The associations of thiopurines with male fertility and paternally exposed offspring: A systematic review and meta-analysis

Abstract

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.