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 accessAbstract
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.
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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.
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Claims the paper makes
33 Own result · 23 Own method · 13 Sources not found · 6 Own interpretation · 4 No basis given
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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%]).”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Early embryonic development parameters in the IVF stratum were not significantly different by treatment group (eTable 5 in Supplement 2).”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Results
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In the paper
“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%])”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Results
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In the paper
“and none were judged to be related to the intervention.”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Results
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Results
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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%]).”
- Also stated in: § Results · plain
“A statistically significant increase in DNA fragmentation index was observed with folic acid and zinc supplementation overall (mean of 29.7% for percentage of DNA fragmentation vs 27.2% for the placebo group; mean difference, 2.4% [95% CI, 0.5% to 4.4%]).”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Abstract
plaindirectn = 1,629- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Results · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The trial recorded a total of 12 serious adverse events (7 in the folic acid and zinc group and 5 in the placebo group)”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Results
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“The findings also were similar when restricted to men with known male factor infertility or poor semen quality at baseline (eTables 3 and 4 in Supplement 2).”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Results
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Regarding the semen quality parameters, the results were similar when accounting for those lost to follow-up using weighted sensitivity analyses (far right column in Table 3 [adjusted weighted mean difference]) and when using nonparametric testing (eTable 1 in Supplement 2).”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Results
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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%]).”
- Also stated in: § Results · plain
“For the primary outcome of live birth, 820 participants (35%) attained a live birth, which did not significantly differ by intervention group overall (404 [34%] in the folic acid and zinc group vs 416 [35%] in the placebo group; risk difference, -0.9% [95% CI, -4.7% to 2.8%]) and within infertility treatment stratum (Table 2).”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Abstract
plainn = 820- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Results · plain
- It may state two separate claims as one. 21
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In the paper
“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.”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Discussion
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In the paper
“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).”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Results
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“In the other treatment onsite stratum, poorer morphology was observed.”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Results
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Folic acid and zinc supplementation in male partners did not notably affect stillbirth, neonatal morbidity, neonatal mortality, or severe postpartum maternal morbidity.”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Results
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Abstract
plainn = 1,629- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Results · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Results
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“There were 29 structural malformations reported (26 among births and 3 among pregnancy losses).”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Results
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In the paper
“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.”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Limitations
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In the paper
“Despite a statistically significant risk difference of 1.9% in preterm birth, mean gestational ages and birth weights were not significantly different.”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Discussion
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Twenty-one malformations were categorized as major defects (6 with known genetic cause), 6 were minor, and 2 could not be classified.”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Results
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In the paper
“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.”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Randomization and Masking
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In the paper
“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”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Procedures
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In the paper
“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”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Statistical Analysis
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What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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%.”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Statistical Analysis
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“Previous studies of zinc have reported higher rates of gastrointestinal adverse effects.”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Discussion
What the sources say
- Not matchedcites [16]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [38]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
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In the paper
“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.”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Abstract
What the sources say
- Not matchedcites [7]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [8]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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- Not matched
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In the paper
“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%]).”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Results
plainn = 597- Asserted: passes — The authors put it forward as true.
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In the paper
“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%).”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Results
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In the paper
“A data and safety monitoring board provided external oversight.”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Study Design
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In the paper
“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.”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Statistical Analysis
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In the paper
“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.”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Primary Outcomes
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- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Randomization and Masking
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Live birth was analyzed among all randomized couples, permitting the prespecified strict intent-to-treat analysis.”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Statistical Analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Statistical Analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Each laboratory underwent standardized training and interlaboratory quality control testing to comply with World Health Organization criteria (fifth edition).”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Primary Outcomes
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Participants, trial staff, and investigators were blinded to treatment throughout the trial.”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Randomization and Masking
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“Sperm are particularly sensitive to oxidative stress, which is linked to chromatin damage, peroxidation of sperm membranes, impaired motility, and increased apoptosis.”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Abstract
What the sources say
- Not matchedcites [9]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Statistical Analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Statistical Analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Statistical Analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Limitations
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“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”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Discussion
What the sources say
- Not matchedcites [30]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Neither the live birth rate nor any of the secondary outcomes was evaluated in the interim analysis and thus no α was spent.”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Statistical Analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“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]”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Discussion
What the sources say
- Not matchedcites [31]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [32]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [33]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
- Not matched
In the paper
“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.”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Discussion
What the sources say
- Not matchedcites [29]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
In the paper
“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.”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Abstract
What the sources say
- Not matchedcites [14]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
- Not matched
In the paper
“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”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Statistical Analysis
What the sources say
- Not matchedcites [24]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
- Not matched
In the paper
“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.”
§ Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment A Randomized Clinical Trial > Abstract
What the sources say
- Not matchedcites [14]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plainn = 30- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
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.”
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.
Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
Cited work 10.1002/14651858.cd001364.pub4 · retracted 2015-04-30 · notice 10.1002/14651858.cd001364.pub5 · this paper published 2020-01-07
Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
“Singh, 2011, Zinc for the common cold., Cochrane Database Syst Rev, 10.1002/14651858.CD001364.pub3”
Cited work 10.1002/14651858.cd001364.pub3 · retracted 2015-04-30 · notice 10.1002/14651858.cd001364.pub5 · this paper published 2020-01-07
Citations
Cites
2 retracted
Singh, M., & Das, R. R. (2013) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd001364.pub4 · Cited by 243
RetractedSingh, M., & Das, R. R. (2011) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd001364.pub3 · Cited by 59
RetractedWorld Health Organization reference values for human semen characteristics*‡
Cooper, T. G., Noonan, E., von Eckardstein, S., Auger, J., Baker, H. W. G., Behre, H. M., Haugen, T. B., Kruger, T., Wang, C., Mbizvo, M. T., et al. (2010) · Human Reproduction Update · doi:10.1093/humupd/dmp048 · Cited by 2,827
Discrete sequential boundaries for clinical trials
GORDON LAN, K. K., & DEMETS, D. L. (1983) · Biometrika · doi:10.1093/biomet/70.3.659 · Cited by 2,310
Discrete Sequential Boundaries for Clinical Trials
Lan, K. K. G., & DeMets, D. L. (1983) · Biometrika · doi:10.2307/2336502 · Cited by 2,310
Oken, E., Kleinman, K. P., Rich-Edwards, J., & Gillman, M. W. (2003) · BMC Pediatrics · doi:10.1186/1471-2431-3-6 · Cited by 940
Sperm DNA fragmentation: mechanisms of origin, impact on reproductive outcome, and analysis.
Sakkas, D., & Alvarez, J. (2010) · Fertility and Sterility · doi:10.1016/j.fertnstert.2009.10.046 · Cited by 734
Trends in dietary supplement use among US adults from 1999-2012.
Kantor, E. D., Rehm, C. D., Du, M., White, E., & Giovannucci, E. L. (2016) · JAMA · doi:10.1001/jama.2016.14403 · Cited by 644
Oxidative stress and male reproductive health
Aitken, R. J., Smith, T., Jobling, M. S., Baker, M., & Iuliis, G. N. D. (2014) · Asian Journal of Andrology · doi:10.4103/1008-682x.122203 · Cited by 637
Stratified Randomization for Clinical Trials
Kernan, W. N., Viscoli, C. M., Makuch, R. W., Brass, L. M., & Horwitz, R. I. (1999) · Journal of Clinical Epidemiology · doi:10.1016/s0895-4356(98)00138-3 · Cited by 627
Research works printed but not linked: 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
Sorted by citations
Eisenberg, M. L., Esteves, S. C., Lamb, D. J., Hotaling, J. M., Giwercman, A., Hwang, K., & Cheng, Y.-S. (2023) · Nature Reviews Disease Primers · doi:10.1038/s41572-023-00459-w · Cited by 536
Self-citationSperm DNA Fragmentation: A New Guideline for Clinicians
Agarwal, A. K., Majzoub, A. A., Baskaran, S., Selvam, M. K. P., Cho, C., Henkel, R., Finelli, R., Leisegang, K., Sengupta, P., Zenoaga-Barbăroşie, C., et al. (2020) · The World Journal of Men s Health · doi:10.5534/wjmh.200128 · Cited by 341
“As a result, the indiscriminate use of oral antioxidants in men without elevated OS should be avoided [210].”
BackgroundOxidative Stress and Male Infertility: The Protective Role of Antioxidants
Kaltsas, A. (2023) · Medicina · doi:10.3390/medicina59101769 · Cited by 221
“It is vital to maintain consistency in taking the supplements as per guidelines and to be patient, allowing sufficient time for the supplements to work [213].”
BackgroundUpdates to Male Infertility: AUA/ASRM Guideline (2024)
Brannigan, R. E., Hermanson, L., Kaczmarek, J., Kim, S. K., Kirkby, E., & Tanrikut, C. (2024) · Journal of Urology · doi:10.1097/ju.0000000000004180 · Cited by 189
The Role of Zinc in Male Fertility
Allouche‐Fitoussi, D., & Breitbart, H. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21207796 · Cited by 149
Antioxidants for male subfertility.
de Ligny, W. D., Smits, R., Mackenzie-Proctor, R., Jordan, V., Fleischer, K., de Bruin, J., & Showell, M. (2022) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd007411.pub5 · Cited by 10
Genes and Diet in the Prevention of Chronic Diseases in Future Generations
Franzago, M., Santurbano, D., Vitacolonna, E., & Stuppia, L. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21072633 · Cited by 142
Agarwal, A. K., Leisegang, K., Majzoub, A. A., Henkel, R., Finelli, R., Selvam, M. K. P., Tadros, N. N., Parekh, N. V., Ko, E., Cho, C., et al. (2021) · The World Journal of Men s Health · doi:10.5534/wjmh.200196 · Cited by 110
“Analysis of the most recent publications A total of 21 articles published between January 2019 and July 2020 investigated the effects of antioxidant treatment on semen quality (Table 4) [25,42-46,56,57,92101,104,115,121].”
BackgroundMethodWalke, G., Gaurkar, S. S., Prasad, R., Lohakare, T., & Wanjari, M. B. (2023) · Cureus · doi:10.7759/cureus.42583 · Cited by 127
“It is advisable not to expect immediate results and to give the supplements sufficient time to exert their effects [51].”
BackgroundThe Influence of Metabolic Factors and Diet on Fertility
Łakoma, K., Kukharuk, O., & Śliż, D. (2023) · Nutrients · doi:10.3390/nu15051180 · Cited by 113
Ferlin, A., Calogero, A. E., Krausz, C. G., Lombardo, F. P., Paoli, D., Rago, R., Scarica, C., Simoni, M., Foresta, C., Rochira, V., et al. (2022) · Journal of Endocrinological Investigation · doi:10.1007/s40618-022-01741-6 · Cited by 96
Sengupta, P., Pinggera, G., Calogero, A. E., & Agarwal, A. K. (2024) · Reproductive Medicine and Biology · doi:10.1002/rmb2.12598 · Cited by 79
Frequency, morbidity and equity — the case for increased research on male fertility
Kimmins, S., Anderson, R. A., Barratt, C. L. R., Behre, H. M., Catford, S. R., Jonge, C. J. D., Delbès, G., Eisenberg, M. L., Garrido, N., Houston, B. J., et al. (2023) · Nature Reviews Urology · doi:10.1038/s41585-023-00820-4 · Cited by 71
“Large and well-controlled trials are clearly needed 74,86 .”
Akhatova, A., Jones, C., Coward, K., & Yeste, M. (2025) · Clinical Epigenetics · doi:10.1186/s13148-025-01815-1 · Cited by 87
Dietary Antioxidants in the Treatment of Male Infertility: Counteracting Oxidative Stress
Torres-Arce, E., Vizmanos-Lamotte, B., Babió, N., Márquez‐Sandoval, F., & Salas‐Huetos, A. (2021) · Biology · doi:10.3390/biology10030241 · Cited by 79
“Interestingly, a 2020 large RCT further researched the effects the folic acid-zinc duo causes in male fertility parameters and concluded it does not significantly improve semen quality or couple’s live rates [106].”
BackgroundInfluentialEffects of Environmental and Pathological Hypoxia on Male Fertility
Li, Z., Wang, S., Gong, C., Hu, Y., Liu, J., Wang, W., Chen, Y., Liao, Q., He, B., Huang, Y., et al. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.725933 · Cited by 70
Marinaro, J., & Schlegel, P. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24021446 · Cited by 57
“This combination was selected based on previous evidence that both compounds are essential for spermatogenesis and may have synergistic properties [59].”
BackgroundInfluentialAgarwal, A., Cannarella, R., Saleh, R., Harraz, A., Kandil, H., Salvio, G., Boitrelle, F., Kuroda, S., Farkouh, A., Rambhatla, A., et al. (2022) · The World Journal of Men's Health · doi:10.5534/wjmh.220067 · Cited by 49
Antioxidant Paradox in Male Infertility: ‘A Blind Eye’ on Inflammation
Dutta, S., Sengupta, P., Roychoudhury, S., Chakravarthi, S., Wang, C. W., & Sláma, P. (2022) · Antioxidants · doi:10.3390/antiox11010167 · Cited by 56
“SC = sperm concentration, Smot = sperm motility, and Smorph = sperm morphology, DFI = DNA fragmentation index.”
BackgroundMethodMale fertility as a marker for health
Chen, T., Belladelli, F., Giudice, F. D., & Eisenberg, M. L. (2021) · Reproductive BioMedicine Online · doi:10.1016/j.rbmo.2021.09.023 · Cited by 53
Farkouh, A., Salvio, G., Kuroda, S., Saleh, R., Vogiatzi, P., & Agarwal, A. (2022) · Translational Andrology and Urology · doi:10.21037/tau-22-149 · Cited by 50
Impacts of Immunometabolism on Male Reproduction
Ye, L., Huang, W., Liu, S., Cai, S., Hong, L., Xiao, W., Thiele, K., Zeng, Y., Song, M., & Diao, L. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.658432 · Cited by 54
Age-Related Decline of Male Fertility: Mitochondrial Dysfunction and the Antioxidant Interventions
Wang, J., Wang, S.-X., Tehmina, Feng, Y., Zhang, R., Li, X., Sun, Q., & Ding, J. (2022) · Pharmaceuticals · doi:10.3390/ph15050519 · Cited by 50
l-carnitine and l-acetylcarnitine supplementation for idiopathic male infertility
Khaw, S. C., Wong, Z. Z., Anderson, R. A., & da Silva, S. M. (2020) · Reproduction and Fertility · doi:10.1530/raf-20-0037 · Cited by 46
Pascoal, G. D. F. L., Geraldi, M. V., Maróstica, M. R., & Ong, T. P. (2022) · Nutrients · doi:10.3390/nu14102150 · Cited by 46
Kopets, R., Kuibida, I. S., Chernyavska, I., Cherepanyn, V., Mazo, R., Fedevych, V. S., & Gerasymov, S. (2020) · Andrology · doi:10.1111/andr.12805 · Cited by 45
Drevet, J. R., Hallak, J., Nasr-Esfahani, M.-H., & Aitken, R. J. (2021) · Antioxidants and Redox Signaling · doi:10.1089/ars.2021.0235 · Cited by 51
“In this instance, antioxidant treatment improved semen quality, decreased sperm DNA damage, and improved both embryo quality and live birth rate (147).”
Can Nutrition Help in the Treatment of Infertility?
Aoun, A., Khoury, V. E., & Malakieh, R. (2021) · Preventive Nutrition and Food Science · doi:10.3746/pnf.2021.26.2.109 · Cited by 42
“The use of Fa and Zn supplementation by male partners in the treatment of infertility compared with placebo did not significantly enhance semen quality or couples’ live births (Schisterman et al., 2020).”
MethodMale Attitudes towards Infertility: Results from a Global Questionnaire
Jonge, C. J. D., Gellatly, S. A., Vazquez-Levin, M. H., Barratt, C. L. R., & Rautakallio-Hokkanen, S. (2022) · The World Journal of Men s Health · doi:10.5534/wjmh.220099 · Cited by 41
Are antioxidants a viable treatment option for male infertility?
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Zinc oxide nanoparticle causes toxicity to the development of mouse oocyte and early embryo
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Nonsurgical Management of Oligozoospermia
Choy, J. T., & Amory, J. K. (2020) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaa390 · Cited by 43
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“In addition, another randomized trial using a combination of both zinc and folic acid supplementation demonstrated no change in sperm parameters, levels of sperm DNA methylation, and live birth rates [130,131].”
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Leukocytospermia and/or Bacteriospermia: Impact on Male Infertility
Henkel, R. (2024) · Journal of Clinical Medicine · doi:10.3390/jcm13102841 · Cited by 34
“On the contrary, Jenkins et al. [319] and Schisterman et al. [320] did not find any beneficial effects on life birth outcomes.”
BackgroundBiological, dietetic and pharmacological properties of vitamin B9
Siatka, T., Máťuš, M., Moravcová, M., Harčárová, P., Lomozová, Z., Matoušová, K., Suwanvecho, C., Krčmová, L. K., & Mladěnka, P. (2025) · npj Science of Food · doi:10.1038/s41538-025-00396-w · Cited by 44
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“Considering the results of a recent RCT, the FASZT trial, comparing supplementation of zinc combined with folic acid to a placebo group in males, no statistically significant difference was reported with regard to IVF outcomes [268].”
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Aitken, R. J. (2021) · Human Reproduction Open · doi:10.1093/hropen/hoab007 · Cited by 28
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“Conversely, other studies based on theadministration of antioxidants did not show any improvement of semen biomarkers and DNA integrity in infertile men [145,146].”
ResultDietary trends and the decline in male reproductive health
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“The majority of previous studies on antioxidants and male infertility investigated the change in clinical outcomes with the use of supplementation [15, 18, 19].”
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“Although these results are promising, further research is needed to determine the optimal dosage and duration of supplementation and underlying mechanisms [25].”
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Relationship between nutrition and reproduction
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“However, in a recent multi-center trial with 2370 men, folic acid and zinc supplementation did not improve semen quality or birth rates [33].”
BackgroundDeVilbiss, E. A., Sjaarda, L. A., Peterson, C. M., Hotaling, J. M., Mills, J. L., Mendola, P., Carrell, D. T., Johnstone, E. B., Chen, Z., Perkins, N. J., et al. (2022) · Fertility and Sterility · doi:10.1016/j.fertnstert.2022.08.012 · Cited by 17
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“From these, the largest 100 RCTs reporting data from 24 542 men (range: 80–2772 men) were used to identify and report outcomes (Abdel-Maguid and Othman, 2010; Fang et al., 2010; Fayez et al., 2010; Kovacic et al., 2010; Abdel-Meguid et al., 2011; Azadi et al., 2011; Balaban et al., 2011; Figueira Rde et al., 2011; Haf…”
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The Role of Long Non-coding RNAs in Sepsis-Induced Cardiac Dysfunction
Li, J., Zhang, Y., Zhang, D., & Li, Y. (2021) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2021.684348 · Cited by 16
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Unraveling the Impact of Sperm DNA Fragmentation on Reproductive Outcomes
Nielsen, J. L., Majzoub, A., Esteves, S., & Humaidan, P. (2023) · Seminars in Reproductive Medicine · doi:10.1055/s-0043-1777324 · Cited by 15
Homocysteine, vitamin B status and MTHFR polymorphisms in Italian infertile women
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“Schisterman [20] Abdominal discomfort, 66 (5.”
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Antioxidant Treatment and the Chance to Conceive in Men Seeking Fertility Care
Ligny, W. R. D., de Bruin, J. P., Smits, R. M., Goovaerts, I., Peeters, K., Nap, A. W., Boxmeer, J. C., Donker, R. B., Schoonenberg, M. P. G., Koks, C. A. M., et al. (2025) · JAMA Network Open · doi:10.1001/jamanetworkopen.2025.32405 · Cited by 13
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Micronutrient–Antioxidant Therapy and Male Fertility Improvement During ART Cycles
Lahimer, M., Capelle, S., Lefranc, É., Bosquet, D., Kazdar, N., Ledu, A., Agina, M., Cabry, R., & Benkhalifa, M. (2025) · Nutrients · doi:10.3390/nu17020324 · Cited by 13
“Diets rich in antioxidants and vitamins A, B, C, and E can protect sperm DNA from damage, improve sperm function, and enhance male fertility [33,36–38].”
Mitsunami, M., Salas‐Huetos, A., Mínguez‐Alarcón, L., Attaman, J., Ford, J. B., Kathrins, M. N., Souter, I. C., Chavarro, J. E., & for the EARTH Study Team (2021) · Journal of Assisted Reproduction and Genetics · doi:10.1007/s10815-021-02251-9 · Cited by 15
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“including 2370 men who received 5 mg of folic acid and 30 mg of elemental zinc daily (n = 1185) or placebo (n = 1185) for 6 months, no significant difference in live birth rates was found [19].”
BackgroundWu, S., Zhang, X., Zhao, X., Hao, X., Zhang, S., Li, P., & Tan, J. (2022) · Frontiers in Nutrition · doi:10.3389/fnut.2022.808355 · Cited by 14
Miller, R. H., DeVilbiss, E. A., Brogaard, K., et al. (2023) · F&S Science · doi:10.1016/j.xfss.2023.09.001 · Cited by 12
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“Evidence-based medicine has progressively transformed in to the standard approach for numerous diagnosis and treatment of several health complications [14].”
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Food, nutrition, and fertility: from soil to fork
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“…such as calcium (Ca), vitamin D (Vit D), phosphorus (P), protein, and other nutrients that are beneficial to bone, the regular and quantitative supplementation of folic acid for middle-aged and older individuals is also of vital significance (Schisterman et al., 2020; Zhang, Li, et al., 2021).”
BackgroundBollig, K. J., Barnhart, K. T., Schisterman, E. F., Johnstone, E. B., Peterson, C. M., Hotaling, J. M., Ryan, G. L., Voorhis, B. J. V., Carrell, D. T., Mendola, P., et al. (2024) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgae427 · Cited by 11
Self-citationDenosumab stimulates spermatogenesis in infertile men with preserved Sertoli cell capacity
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“Similarly, Schisterman et al. (2020) found no improvement in sperm quality or pregnancy rates from folic acid and Zn supplementation in 2370 couples [114].”
Global Andrology Forum Clinical Guidelines on Antioxidant Use in the Treatment of Male Infertility.
Agarwal, A., Mostafa, T., Hashimi, M. A., Çayan, S., Pescatori, E., Singh, K., Şahin, B., Zini, A., Chung, E., Arafa, M., et al. (2026) · The World Journal of Men's Health · doi:10.5534/wjmh.250290 · Cited by 9
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“In the same vein as our study, a recent study showed an increase of SDF following high-dose folic acid supplementation (5 mg daily intake, corresponding to more than 10 times the 400 μg recommended daily allowance) for 6 months, combined with zinc [28].”
BackgroundDabagh, M., Jahangiri, N., Madah, A. T., Rostami, S., Amidi, F., Khodarahmian, M., Tavoosian, A., Nashtaei, M. S., & Vatannejad, A. (2023) · Frontiers in Nutrition · doi:10.3389/fnut.2023.1284379 · Cited by 7
The dual nature of micronutrients on fertility: too much of a good thing?
Moazamian, A., Hug, E., Villeneuve, P., Bravard, S., Geurtsen, R., Hallak, J., Saez, F., Aitken, R. J., Gharagozloo, P., & Drevet, J. R. (2025) · F&S Science · doi:10.1016/j.xfss.2025.02.004 · Cited by 9
Li, F., Tian, Y., Kong, H., et al. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.630832 · Cited by 7
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DiTosto, J. D., Caniglia, E. C., Hinkle, S. N., et al. (2024) · Fertility and Sterility · doi:10.1016/j.fertnstert.2024.08.332 · Cited by 6
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“However, the effectiveness of this treatment is only observed in a small number of patients, indirectly suggesting that Zn 2+ is a minor factor affecting sperm quality [42].”
Estimation of folic acid/micro nutrients levels; Does it reflect sperm parameters
Tariq, H., Zahid, N., Amir, D., Ashraf, M., Aftab, M. A., Yousaf, S., & Rehman, R. (2020) · International Journal of Clinical Practice · doi:10.1111/ijcp.13790 · Cited by 7
Moyad, M. A. (2022) · Urologic Clinics of North America · doi:10.1016/j.ucl.2021.12.006 · Cited by 6
The role of immune cell death in spermatogenesis and male fertility
Jiahong, C., Junfeng, D., Shuxian, L., et al. (2024) · Journal of Reproductive Immunology · doi:10.1016/j.jri.2024.104291 · Cited by 5
Folic acid and sperm quality improvement: insights from snRNA sequencing and RNA splicing mechanisms
He, Q., Zhang, M., Xiao, S., & Guo, Z. (2025) · Frontiers in Nutrition · doi:10.3389/fnut.2025.1648307 · Cited by 5
Novel bioinformatic analyses of somatic cell contamination in sperm samples
Norton, C., Pollard, C. A., Stalker, K., et al. (2024) · Systems Biology in Reproductive Medicine · doi:10.1080/19396368.2024.2368716 · Cited by 5
“When the model was applied to the entire Folic Acid and Zinc Supplementation Trial (FAZST) dataset minus the 489 used in training ( n ¼ 897), it predicted that 5.7% of samples ( n ¼ 51) were highly likely to be contaminated (Figure 3) (Schisterman et al. 2020).”
MethodInfluentialRole of Antioxidants Supplementation in the Treatment of Male Infertility
Amor, H., Shelko, N., Mohammed, M., Jankowski, P. M., & Hammadeh, M. E. (2021) · IntechOpen eBooks · doi:10.5772/intechopen.95891 · Cited by 5
“The authors reported that these dietary supplements have a very little to no impact on fertility and may even provoke mild gastrointestinal symptoms [119].”
Background
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.
- 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
- 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
- bronze
- doi.org
- 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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