fragmentation.
  • Gastrointestinal symptoms were more common with folic acid and zinc than placebo: abdominal discomfort or pain, 66 (6%) vs 40 (3%); nausea, 50 (4%) vs 24 (2%); vomiting, 32 (3%) vs 17 (1%). Preterm delivery was also higher (67 [6%] vs 45 [4%]; risk difference, 1.9% [95% CI, 0.2% to 3.6%]), but sensitivity analyses at 36 and 38 weeks were not significant.

Methods

  • Multicenter, double-blind, block-randomized, placebo-controlled trial (FAZST) at 4 US reproductive endocrinology and infertility care centers; 2370 couples enrolled June 2013–December 2017, with men randomized 1:1 to 5 mg folic acid plus 30 mg elemental zinc (n = 1185) or placebo (n = 1185) daily for 6 months.
  • Co-primary outcomes were live birth from pregnancies within 9 months of randomization and semen quality parameters at 6 months (sperm concentration, motility, morphology, volume, DNA fragmentation index, total motile sperm count).
  • Live birth was analyzed among all randomized couples; semen quality used complete-case analysis with adjustment for infertility treatment stratum and study site, plus permutation testing and post hoc sensitivity analyses.

Limitations

  • The paper states that findings are generalizable to a general infertility clinic population rather than subfertile men specifically, and most patients were white, non-Hispanic, and of high socioeconomic status, limiting generalizability.
  • The paper notes that couples may have conceived via sperm produced before the intervention, though median time receiving intervention before first attempted fertilization was 85 days; 6-month semen quality was missing for 31% of men, and multiple comparisons mean significant findings should be interpreted as exploratory.
  • The paper states the trial was not powered for fetal and maternal complications, and the unexpected preterm birth finding may be a chance finding; the text also makes evident that the lower-than-assumed placebo live birth rate reduced precision, though the observed 95% CI excluded the targeted 7% risk difference.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1001/jama.2019.18714

Cites

41 of 42 references verified0 citation errors · 1 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

33 Own result · 23 Own method · 13 Sources not found · 6 Own interpretation · 4 No basis given

Show all 38 claims

  • It may state two separate claims as one. 21
  • Probably not a substantial claim. 29
41 of 41
  • The paper relies on this without support.

    Most supplements for male fertility contain folic acid and zinc.

    “Most supplements for male fertility contain folic acid and zinc.”
  • The paper relies on this without support.

    The spermatogenic cycle is approximately 74 days.

    “Although the spermatogenic cycle is approximately 74 days, this timing ensures a minimum time of receiving the intervention that covers the stages of spermatocytogenesis (mitotic and meiotic phases) as well meeting the practical needs of patients to initiate infertility treatment promptly.”
  • The paper relies on this without support.

    Late-stage exposure of sperm to the intervention would not affect any hypothesized effects of supplementation on protection of sperm quality during maturation and storage.

    “Late-stage exposure of sperm to the intervention would not affect any hypothesized effects of supplementation on protection of sperm quality during maturation and storage.”
  • The authors state this as an assumption.

    The theoretically ideal target of 74 days for sperm maturation and storage is valid.

    “which is even later than the theoretically ideal target of 74 days.”
4 of 4

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Self-check results appear here once an independent check has confirmed them.

Cited works that were retracted

Works this paper cites that were later retracted, from the retraction notices publishers deposit. Major when the notice came out before this paper was published.

2 of 2

Citations

Cites

2 retracted

Show all 41 references

Research works printed but not linked: 1

  1. Steiner, 2018, O-064, antioxidants in the treatment of male factor infertility: results from the double blind, multi-center, randomized controlled Males, Antioxidants, and Infertility (MOXI) trial., Hum Reprod, 33, i30

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Items 101–180 of 180

Metadata

Authors
Schisterman, E. F., Sjaarda, L. A., Clemons, T., Carrell, D. T., Perkins, N. J., Johnstone, E., Lamb, D., Chaney, K., Van Voorhis, B. J., Ryan, G., Summers, K., Hotaling, J., Robins, J., Mills, J. L., Mendola, P., Chen, Z., DeVilbiss, E. A., Peterson, C. M., & Mumford, S. L.
Affiliations
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (US)
  • Emmes (United States) (US)
  • University of Utah (US)
  • Department of Obstetrics and Gynecology, Carver College of Medicine, University of Iowa, Iowa City
  • University of Iowa (US)
  • Northwestern University (US)
  • National Institutes of Health (US)
Corresponding author
Schisterman, Enrique F.
Venue
JAMA
Published
2020-01-07
Volume
323
Issue
1
Pages
35
ISSN
  • 0002-9955 (ISSN-L)
  • 0098-7484
OpenAlex
W2999455759
Cited by
179
References
41
Citations by year
2026: 21 · 2025: 25 · 2024: 31 · 2023: 23 · 2022: 33 · 2021: 25 · 2020: 21
FWCI
18.59
Type
journal article
Language
en
Open access
Locations
  • JAMA (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
Funders
Eunice Kennedy Shriver National Institute of Child Health and Human Development (#HHSN275201300026I, HHSN275201200007C)
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
  • Health Sciences › Medicine › Reproductive Medicine › Reproductive Health and Technologies
  • Health Sciences › Medicine › Urology › Male Reproductive Health Studies
Keywords
folic acid supplementation, zinc supplementation, male infertility, semen quality, live birth, sperm DNA fragmentation, sperm motility, sperm morphology, in vitro fertilization, sperm concentration, total motile sperm count, semen volume, pregnancy outcomes, infertility treatment outcomes
MeSH terms
Adolescent, Adult, Female, Fertilization in Vitro, Folic Acid, Humans, Infertility, Male, Male, Middle Aged, Semen, Sperm Count, Zinc, Treatment Failure, Dietary Supplements, Live Birth, DNA Fragmentation, Semen Analysis, Young Adult

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