Reported congenital malformations after exposure to non-tumour necrosis factor inhibitor biologics: A retrospective comparative study in EudraVigilance

Br J Clin Pharmacol. 2022 Dec;88(12):5378-5388. doi: 10.1111/bcp.15471. Epub 2022 Aug 5.


Aims: To evaluate the number and nature of reported congenital malformations (CMs) after intrauterine exposure to non-tumour necrosis factor inhibitor biologics (non-TNFi biologics) compared to certolizumab pegol (CZP).

Methods: A retrospective comparative study was conducted in the EudraVigilance (EV) database. A safe biologic (CZP) was considered as the reference group. Odds ratios (ORs) for CMs were calculated for each non-TNFi biologic (including abatacept, anakinra, belimumab, ixekizumab, rituximab, secukinumab, tocilizumab, ustekinumab and vedolizumab), versus CZP (quantitative assessment). Then, CM patterns were reviewed in consultation with a clinical geneticist (qualitative assessment).

Results: ORs were not statistically significant except for belimumab and vedolizumab (similar in magnitude). Except for vedolizumab, no specific CM patterns were observed for the included non-TNFi biologics. Three cases of corpus callosum agenesis (CCA) were identified for vedolizumab (versus none in CZP and other investigated non-TNFi biologics). Two of the CCA cases were associated with other neurological CMs (one cerebral ventriculomegaly with microcephaly and one polymicrogyria). This may indicate that these CCAs are related to undiagnosed genetic alterations or are associated with the underlying maternal disease, although a definite relationship with vedolizumab exposure cannot be ruled out.

Conclusion: No special safety signal was identified regarding the occurrence of CMs after exposure to abatacept (n = 64), anakinra (n = 20), belimumab (n = 93), ixekizumab (n = 29), rituximab (n = 57), secukinumab (n = 128), tocilizumab (n = 124) and ustekinumab (n = 215). Regarding observed CCAs in the vedolizumab group (n = 113), no firm conclusions can be made based on available information.

Keywords: EudraVigilance database; autoimmune diseases; non-TNFi biologics; pregnancy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abatacept
  • Antirheumatic Agents* / adverse effects
  • Arthritis, Rheumatoid* / drug therapy
  • Biological Products* / adverse effects
  • Certolizumab Pegol / adverse effects
  • Humans
  • Interleukin 1 Receptor Antagonist Protein / therapeutic use
  • Necrosis
  • Retrospective Studies
  • Rituximab / therapeutic use
  • Tumor Necrosis Factor-alpha
  • Ustekinumab / therapeutic use


  • Abatacept
  • Antirheumatic Agents
  • Biological Products
  • Certolizumab Pegol
  • Interleukin 1 Receptor Antagonist Protein
  • Rituximab
  • Tumor Necrosis Factor-alpha
  • Ustekinumab