(236) Reported Congenital Malformations After Exposure to Non-TNF-Α Inhibitors: A Retrospective Comparative Study in EudraVigilance Database

Publication Number: 567

Background: From biologics indicated for the treatment of autoimmune diseases, tumor necrosis factor-α inhibitors (TNFis) such as certolizumab pegol (CZP), have shown no increase in risk of congenital malformations (CMs) after use during pregnancy. However, for the subgroup of non-TNFis, very scarce data is available.

Objectives: To evaluate the number and nature of reported CMs after intrauterine exposure to non-TNFis compared to CZP, in Eudravigilance database.

Methods: A retrospective comparative study in EudraVigilance database was conducted. Reports of all pregnancies exposed to non-TNFis (abatacept, anakinra, belimumab, ixekizumab, rituximab, secukinumab, tocilizumab, ustekinumab, vedolizumab) and CZP, were extracted. After reading the full texts, multiple versions of a unique case (n=5767), pregnancies with unknown outcome (n=523), paternal exposures (n=92), CMs due to known genetic abnormalities (n=29), and cases exposed only via breast milk were excluded (n=13). Odd ratios (ORs) and their 95% confidence intervals [95%CIs] for CMs were calculated for each non-TNFi, with CZP as the reference group. Thereafter, in consultation with a clinical geneticist, CM patterns were compared to those reported in association with the CZP group.

Results: In total 2030 pregnancy reports were included (851 non-TNFi and 1179 CZP exposed). Numerical differences for CMs after exposure to non-TNFis were not statistically significant (p>0.05) except for belimumab and vedolizumab (adjusted ORs [95%CIs] for teratogen unexposed cases: 2.65 [1.35, 5.20] and 2.27 [1.24, 4.15], respectively). Except for vedolizumab, no specific CM patterns were observed.
For vedolizumab, three cases of corpus callosum agenesis (CCA) were reported (versus null in CZP and other investigated non-TNFis). Two of the CCA cases were associated with other neurological CMs such as a neural tube defect, microcephaly, and polymicrogyria. This may indicate that the reported CCAs may have been related to undiagnosed genetic alterations or were associated with underlying maternal disease, although a definite relationship with vedolizumab exposure cannot be ruled out.

Conclusions: Except for vedolizumab, no special safety signal was identified regarding the occurrence of CMs after exposure to non-TNFis. Based on available information, no firm conclusions can be made regarding observed CCA cases in the vedolizumab group. Since the analysis is based on spontaneous reports/retrospective data, additional studies are needed to confirm the results.