Paternal use of azathioprine/6-mercaptopurine or methotrexate within 3 months before conception and long-term health outcomes in the offspring-A nationwide cohort study

Abstract

Purpose: We examined the effect of preconception paternal use of azathioprine (AZA)/6-mercaptopurine (6-MP) or methotrexate (MTX) and the risk of adverse long-term outcomes in the offspring.

Methods: This study included all children born in Denmark from 1 January 1997 through 2013. Exposed cohort: children fathered by men who used AZA/6-MP (N=735) or MTX (N=209) within three months before conception; unexposed cohort: children fathered by men who did not use AZA/6-MP/MTX (N=1,056,524).

Outcomes: malignancies, autism spectrum disorders (ASD)/schizophrenia/psychosis, and attention deficit hyperactivity disorder (ADHD).

Results: Outcomes: of children: AZA/6-MP exposure: one with leukemia (0.14%), one with ASD/schizophrenia (0.14%) and three with ADHD (0.41%); MTX exposure: three with ADHD (1.4%). Unexposed: 1710 with malignancies (0.16%), 2107 with ASD/schizophrenia (0.20%), 2799 with ADHD (0.26%). Median follow up times were 6.7 [IQR:3.6-11.3] and 9.9 [IQR:5.7-14.3] years respectively.

Conclusions: There was no negative impact of paternal preconception use of AZA/6-MP/MTX on selected childhood health outcomes.

Keywords: Cancer; Epidemiology; Methotrexate; Offspring; Paternal; Reproduction; Thiopurines.