Effects of paternal preconception exposure to conventional and biologic DMARDs on newborn outcomes.

backgroundBirth outcomes associated with conventional synthetic and biologic disease-modifying antirheumatic drugs (csDMARDs, bDMARDs and tsDMARDs) in fathers with autoimmune rheumatic diseases (AIRDs) is not well understood.

methodsTo examine the impact of paternal exposure to csDMARDs, bDMARDs or tsDMARDs on birth outcomes of offspring, specifically with regards to small for gestational age infants, preterm labor, and congenital abnormalities. We constructed a population-based birth cohort with fathers diagnosed with AIRDs from 2004 to 2020 using data from the Maternal and Child Health Database, Taiwan Birth Certificate Registry, and Taiwan National Health Insurance Research Data. Paternal preconception exposure was fathers who had been prescribed immunosuppressants or biologic drugs between 38 and 60 weeks before their newborn's delivery date. Inverse probability of treatment-weighted (IPTW) logistic regression models were used to assess the effects of variables on associations of interest considering other covariates.

resultsThe study analyzed 42,493 births to fathers with autoimmune conditions, with 14.3% of fathers exposed to immunosuppressants or biologic medications during the preconception period. The IPTW logistic regression analysis showed drug-specific risks during the preconception in preterm birth, birth defects, or very small for gestational age (VSGA). Individually, methotrexate showed no adverse effect on birth outcomes. However, certain medications, such as ciclosporin was associated with an increased risk of VSGA and preterm by 45% (95% confidence interval [CI] = 1.19 ~ 1.76) and 51% (95% CI = 1.35 ~ 1.70) respectively. Azathioprine (OR = 1.47, 95% CI = 1.31 ~ 1.65) was linked to higher birth defect risks, as were non-TNFis (OR = 1.69, 95% CI = 1.48 ~ 1.93) and tsDMARDs (OR = 5.19, 95% CI = 2.33 ~ 11.39). Fathers who received csDMARDs alone or combined with bDMARDs or tsDMARDs had an increased risk of birth defects (OR = 1.71, 95% CI = 1.47-2.00). Specific birth defects associated with bDMARDs included cardiovascular anomalies (OR: 1.61; 95% CI: 1.37-1.89), oral clefts (OR: 1.62; 95% CI: 1.15-2.29), and musculoskeletal defects (OR: 2.29; 95% CI: 1.82-2.89). Fathers exposed to csDMARDs combined with bDMARDs or tsDMARDs had increased risks of cardiovascular anomalies, oral clefts, and musculoskeletal defects.

conclusionWhile paternal use of methotrexate did not associate with adverse birth outcome, exposure to other immunosuppressants or biologic drugs may link to possible adverse birth outcomes despite small event numbers. This result highlight the importance of further clarification of drug safety in this field and medication use before planning a pregnancy, even in male patients.