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.

中文翻译：

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男性补充叶酸和锌对接受不孕症治疗的夫妇的精液质量和活产的影响

重要性基于改善精液质量的有限先前证据，销售用于男性生育能力的膳食补充剂通常含有叶酸和锌。然而，没有大规模试验检验过这种疗法在改善精液质量或活产方面的功效。目的确定每日补充叶酸和锌对精液质量和活产的影响。设计、设置和参与者 叶酸和锌补充剂试验是一项多中心随机临床试验。2013 年 6 月至 2017 年 12 月期间，在 4 个美国生殖内分泌学和不孕症护理研究中心招募了计划进行不孕症治疗的夫妇（n = 2370；男性年龄≥18 岁，女性年龄在 18-45 岁之间）。最近 6 个月的精液研究访问收集发生在 2018 年 8 月，2019 年 4 月完成的活产和妊娠信息图表抽象。 干预措施 男性按研究中心随机分组并计划进行不孕症治疗（体外受精、研究地点的其他治疗和外部诊所的其他治疗），以接受 5每天服用毫克叶酸和 30 毫克元素锌 (n = 1185) 或安慰剂 (n = 1185)，持续 6 个月。主要结果和测量 共同主要结果是活产（来自随机化后 9 个月内发生的怀孕）和精液质量参数（精子浓度、运动性、形态、体积、DNA 碎片和活动精子总数）后 6 个月随机化。结果 在随机分组的 2370 名男性（平均年龄 33 岁）中，1773 名（75%）参加了最后 6 个月的研究访问。所有夫妇都可以获得活产结果，1629 名男性（69%）在随机化后 6 个月时有可供分析的精液。活产率在治疗组之间没有显着差异（叶酸和锌组为 404 [34%]，安慰剂组为 416 [35%]；风险差异，-0.9% [95% CI，-4.7% 至 2.8%] ]）。大多数精液质量参数（精子浓度、活力、形态、体积和活动精子总数）在随机化后 6 个月时在治疗组之间没有显着差异。补充叶酸和锌后观察到 DNA 断裂的统计学显着增加（叶酸和锌组 DNA 断裂百分比的平均值为 29.7%，安慰剂组为 27.2%；平均差异，2.4% [95% CI， 0.5% 到 4.4%]）。与安慰剂相比，补充叶酸和锌的胃肠道症状更常见（腹部不适或疼痛：分别为 66 [6%] 和 40 [3%]；恶心：50 [4%] 对 24 [2%]；和呕吐） ：32 [3%] 对 17 [1%]）。结论和相关性 在寻求不孕症治疗的一般夫妇中，与安慰剂相比，男性伴侣使用叶酸和锌补充剂并没有显着提高精液质量或夫妇的活产率。这些发现不支持男性伴侣使用叶酸和锌补充剂治疗不孕症。试验注册 ClinicalTrials.gov 标识符：NCT01857310。32 [3%] 对 17 [1%]）。结论和相关性 在寻求不孕症治疗的一般夫妇中，与安慰剂相比，男性伴侣使用叶酸和锌补充剂并没有显着提高精液质量或夫妇的活产率。这些发现不支持男性伴侣使用叶酸和锌补充剂治疗不孕症。试验注册 ClinicalTrials.gov 标识符：NCT01857310。32 [3%] 对 17 [1%]）。结论和相关性 在寻求不孕症治疗的一般夫妇中，与安慰剂相比，男性伴侣使用叶酸和锌补充剂并没有显着提高精液质量或夫妇的活产率。这些发现不支持男性伴侣使用叶酸和锌补充剂治疗不孕症。试验注册 ClinicalTrials.gov 标识符：NCT01857310。这些发现不支持男性伴侣使用叶酸和锌补充剂治疗不孕症。试验注册 ClinicalTrials.gov 标识符：NCT01857310。这些发现不支持男性伴侣使用叶酸和锌补充剂治疗不孕症。试验注册 ClinicalTrials.gov 标识符：NCT01857310。