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 in adults and juvenile idiopathic (poly)arthritis. It is also used off-license as an acutely administered treatment for severe COVID-19.

While 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). Given the lack of dose equivalence, this finding is not considered relevant to human pregnancy exposure.

Human pregnancy safety data are provided by case reports/series which collectively describe 367 pregnancies among women with chronic conditions who were receiving regular treatment with tocilizumab, mainly from the time of conception. Where details were provided, most women discontinued tocilizumab use early in pregnancy; as such, evidence is generally lacking regarding the safety of longer-term use in pregnancy. An additional 51 cases of late gestational tocilizumab exposure have been reported in case reports/series which describe acute tocilizumab treatment of severe COVID-19. Few controlled studies exist and have only been conducted using non-denominator-based adverse drug event datasets. These studies include 357 adverse reaction reports where maternal tocilizumab use was used in pregnancy.

Due to minimal placental transfer of IgG antibodies prior to approximately 14 weeks’ gestation, direct fetal exposure following maternal use in early pregnancy is not anticipated. Studies using non-denominator-based adverse drug event datasets found no signal of adverse fetal or pregnancy outcomes. 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 expected background rates and no pattern of malformation has been observed. Furthermore, these observations are based on small numbers of exposed and affected pregnancies/infants which produced imprecise risk estimates. Of note, no adverse events considered attributable to tocilizumab exposure were described among the small number of women with acute treatment of severe COVID-19.

There is a 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 no data regarding the effect of in utero tocilizumab exposure on the neonatal/infant immune system. Guidance from Public Health England (PHE), issued 2017, specified that live vaccines should not be used until the infant is 6 months old following in utero biologic immunosuppressant exposure. It is unclear if an acute exposure to tocilizumab, such as in the treatment of severe COVID-19, could sufficiently impact neonatal immune function. In cases where there are clear risks with leaving a child unvaccinated, it may be important to consider the potential benefits of live vaccine 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.