Background: During pregnancy, maternal circulating antibodies cross the placenta. Offspring exposed in utero to tumour necrosis factor inhibitors (TNFi) may experience immunosuppression and subsequent infections in their first year of life due to TNFi entering the fetal bloodstream. TNFi subtypes have differential trans-placental passage capabilities. Most (i.e. adalimumab, infliximab, golimumab) are monoclonal antibodies, with adalimumab and infliximab having the highest transfer, reaching higher fetal than maternal levels. Certolizumab (a pegylated Fab fragment) and etanercept (a fusion protein) display the lowest passage. Thus, depending on the TNFi subtype, the risk of immunosuppression may differ, and some offspring may be exposed to supra-therapeutic doses of TNFi. Therefore, the risk of serious infections in offspring by TNFi subtype needs to be clarified.

Objectives: We evaluated the risk of serious infections leading to hospitalization in offspring born to mothers with chronic inflammatory diseases who used TNFi during pregnancy depending on whether they had low or high placental transfer.

Methods: In this population cohort study, we identified offspring born in 2011-2019 to women with a prior diagnosis of rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, and/or inflammatory bowel diseases in the IBM MarketScan commercial database using commercial claims only. Women were included if they had been continuously enrolled within MarketScan with medical and pharmacy coverage for ≥12 months prior to delivery and had a child linked to them. TNFi exposure was defined as ≥1 filled prescription and/or infusion procedure code during pregnancy. Exposure was further categorized into high (i.e. infliximab, adalimumab, golimumab) and low (i.e. certolizumab, etanercept) placental transfer ability. Serious infections were ascertained based on ≥1 hospitalization with infection as the primary diagnosis in the offspring’s first year of life. We performed multivariable time-to-event analysis using a Cox proportional hazards model, adjusting for maternal age at delivery, chronic inflammatory disease diagnosis, maternal co-morbidities (pre-gestational diabetes, asthma), pregnancy complications (gestational diabetes, preterm birth), and other drug use (corticosteroids and non-biologic DMARDs).

Results: We identified 26,088 offspring, among whom 2,902 (11.1%) were exposed to TNFi during pregnancy. The majority of offspring (1,506; 51.9%) were born to mothers with inflammatory bowel diseases. Out of the 2,902 offspring with TNFi exposure, 797 (27.5%) and 2,105 (72.5%) were low and high placental transfer drugs, respectively. The frequency of serious infections was 1.3% and 1.8% in those offspring exposed to TNFi with low and high placental transfer, respectively. The incidence rate (IR) of serious infections in offspring exposed to TNFi with high vs. low placental transfer was, respectively, 2.27 (95% confidence interval, CI 1.61, 3.12) cases per 100 person-years at risk vs. IR 1.59 cases per 100 person-years at risk (95% CI 0.76, 2.92). In multivariable analyses, the adjusted hazard ratio for serious infections with the use of TNFi with high versus low placental transfer was 1.20 (95% CI 0.54, 2.64).

Conclusion: Although children exposed to high transfer TNFi may have a higher risk of serious infection, we saw no clear excess risk of serious infections in children exposed in utero to TNFi with high versus low placental transfer due to the wide confidence interval.

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Disclosure of Interests: None declared