Folic Acid and Zinc Supplementation Trial

不孕症影响了10%到15%的试图怀孕的夫妇。男性因素不育在约50%的亚生育夫妇中起作用，病因大多不明。对男性因素不育症的任何组成部分的干预，即使只有很小的绝对影响，也会在人口层面产生巨大的影响，因为它具有巨大的潜在可归因性。对精子发生过程至关重要的两种微量营养素--叶酸和锌--特别令人感兴趣，因为它们提供了一种潜在的低成本和广泛可用的治疗方法。虽然证据不一致，但小型随机试验和观察性研究表明，叶酸和锌在精子发生和改善精液参数方面具有生物学上可信的影响。这些结果表明，补充叶酸和锌可能会改善精液质量，或许还会改善辅助生殖技术(ART)的结果。虽然市场上销售的男性生育能力膳食补充剂通常含有叶酸和锌，这是基于有限的先前证据，以改善精液质量，但还没有大规模试验检验这种疗法在改善精液质量或活产方面的效果。 叶酸和锌补充试验(FAZST)是一项多中心、双盲、区组随机、安慰剂对照试验，旨在确定男性补充叶酸和锌是否可以改善精液质量，并在计划治疗不育症的夫妇中提高活产率。符合条件的男性年龄在18岁或以上，女性伴侣年龄在18-45岁之间。总体而言，在2013年6月至2017年12月期间，2370名男性在美国4个生殖和不育护理研究中心随机进行了调查。男性按研究中心随机分组和计划的不孕症治疗(体外受精、研究地点的其他治疗和外部诊所的其他治疗)，每天接受5毫克叶酸和30毫克元素锌(n=1185)或匹配的安慰剂(n=1185)，持续6个月。男性在基线、2个月、4个月和6个月时完成研究访问，女性伴侣被被动跟踪至少9个月。怀孕的女性在整个怀孕期间都被跟踪。该试验于2017年12月完成招募，最后一次为期6个月的精液采集学习访问发生在2018年8月，活产和怀孕信息的图表提取于2019年4月完成。共同的主要结果是活产(由随机化后9个月内怀孕引起)和随机化后6个月的精液质量参数(精子密度、活力、形态、体积、DNA片段化和活动精子总数)。 男性参与者的平均年龄为33岁，身体质量指数(体重(公斤)/身高(米)2)为29.8。大多数参与者是白人(82%)，受过良好教育(83%有大学学历)，有工作(72%)。参与者的特征在干预组中是平衡的。在2、4和6个月时，分别有77%和75%的男性完成了研究访问。所有夫妇都可以获得活产结局，在随机分组后6个月，1629名男性(69%)有精液可供分析。 该试验的初步结果被接受并于2019年发表在《美国医学会杂志》(JAMA)上，并发表在2020年1月的《美国医学会杂志》上。总的来说，在寻求不孕不育治疗的普通夫妇中，与安慰剂相比，男性伴侣使用叶酸和锌补充剂并没有显著提高精液质量或夫妇的活出生率。然而，与随机服用安慰剂的男性相比，随机服用叶酸和锌的男性在6个月时精子DNA碎片显著增加，并报告更频繁的胃肠道症状。

Infertility affects 10 to 15% of couples attempting to conceive. Male factor subfertility plays a role in about 50% of sub-fertile couples, with largely unknown etiology. An intervention with even a small absolute effect on any component of male factor infertility has tremendous implications at the population level because of the large potential attributable benefit. Two micronutrients fundamental to the process of spermatogenesis, folic acid and zinc, are of particular interest as they offer a potential low cost and widely available treatment. While evidence has been inconsistent, small randomized trials and observational studies show that folate and zinc have biologically plausible effects on spermatogenesis and improved semen parameters. These results suggest that supplementation with folate and zinc may improve semen quality, and perhaps, assisted reproductive technology (ART) outcomes. While dietary supplements marketed for male fertility commonly contain folic acid and zinc based on limited prior evidence for improving semen quality, no large-scale trial has examined the efficacy of this therapy for improving semen quality or live birth. The Folic Acid and Zinc Supplementation Trial (FAZST) is a multi-center, double-blind, block-randomized placebo-controlled trial designed to determine whether folic acid and zinc supplementation in men improves semen quality and increases live birth rate among couples planning infertility treatment. Eligible men were aged 18 years or older with female partners aged 18-45 years. Overall, 2,370 men were randomized between June 2013 and December 2017 at 4 US reproductive and infertility care study centers. 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 matching placebo (n = 1185) daily for 6 months. Study visits were completed by men at baseline, 2, 4, and 6 months, and female partners were passively followed for a minimum of 9 months. Women who conceived were followed throughout pregnancy. The trial completed recruitment in December 2017, the last 6-month study visit for semen collection occurred in August 2018, and chart abstraction of live birth and pregnancy information was completed in April 2019. 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. Male participants had a mean age of 33 years and body mass index (weight (kg)/height (m)2) of 29.8. Most participants were white (82%), well educated (83% with some college), and employed (72%). Participant characteristics were balanced across intervention arms. Study visits were completed by 89%, 77%, and 75% of men at months 2, 4, and 6, respectively. Live birth outcomes were available for all couples, and 1629 men (69%) had semen available for analysis at 6 months after randomization. The primary findings for the trial were accepted for publication in the Journal of the American Medical Association (JAMA) in 2019 and published in the January 2020 issue of JAMA. Broadly, 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. However, men randomized to folic acid and zinc had significantly higher sperm DNA fragmentation at 6 months and reported gastrointestinal symptoms more frequently than men randomized to placebo.