Background/Purpose:

During pregnancy, maternal circulating immunoglobulins G (IgG) are actively transported across the placenta through their Fc portion. Thus, TNFi and other biologics harbouring an Fc part have the potential to transfer across the placenta, often reaching higher fetal than maternal levels. In addition, it is postulated that small-molecule drugs may cross the placenta, although this remains unconfirmed.  As fetuses could be exposed to therapeutic (or potentially supra-therapeutic) levels of biologics and small molecules, there are concerns that these agents could cause immunosuppression in exposed offspring. We compared the risk of serious infections in children born to mothers with chronic inflammatory diseases who used non-TNFi biologics or tofacitinib during pregnancy, versus unexposed offspring and children exposed to TNFi in utero.

Methods: We identified all women with ≥1 hospitalization for delivery after a diagnosis of rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriasis (PsO), psoriatic arthritis (PsA), or inflammatory bowel diseases (IBD), and a randomly selected group of unaffected mothers, matched ≥4:1 for age, year of delivery, and state of residence, using MarketScan database (2011-2016). Only women continuously enrolled within MarketScan for ≥12 months prior to delivery and with available child linkage were included. We defined tofacitinib, TNFi and non-TNFi biologic (i.e. abatacept, rituximab, tocilizumab, ustekinumab, vedolizumab) exposure based on ≥1 filled prescription and/or infusion procedure code during pregnancy and/or the preconception period. We ascertained serious infections in the offspring based on ≥1 hospitalization with infection as a primary diagnosis, within the first year of life. We also characterized all exposure groups according to maternal demographics, disease type, co-morbidities, pregnancy complications, and drug use (i.e. corticosteroids, DMARDs, biologics).

Results: We identified 16,490 offspring of mothers with RA (4,142), AS (381), PsO/PsA (5,743), and IBD (6,731), as well as 164,553 children born to unaffected matched mothers. Among offspring whose mothers had inflammatory diseases, 105 were exposed to tofacitinib or non-TNFi biologics (tofacitinib 4, abatacept 33, rituximab 4, tocilizumab 12, ustekinumab 42, vedolizumab 10) and 1,611 to TNFi during pregnancy. We observed 2 cases of serious infections in children exposed to tofacitinib or non-TNFi biologics (1.9%; 95% CI 0.3, 7.4): one case was exposed to tofacitinib, while the other was exposed to abatacept. The percent of serious infections in offspring of inflammatory disease mothers with no TNFi exposure was 2.1% (95% CI 1.9, 2.3), while for those with TNFi in utero exposure, it was 2.3% (95% CI 1.6, 3.0). In children born to unaffected mothers, the percent of serious infections was 1.6% (95% CI 1.6, 1.7).

Conclusion: In the largest cohort of inflammatory disease offspring ever assembled, we detected very few serious infections in children exposed to non-TNFi biologics or tofacitinib. More studies are necessary to precisely determine the specific effects of individual non-TNFi biologic and small-molecule drugs.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/serious-infections-in-offspring-exposed-in-utero-to-non-tnfi-biologics-and-tofacitinib/