BACKGROUND Thiopurines are widely used immunosuppressive agents. In high dosages, they inhibit the purine synthesis and are considered to be possibly harmful to spermatogenesis, and subsequently to men's fertility and their offspring. However, the clear association between thiopurine exposure and male fertility and reproduction safety, if any, is still poorly understood. OBJECTIVE AND RATIONALE The aim of this review was to systematically summarize and meta-analyse the available data, derived from animal and human studies, regarding the influence of thiopurine exposure on fertility and conception safety in men and their offspring. SEARCH METHODS A systematic literature search of the MEDLINE and EMBASE databases was performed using a combination of relevant terms related to 'thiopurines', 'fertility', 'conception', 'reproduction', 'semen quality' and 'birth outcome', combined with 'male', 'men', 'father' and 'paternal'. The search was not restricted exclusively to human subjects, neither to a type of disease or condition, to gather all available studies with regards to this topic. All published articles on thiopurines and male fertility, written in English and published until May 2017, were screened for eligibility. The GRADE guidelines were used to assess the quality of evidence of the included articles. OUTCOMES A total of 28 studies (including 14 observational studies in humans) were included in this review and six of these were included in the meta-analysis. In various rodents, thiopurines adversely affected the germ cells (in administered doses of 2 to 20 times the human equivalent dose). In human studies, thiopurine therapy was not evidently associated with impaired testicular function or semen quality in 83 men with a variety of underlying diseases. In total, 53 out of 975 offspring with congenital anomalies (5.4%, the background prevalence is 3%), possibly as a result of paternal thiopurine exposure, were described in all studies together. The risk of congenital anomalies was not significantly increased when compared with offspring without paternal thiopurine exposure (4.7%) (pooled odds ratio 1.32, 95% confidence interval 0.75, 2.34). WIDER IMPLICATIONS Thiopurines have spermatotoxic effects in rodents. In humans, overall data are limited and derived from underpowered studies, and therefore not conclusive with regards to the possible effects of thiopurines on spermatogenesis or paternally exposed offspring. Larger, epidemiological trials evaluating the safety of thiopurines to men's fertility and their offspring are mandatory to adequately counsel thiopurine treated men who wish to conceive.

中文翻译：

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硫嘌呤与男性生育力和父系暴露后代的关系：系统评价和荟萃分析。

背景硫嘌呤是广泛使用的免疫抑制剂。在高剂量下，它们会抑制嘌呤合成，并被认为可能对精子发生有害，进而对男性的生育能力及其后代造成伤害。然而，硫嘌呤暴露与男性生育能力和生殖安全之间的明确关联（如果有的话）仍然知之甚少。目的和理由 本综述的目的是系统地总结和荟萃分析来自动物和人类研究的可用数据，这些数据涉及硫嘌呤暴露对男性及其后代生育力和受孕安全性的影响。搜索方法 使用与“硫嘌呤”、“生育力”、“受孕”相关的相关术语对 MEDLINE 和 EMBASE 数据库进行系统的文献搜索 “生殖”、“精液质量”和“生育结果”，结合“男性”、“男性”、“父亲”和“父亲”。搜索不仅限于人类受试者，也不限于某种疾病或状况，以收集有关该主题的所有可用研究。所有发表的关于硫嘌呤和男性生育力的文章均以英文撰写并发表至 2017 年 5 月，均经过资格筛选。GRADE 指南用于评估纳入文章的证据质量。结果 本综述共纳入 28 项研究（包括 14 项人类观察性研究），其中 6 项纳入荟萃分析。在各种啮齿动物中，硫嘌呤对生殖细胞产生不利影响（给药剂量为人体等效剂量的 2 至 20 倍）。在人体研究中，硫嘌呤治疗与 83 名患有各种基础疾病的男性的睾丸功能或精液质量受损没有明显关联。总共有 975 名先天性异常的后代中有 53 名（5.4%，背景患病率为 3%），可能是由于父亲暴露于硫嘌呤，在所有研究中一起被描述。与父亲未接触硫嘌呤的后代（4.7%）相比，先天性异常的风险没有显着增加（合并优势比 1.32, 95% 置信区间 0.75, 2.34）。更广泛的影响硫嘌呤对啮齿动物具有精子毒性作用。在人类中，总体数据有限，并且来自动力不足的研究，因此对于硫嘌呤对精子发生或父系暴露后代的可能影响尚无定论。更大，