According to a new study, paternal exposure to immunosuppressive and biologic antirheumatic drugs before conception has adverse birth outcomes, which indicates the need for further emphasis on medication safety in men planning a family. This large population-based study found that while methotrexate was without a harmful association, other csDMARDs, bDMARDs, and tsDMARDs could be associated with increased risks of preterm birth for gestational age infants, and congenital anomalies. The study was published in the journal Arthritis Research & Therapy by Yu-Hsuan and colleagues.
The use of disease-modifying antirheumatic drugs (DMARDs), such as conventional synthetic (csDMARDs), biologic (bDMARDs), and targeted synthetic (tsDMARDs), is prevalent in autoimmune rheumatic diseases. Though maternal exposure to DMARDs is well studied, little is known about paternal exposure to DMARDs before conception in relation to offspring outcomes. A birth cohort analysis was conducted in this study among 42,493 offspring whose fathers had been diagnosed with autoimmune rheumatic diseases between 2004 and 2020.
The information was collected from the Maternal and Child Health Database, Taiwan Birth Certificate Registry, and Taiwan National Health Insurance Research Databases. Fathers were considered exposed if they received immunosuppressive medication/biologic therapy between 38 and 60 weeks before the offspring's birth; this is considered paternal exposure before conception.
Key findings
Among the 42,493 births, 14.3% of fathers were exposed to immunosuppressants or biologic medications during the preconception period.
Methotrexate showed no significant association with adverse birth outcomes.
Ciclosporin exposure was associated with a 45% increased risk of VSGA (OR = 1.45; 95% CI 1.19–1.76) and a 51% increased risk of preterm birth (OR = 1.51; 95% CI 1.35–1.70).
Azathioprine was linked to a higher risk of birth defects (OR = 1.47; 95% CI 1.31–1.65).
Non-TNF biologics were associated with increased birth defect risk (OR = 1.69; 95% CI 1.48–1.93).
tsDMARDs showed the highest association with birth defects (OR = 5.19; 95% CI 2.33–11.39).
Fathers treated with csDMARDs alone or in combination with bDMARDs or tsDMARDs had a 71% higher risk of birth defects (OR = 1.71; 95% CI 1.47–2.00).
Cardiovascular anomalies (OR = 1.61; 95% CI 1.37–1.89)
Oral clefts (OR = 1.62; 95% CI 1.15–2.29)
Musculoskeletal defects (OR = 2.29; 95% CI 1.82–2.89)
This national cohort study demonstrates that paternal use of methotrexate was not found to increase adverse birth outcomes, but that exposure to other immunosuppressive and biologic or targeted synthetic DMARDs could potentially be associated with the development of adverse birth outcomes such as preterm birth, VSGA, and congenital anomalies. The findings emphasize the importance of individualized counseling before pregnancy planning in these men with autoimmune rheumatic disease.
Reference:
Shao, YH.J., Kuo, TT., Wang, WH. et al. Effects of paternal preconception exposure to conventional and biologic DMARDs on newborn outcomes. Arthritis Res Ther 27, 223 (2025). https://doi.org/10.1186/s13075-025-03641-5
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