Background: Tumor necrosis factor inhibitors (TNFi) used during pregnancy cross the placenta, particularly in the third trimester, and may persist in neonatal circulation for several months after birth. As TNF is essential for early lymphoid development and IL-12/IFN-γ–mediated responses to mycobacterial infection, prenatal TNFi exposure may disrupt neonatal immune maturation and increase the risk of immune dysfunction.

Objectives: This study aims to assess the safety of TNFi exposure during pregnancy in relation neonatal immune system development.

Methods: We conducted a longitudinal evaluation of immune development in infants exposed to TNFi in utero, from birth (umbilical cord blood) through one year of age (peripheral blood). Analyses included: (1) lymphocyte subset development; (2) cytokine responses to mycobacterial stimulation to assess IL-12/IFN-γ axis functionality; and (3) humoral immunity, including immunoglobulin levels and vaccine responses. Outcomes were compared with those from an age-matched healthy pediatric cohort. Clinical follow-up was performed by a pediatric immunologist, monitoring growth, infection incidence, and signs of immune dysregulation until one year of age.

Results: Fifty infants born to mothers with rheumatic diseases or inflammatory bowel disease were enrolled, including pregnancies treated with TNFi (adalimumab [ADA], n=16; infliximab [IFX], n=11; etanercept [ETN], n=5; certolizumab pegol [CZP], n=11) and untreated controls (n=7). Infants exposed to TNFi with higher placental transfer (ADA and IFX) showed delayed T cell maturation during the first year of life, characterized by increased naïve T cells, reduced memory T cells, and decreased regulatory T cells at birth. In contrast, minimal immunological alterations were observed in CZP- and ETN-exposed infants, and B cell immunity remained largely intact across groups. Functional impairment of the IL-12/IFN-γ axis was detected at birth in ADA- and IFX-exposed newborns, with progressive recovery following postnatal drug clearance, supporting postponement of BCG vaccination until complete elimination of TNFi. Clinically, no increase in infection rates was observed; however, 12 of 50 children developed mild to moderate allergic manifestations, which were associated with reduced regulatory T cell frequencies.

Conclusions: Exposure to TNFi during pregnancy may have lasting implications for neonatal immune development. Targeted immunological monitoring and specialized follow-up are warranted in exposed infants.

REFERENCES: NIL.

Acknowledgments: NIL.

Disclosure of Interests: None declared.