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

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

Open access
Schisterman, Enrique F., Sjaarda, Lindsey A., Clemons, Traci, Carrell, Douglas T., Perkins, Neil J., Johnstone, Erica, Lamb, Denise, Chaney, Kayla +11 more·2020·JAMA
DOI 10.1001/jama.2019.18714PMC PMC6990807
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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.

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.

Claims the paper makes

0 of 19 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Abdominal discomfort or pain was more common with folic acid and zinc supplementation than with placebo (66 [6%] vs 40 [3%]).

    “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%]).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Early embryonic development parameters in the IVF stratum were not significantly different by treatment group.

    “Early embryonic development parameters in the IVF stratum were not significantly different by treatment group (eTable 5 in Supplement 2).”
    Quote in the paperNot a substantial claim
  • Findingown data

    A post hoc sensitivity analysis for preterm birth indicated no significant effect using a cut point at 36 weeks' gestation (41 [3.5%] vs 33 [2.8%]; risk difference, 0.68% [95% CI, -0.70% to 2.08%]).

    “A post hoc sensitivity analysis for preterm birth indicated no significant effects using cut points at 36 weeks' gestation (41 [3.5%] in the folic acid and zinc group vs 33 [2.8%] in the placebo group; risk difference, 0.68% [95% CI, -0.70% to 2.08%])”
    Quote in the paperNot a substantial claim
  • Findingown data

    None of the serious adverse events were judged to be related to the intervention.

    “and none were judged to be related to the intervention.”
    Quote in the paperNot a substantial claim
  • Findingown data

    There was no statistically significant effect of supplementation on most prespecified secondary outcomes, including β-human chorionic gonadotropin-detected pregnancy, clinical intrauterine pregnancy, ectopic pregnancy, pregnancy with multiple fetuses, early pregnancy loss, cesarean delivery, preeclampsia or gestational hypertension, gestational diabetes, gestational age, birth weight, or small for

    “There was no statistically significant effect of supplementation on most of the prespecified secondary outcomes, including β-human chorionic gonadotropin-detected pregnancy, clinical intrauterine pregnancy, ectopic pregnancy, pregnancy with multiple fetuses, early pregnancy loss, cesarean delivery, preeclampsia or gestational hypertension, gestational diabetes, gestational age, birth weight, or”
    Quote in the paperSubstantial claim
  • May combine two claims. 21
  • Classified as probably not a substantial claim. 29

  • May combine two claims.

    Findingown data

    The frequency of fetal and maternal complications was similar between groups, except an unexpected increase in preterm birth in the folic acid and zinc group.

    “The frequency of fetal and maternal complications was similar between groups (though the trial was not powered for these outcomes), except an unexpected increase in preterm birth in the folic acid and zinc group.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Setting samples with inadequate sperm concentration as missing produced null findings for the DNA fragmentation index and similar results for the other semen quality parameters.

    “Furthermore, setting samples with inadequate sperm con- centration as missing produced null findings for the DNA fragmentation index and similar results for the other semen quality parameters (eTable 2 in Supplement 2).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingnone given

    In the other treatment onsite stratum, poorer morphology was observed.

    “In the other treatment onsite stratum, poorer morphology was observed.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Folic acid and zinc supplementation in male partners did not notably affect stillbirth, neonatal morbidity, neonatal mortality, or severe postpartum maternal morbidity.

    “Folic acid and zinc supplementation in male partners did not notably affect stillbirth, neonatal morbidity, neonatal mortality, or severe postpartum maternal morbidity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Sperm concentration, motility, morphology, volume, and total motile sperm count were not significantly different between treatment groups at 6 months after randomization.

    “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.”
    • Also stated in: § Results · plain
      “For the semen quality parameters, sperm concentration, motility, morphology, volume, and total motile sperm count were not significantly different after 6 months (Table 3).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    Results of the interim analysis did not reach the prespecified bound for harm on semen parameters; therefore, the trial continued unchanged.

    “Results of the interim analysis did not reach the prespecified bound (Supplement 1 and detailed elsewhere 15 ) for harm on semen parameters; therefore, the trial continued unchanged.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    There were 29 structural malformations reported (26 among births and 3 among pregnancy losses).

    “There were 29 structural malformations reported (26 among births and 3 among pregnancy losses).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Most patients in the trial were white and non-Hispanic, with high socioeconomic status, limiting generalizability.

    “First, the present findings are generalizable to a general infertility clinic population and not subfertile men specifically; most patients were white and non-Hispanic, with high socioeconomic status, thus limiting generalizability.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Despite a statistically significant risk difference of 1.9% in preterm birth, mean gestational ages and birth weights were not significantly different.

    “Despite a statistically significant risk difference of 1.9% in preterm birth, mean gestational ages and birth weights were not significantly different.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    Twenty-one malformations were categorized as major defects (6 with known genetic cause), 6 were minor, and 2 could not be classified.

    “Twenty-one malformations were categorized as major defects (6 with known genetic cause), 6 were minor, and 2 could not be classified.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The computerized randomization algorithm was based on a permuted block design with block sizes of 2, 4, or 6 within each infertility treatment stratum and study site and was implemented by blinded study coordinators.

    “The computerized randomization algorithm was developed by the trial data coordinating center based on a permuted block design with block sizes of 2, 4, or 6 (in random order) within each infertility treatment stratum and study site and was implemented by blinded study coordinators.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Quality control measures for tablets included testing to meet United States Pharmacopeia specifications and quality standards for nutritional and dietary supplements.

    “Quality control measures for tablets included testing to meet United States Pharmacopeia specifications and quality standards for nutritional and dietary supplements and to prevent issues of potential contamination”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Risk differences and risk ratios for live birth and binary secondary outcomes were estimated using generalized linear models adjusting for infertility treatment stratum and study site to improve precision.

    “Risk differences and risk ratios were estimated for live birth and for the secondary outcomes with binary end points using generalized linear models, adjusting for infertility treatment stratum and study site to improve precision”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    A sample size of 2310 couples (rounded to 2400) was targeted to provide 90% power at a 2-sided α level of .05 to detect a risk difference of 7% in live birth, allowing for a 15% dropout rate.

    “A sample size of 2310 couples (rounded to 2400), divided equally between the folic acid and zinc supplementation group and the placebo group, was targeted to provide 90% power at a 2-sided α level of .05 to detect a risk difference of 7% in live birth (implying a risk ratio of 1.10), with continuity correction and allowing for a dropout rate of 15%.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Previous studies of zinc have reported higher rates of gastrointestinal adverse effects.

    “Previous studies of zinc have reported higher rates of gastrointestinal adverse effects.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [16]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [38]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Zinc's high concentration in seminal fluid (approximately 30 times higher than in blood) suggests a link to semen quality, potentially through its antioxidant functions.

    “Furthermore, zinc's high concentration in seminal fluid (approximately 30 times higher than in blood 7 ) suggests a link to semen quality, potentially through its antioxidant functions.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [7]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [8]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Semen quality parameters were missing for 31% of men because they were lost to follow-up (25%) or lacked samples at the 6-month study visit (6%).

    “Live birth was assessed for all 2370 participants; however, semen quality parameters were missing for 31% of men because they were lost to follow-up (n = 597 [25%]) or lacked samples at the 6-month study visit (n = 144 [6%]).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Most participants reported missing no more than 5 daily doses during each follow-up interval (87% baseline to 2 months, 86% 2-4 months, and 83% 4-6 months).

    “Most participants reported missing no more than 5 daily doses during the interval between each follow-up visit (from baseline to 2 months, 87% adherence; 2-4 months, 86%; and 4-6 months, 83%).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    A data and safety monitoring board provided external oversight.

    “A data and safety monitoring board provided external oversight.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    An interim analysis was conducted after 50% of participants completed the 6-month visit to determine whether the study should be stopped for strong evidence of harm to semen quality.

    “An interim analysis (detailed elsewhere 15 ) was conducted by the data coordinating center under the direction of the data and safety monitoring board after 50% of participants completed the 6-month visit to determine whether the study should be stopped for strong evidence of harm to semen quality.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The DNA fragmentation index was determined at a central laboratory using a Comet assay.

    “In addition, the DNA fragmentation index was determined at a central laboratory using a Comet assay, which is a single-cell gel electrophoresis approach for measuring DNA breaks.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Eligible male participants were randomized in a 1:1 ratio to daily folic acid and zinc or placebo by study center and planned infertility treatment stratum.

    “Eligible male participants were randomized in a 1:1 ratio to daily folic acid and zinc or placebo by study center and planned infertility treatment stratum”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Supplementation with 5 mg of folic acid and 30 mg of zinc in men did not improve semen quality parameters or increase couples' live birth rates among patients seeking infertility treatment using IVF or other treatment modalities.

    “In this randomized clinical trial, supplementation with 5 mg of folic acid and 30 mg of zinc in men did not improve semen quality parameters or increase couples' live birth rates among patients seeking infertility treatment using IVF or other treatment modalities.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    Live birth was analyzed among all randomized couples, permitting the prespecified strict intent-to-treat analysis.

    “Live birth was analyzed among all randomized couples, permitting the prespecified strict intent-to-treat analysis.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    Because of the potential for type I error due to multiple comparisons for the co-primary and secondary end points, the findings should be interpreted as exploratory.

    “Because of the potential for type I error due to multiple comparisons for the co-primary and secondary end points, the findings should be interpreted as exploratory.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Each laboratory underwent standardized training and interlaboratory quality control testing to comply with World Health Organization criteria (fifth edition).

    “Each laboratory underwent standardized training and interlaboratory quality control testing to comply with World Health Organization criteria (fifth edition).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Participants, trial staff, and investigators were blinded to treatment throughout the trial.

    “Participants, trial staff, and investigators were blinded to treatment throughout the trial.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Sperm are particularly sensitive to oxidative stress, which is linked to chromatin damage, peroxidation of sperm membranes, impaired motility, and increased apoptosis.

    “Sperm are particularly sensitive to oxidative stress, which is linked to chromatin damage, peroxidation of sperm membranes, impaired motility, and increased apoptosis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    The adjustment for randomization block and study site was appropriate and the adjusted and unadjusted findings were similar; therefore, only the adjusted results are presented.

    “Even though the unadjusted analyses were prespecified, the adjustment for randomization block and study site was appropriate and, as expected, the adjusted and unadjusted findings were similar; therefore, only the adjusted results are presented.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Analyses of embryonic parameters among couples in the IVF stratum used generalized linear models and estimating equation methods to account for multiple IVF cycles per couple and multiple embryos per cycle; however, this approach was not prespecified in the statistical analysis plan.

    “Analyses of embryonic parameters among couples in the IVF stratum used generalized linear models and estimating equation methods to account for multiple IVF cycles per couple and multiple embryos per cycle; however, this approach was not prespecified in the statistical analysis plan.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    To account for the α spent from the interim tests, the confidence intervals for sperm concentration, morphology, and motility represent 95.1% confidence intervals.

    “To account for the α spent from the interim tests, the confidence intervals reported herein for sperm concentration, morphology, and motility represent 95.1% confidence intervals.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The present findings are generalizable to a general infertility clinic population and not to subfertile men specifically.

    “First, the present findings are generalizable to a general infertility clinic population and not subfertile men specifically; most patients were white and non-Hispanic, with high socioeconomic status, thus limiting generalizability.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    Prior data on folic acid and zinc and DNA fragmentation index are limited.

    “Although prior data on folic acid and zinc and DNA fragmentation index are limited, the current findings suggest increased sperm DNA damage associated with supplementation.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A methylenetetrahydrofolate reductase gene polymorphism was shown to modify the effect of folic acid and zinc supplementation on sperm count in one small trial.

    “a methylenetetrahydrofolate reductase gene polymorphism was shown to modify the effect of folic acid and zinc supplementation on sperm count in 1 small trial.30”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Premisenone given

    This report addresses the long-standing need for a rigorous large-scale trial to examine the effects of folic acid and zinc supplementation on semen quality.

    “This report addresses the long-standing need for a rigorous large-scale trial to examine the effects of folic acid and zinc supplementation on semen quality.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductreasoning

    Neither the live birth rate nor any of the secondary outcomes was evaluated in the interim analysis and thus no α was spent.

    “Neither the live birth rate nor any of the secondary outcomes was evaluated in the interim analysis and thus no α was spent.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    DNA fragmentation index is a measure of sperm DNA damage from oxidative stress previously associated with infertility and potentially ameliorated by folic acid and zinc.

    “In addition to examining the effects of folic acid and zinc supplementation on clinical measures of semen quality, the present trial examined their effects on DNA fragmentation index, a measure of sperm DNA damage from oxidative stress previously associated with infertility [31][32][33][34][35] and potentially ame-liorated by folic acid and zinc.[7][8][9]”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [31]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [32]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [33]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    A recent smaller trial examining a commercial formula of multiple antioxidant nutrients reported no benefit of supplementation on semen quality, which is consistent with the current trial.

    “A recent smaller trial, 29 which was not included in the meta-analysis, 14 examining a commercial formula of multiple antioxidant nutrients (but with lower doses of folic acid and zinc than used herein) reported no benefit of supplementation on semen quality, which is consistent with the current trial.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    A meta-analysis concluded that large-scale trials were needed and it remains unproven whether supplementation could affect live birth.

    “A meta-analysis 14 concluded that large-scale trials were needed and it remains unproven whether supplementation could affect live birth, which is the outcome of most interest to couples.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    A risk difference of 7% is clinically meaningful and is in line with other large trials assessing pharmacological agents among couples undergoing infertility treatment.

    “A risk difference of 7% is clinically meaningful and is in line with other large trials assessing pharmacological agents among couples undergoing infertility treatment.24”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Human trials of folic acid and zinc supplementation have been heterogenous and have produced varied results among treatment groups of usually fewer than 30 men.

    “Human trials of folic acid and zinc supplementation have been heterogenous and have produced varied results among treatment groups of usually fewer than 30 men 14 ; however, some evidence suggests zinc and folate in combination may be optimal.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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.

  • Cites a retracted work: 10.1002/14651858.cd001364.pub4

    Major

    The cited work was retracted on 2015-04-30 (notice 10.1002/14651858.cd001364.pub5), before this paper was published (2020-01-07). Its authors could have known.

    Cited work 10.1002/14651858.cd001364.pub4 · retracted 2015-04-30 · notice 10.1002/14651858.cd001364.pub5 · this paper published 2020-01-07

  • Cites a retracted work: 10.1002/14651858.cd001364.pub3

    Major

    The cited work was retracted on 2015-04-30 (notice 10.1002/14651858.cd001364.pub5), before this paper was published (2020-01-07). Its authors could have known.

    Cited work 10.1002/14651858.cd001364.pub3 · retracted 2015-04-30 · notice 10.1002/14651858.cd001364.pub5 · this paper published 2020-01-07

2 of 2

Cites

2 retracted

Flagged first, then by citations

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

Cited by

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Related

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.
ORCID
Venue
JAMA
Publisher
American Medical Association (AMA)
Published
2020-01-07
Volume
323
Issue
1
Pages
35
ISSN
  • 0002-9955 (ISSN-L)
  • 0098-7484
DOI
10.1001/jama.2019.18714
PMC
PMC6990807
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 › Health Professions › General Health Professions › 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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-26.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-26.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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