Aim To evaluate the number and nature of reported congenital malformations (CMs) after intrauterine exposure to non-tumour necrosis factor inhibitors (non-TNFis) compared to certolizumab pegol (CZP) Material and methods A retrospective comparative study was conducted in the EudraVigilance (EV) database. EV is a pharmacovigilance database, which can be used for detecting safety signals and generating hypotheses on possible relations between drugs and adverse events. A supposedly safe biologic (CZP) was considered as the reference group. Pregnancy-reports of non-TNFis and CZP were extracted. Odds ratios (ORs) for CMs were calculated for each non-TNFi, versus CZP (quantitative assessment). Then, CM patterns were compared to CZP in consultation with a clinical geneticist (qualitative assessment). Results ORs were not statistically significant except for belimumab and vedolizumab (similar in magnitude). Although qualitative analyses did not show any specific patterns for belimumab but three cases of corpus callosum agenesis (CCA) were identified for vedolizumab (versus null in CZP and other investigated non-TNFis). 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 non-TNFis, except for vedolizumab. Based on available information, no firm conclusions can be made regarding observed CCAs in the vedolizumab group (it warrants further research)

Objective To investigate the risk of congenital heart defects (CHD) and other congenital anomalies (CA) associated with first trimester use of macrolides. Design Population-based case-malformed control study. Setting Thirteen European countries. Population Data on 145,936 livebirths, stillbirths and terminations of pregnancy for CA from 15 EUROCAT registries, covering 9 million births 1995–2012. Methods Cases were babies with CHD, anencephaly, orofacial clefts, genital and limb reduction anomalies associated with antibiotic exposure in the literature. Controls were babies with other CA or genetic conditions. A meta-analysis of the literature, including this study, was conducted for CHD. Main outcome Odds ratios adjusted (AOR) for maternal age and registry, with 95% Confidence Intervals (95%CI). Results Macrolide exposure was recorded for 307 cases, 72 non-genetic controls, 57 genetic controls. AOR for CHD was not significantly raised (AOR 0.94, 95%CI: 0.70 – 1.26 vs non-genetic controls; AOR 1.01, 95%CI: 0.73 – 1.41 vs genetic controls), nor significantly raised for any specific macrolide. The risk of atrioventricular septal defect was significantly raised with exposure to any macrolide (AOR 2.98; 95%CI: 1.48 – 6.01), erythromycin (AOR 3.68, 95%CI: 1.28 – 10.61), and azithromycin (AOR 4.50, 95%CI: 1.30 – 15.58). Erythromycin, clarithromycin, azithromycin and clindamycin, were also associated with an increased risk of at least one other CA. Meta-analysis gave an overall CHD OR 1.14, 95%CI 0.90 –1.49 for macrolides. Conclusions Guidelines for macrolide use in pregnancy should consider the increased risk of specific CA. This is relevant for the potential use of azithromycin in the treatment of COVID-19.