Azathioprine (AZA) and 6-mercaptopurine (6-MP) are immunomodulatory agents that have been used for decades to treat inflammatory bowel disease, autoimmune conditions, and organ transplant recipients. It has recently been realized that fathers can transfer adverse effects to their offspring via exposure of developing sperm to drug or environmental toxicities, but there is no data on the long-term outcomes in the offspring of fathers treated with AZA/6-MP within 3 months of conception. Two of the main concerns are whether paternal use of AZA/6-MP might have an impact on the long-term risk of cancer or developmental disabilities in the offspring. AZA/6-MP may cause chromosomal abnormalities in the sperm of male mice and may be a potential teratogen/carcinogen. Furthermore, preliminary evidence has suggested an association between autism spectrum disorder (ASD) and psychoses, and a family history of autoimmune disease.Background:
To assess the potential toxicity of AZA/6-MP, we examined the effect of paternal use of AZA/6-MP within 3 months before conception and the risk of malignancies, ASD, schizophrenia, psychosis, and attention deficit hyperactivity disorder (ADHD) in the offspring up until an age of 18 years.Methods:
The study was based on Danish nationwide health registries. The study included all children born alive in Denmark in the period of 1 January 1997 to 31 December 2013 as recorded in the Danish Medical Birth Registry. For all children, we linked information on paternal filled prescriptions of AZA/6-MP in the period of 3 months prior to conception. Prescription information was obtained from the nationwide prescription database. Outcome information was derived from the National Patient Registry where we identified whether the children from time of birth until the age of <19 years or the end of follow-up 31 May 2015 had at least one code within the categories of (1) all kinds of malignancies; (2) ASD, schizophrenia, psychosis; or (3) ADHD.Results:
The exposed cohort constituted children fathered by men with at least one filled prescription for AZA/6-MP within 3 months before conception (N = 735), and the unexposed cohort was all children fathered by men who had no filled prescriptions for AZA/6-MP 3 months before conception (N = 1,057,136). We identified the following outcomes among exposed children: one with leukemia (0.14%); one with autism/schizophrenia (0.14%); 3 with ADHD (0.41%). The median follow-up period among exposed children was 6.7 (IQR 3.6–11.3) years.Results:
Among the unexposed cohort we identified 1711 (0.16%) with malignancies; 2109 (0.20%) with autism/schizophrenia; 2803 (0.27%) with ADHD. The median follow-up period among non-exposed children was 9.91 (IQR 5.7–14.2) years. The reason for the shorter follow-up period among exposed versus unexposed was that paternal AZA/6-MP exposure was less frequent at the start of the study period compared to later in the study period.Results:
The low number of outcomes in the exposed cohort did not allow further analyses.Conclusions:
These first data on selected long-term outcomes in children of fathers exposed to AZA/6-MP just before conception do not suggest a negative impact on the health of the child. More data with longer follow-up is warranted.