Abstract
Background/Aims
Increasing utilisation of biologic disease modifying anti-rheumatic drugs (DMARDs) and targeted synthetic (ts)DMARDs in women of reproductive age has potential for informed or accidental use in pregnancy and impact on fetal immunity. Transplacental passage of certain biologic DMARDs result in detectable drug levels in the neonate. Current British Society for Rheumatology (BSR) guidelines recommend all live vaccines be delayed in infants until 7 months of age after in-utero exposure in later pregnancy to the tumour necrosis factor inhibitors (TNFi) etanercept, adalimumab or infliximab. This advice affects administration of rotavirus, BCG and potentially MMR vaccination. Therefore, we performed a systematic review to evaluate vaccine safety in infants exposed to bDMARDs or tsDMARDs in pregnancy.
Methods
A systematic review of Embase, Medline and Cochrane identified live vaccine outcomes in the infants of mothers who took bDMARDs or tsDMARDs during pregnancy, focussing on drugs used in standard rheumatology practice. Studies were reviewed in accordance with the PRISMA guidelines.
Results
A total of 226 titles and abstracts were screened and 8 papers selected for final analysis. Studies included in-utero exposures to adalimumab (n = 326), certolizumab pegol (n = 18), etanercept (n = 1), infliximab (n = 408), golimumab (n = 1), rituximab (n = 1), tocilizumab (n = 3) and ustekinumab (n = 1). No relevant articles on tsDMARDs were identified. Maternal disease included inflammatory bowel disease (n = 849), rheumatoid arthritis (n = 3) and Burkitt’s lymphoma (n = 1). For infants exposed to biologic medications in utero, we identified infant vaccination to: BCG (n = 111) and/or rotavirus (n = 48) in the first year of life, many < 6 months; and MMR (n = 605) at 12 months (n = 590), 6-9 months (n = 12) and at 1, 2 or 4 months (n = 3). Adverse events with BCG vaccination included 1 death, 2 large local skin reactions, and 1 infant with axillary lymphadenopathy. A freedom of information request to the MHRA revealed 4 further suspected fatal BCG infections in infants exposed to TNFi in-utero (2 infliximab, 1 adalimumab, 1 unspecified TNFi). Side-effects noted in infants given rotavirus vaccination were mild and at similar frequency to those in non-biologic exposed infants. No complications were reported with MMR vaccination.
Conclusion
Overall, we found most evidence of clinically harmful effects after administration of BCG to infants < 3 months of age and after in-utero exposure to infliximab. In contrast, outcomes following rotavirus (mostly < 6 months) and MMR (mostly at a year) vaccinations were reassuring. These findings are limited to live vaccine usage at standard time points in Europe/USA following maternal use of TNFis with significant placental transfer. Therefore, further understanding of live vaccine safety after exposure to any bDMARD or tsDMARD is required, including confirmation of the presumed safety of live vaccine use following maternal usage of bDMARDs with negligible rates of placental transfer.
Disclosure
B. Goulden: None. N. Chua: None. E. Parker: None. I. Giles: Consultancies; Educational grant from UCB; speakers fees from UCB; travel fees from UCB. Other; Chair of guideline group on prescribing anti-rheumatic drugs in pregnancy for British Society of rheumatology.
Gadolinium Chelate Safety in Pregnancy: Barely Detectable Gadolinium Levels in the Juvenile Nonhuman Primate after in Utero Exposure