The risk of chronic diseases and congenital malformations during childhood and adolescence after in utero exposure to thiopurines.

Abstract

Women with autoimmune diseases, particularly inflammatory bowel disease (IBD), often need to continue immunomodulatory therapies during pregnancy. While the evidence of birth and short-term outcomes in children exposed in utero to these medicines is reassuring, long-term safety data are lacking. To assess any association between in utero exposure to thiopurines and diagnoses of chronic diseases (type 1 diabetes, coeliac disease, thyroid disease, rheumatoid arthritis, IBD and asthma) and congenital malformations during childhood and adolescence. This nationwide cohort study was based on information using Danish registers and comprised all live-born children from 1995 to 2015 (N=1308778). Children exposed in utero to thiopurines were followed for a median of 8.9years (25%-75% percentiles 5.5-12.4years); children not exposed were followed for 13.9years (25%-75% percentiles 8.7-19.0years). Analyses were adjusted for a number of confounders including the type of maternal underlying disease. A total of 1047 children had been exposed to thiopurines in utero; 96 developed a chronic disease and 126 were diagnosed with congenital malformations during follow-up. The adjusted hazard ratio for rheumatoid arthritis was 0.78 (95% CI 0.35-1.73); for IBD, it was 1.45 (95% CI 0.64-3.27); for asthma 0.94 (95% CI 0.73-1.21), and for congenital malformations, it was 0.95 (95% CI 0.78-1.15). For type 1 diabetes, coeliac disease, thyroid disease and ulcerative colitis, we had insufficient data to perform adjusted analysis. We found no increased risk of seven common chronic diseases or congenital malformations during childhood and adolescence after gestational exposure to thiopurines.