Antirheumatic drugs in reproduction, pregnancy, and lactation: a systematic literature review informing the 2024 update of the EULAR recommendations

This study aimed to summarise and update evidence to inform the 2024 update of the European Alliance of Associations for Rheumatology recommendations for the use of antirheumatic drugs in reproduction, pregnancy, and lactation. A systematic literature review (SLR) was performed, including keywords on reproduction, adverse pregnancy outcomes (APOs), and lactation. Two appraised SLRs were the basis for the SLR on drug safety in men. If sufficient data were available, a meta-analysis was performed on maternal drug exposure and the risk of APOs. Of 6680 screened articles, 255 were included in the final analysis. In pregnancy, most evidence was available for biologic disease-modifying antirheumatic drugs (bDMARDs). Meta-analyses with adjusted risk estimates did not reveal APOs or serious infant infections to be associated with tumour necrosis factor inhibitor (TNFi) use. Data on non-TNFi bDMARDs did not raise concerns. In bDMARD-exposed infants, no serious adverse effects to rotavirus live vaccination were reported. Safety of Bacille Calmette-Guérin vaccination in TNFi-exposed infants could be a concern in the first 6 months of life. Regarding oral glucocorticoids, the SLR and meta-analysis using adjusted risk estimates found a dose-dependent association with an increased risk of preterm birth. Nonsteroidal anti-inflammatory drug use could reversibly reduce fecundability. Concerning lactation, available data on various bDMARDs was reassuring. In male patients, available evidence on methotrexate and most other drugs did not reveal adverse effects on sperm quality or birth outcomes. Cyclophosphamide remains the only drug that causes a dose-dependent irreversible infertility. This SLR provides up-to-date evidence to guide the 2024 update of the European Alliance of Associations for Rheumatology recommendations for the use of antirheumatic drugs in reproduction, pregnancy, and lactation.