USE OF TOCILIZUMAB IN PREGNANCY

Tocilizumab is a recombinant humanized, anti-human monoclonal antibody of the IgG1 subclass directed against soluble and membrane-bound receptors of interleukin 6. It is licensed to treat giant cell arteritis and as second line therapy for rheumatoid arthritis. For rheumatoid arthritis, tocilizumab is licensed for use in combination with methotrexate, but is also used in monotherapy in cases of methotrexate intolerance or contraindication.

Although preclinical animal studies have not demonstrated that tocilizumab exposure in pregnancy is associated with fetal structural anomalies, a possible increase in the crude rate of embryo/fetal deaths has been described. However, this increase in embryo/fetal demise was only observed following high dose maternal exposure (>100 times the human therapeutic dose).

There are currently no controlled studies of tocilizumab use in human pregnancy. The currently available evidence consists of a small number of case reports/series which together describe approximately 360 unique exposed pregnancies. As these reports lack comparator pregnancies, limited conclusions can be provided about the fetal risks of maternal tocilizumab use in pregnancy. Furthermore, where details were provided, most women discontinued tocilizumab use early in pregnancy meaning that there is limited knowledge of the risks posed by ongoing exposure.

Although adverse pregnancy outcomes have been described following in utero exposure to tocilizumab, including cases of congenital anomaly, miscarriage, low birth weight and preterm delivery, the crude rates of these events do not appear notably increased above their respective background rates. Furthermore, these observations are based on small numbers of exposed and affected pregnancies/infants which produced inaccurate risk estimates. Furthermore no pattern of malformation has been observed, concomitant methotrexate exposure (a known teratogen and abortifacient) was common, and methodological biases likely exist.

There is theoretical concern that immunosuppressant antibodies which actively cross the placenta during pregnancy could result in neonatal/infant immunosuppression and an increased risk of infection. There are currently very limited data regarding the effect of in utero tocilizumab exposure on the neonatal/infant immune system. Guidance from Public Health England (issued 2017) specified that live vaccines should not be used until the infant is 6 months old following in utero biologic immunosuppressant exposure.

There is currently no compelling evidence that tocilizumab is teratogenic or fetotoxic. However, owing to the limited evidence currently available, all first trimester exposed patients should have their 20 week ultrasound scan conducted by a clinician experienced in the prenatal detection of malformations. There is currently no evidence to indicate that any additional fetal monitoring is required. However, other risk factors may be present in individual cases which may independently increase the risk of adverse pregnancy outcome. Clinicians are reminded of the importance of consideration of such factors when performing case specific risk assessments.