Tocilizumab for coronavirus disease 2019 in pregnancy and lactation: a narrative review

Abstract

Background Tocilizumab is a monoclonal antibody that interrupts interleukin-6 signaling, reducing downstream effects on inflammation and the innate immune response. It was shown to reduce mortality in patients with severe or critical COVID-19. Pregnant and breastfeeding people were largely excluded from clinical trials and hence, the extent to which results can be applied to these populations is not clear. Objectives To synthesize published data on tocilizumab in pregnancy and lactation, highlight important knowledge gaps, and help inform clinical decision-making about tocilizumab’s use in these populations with COVID-19. Sources PubMed was searched for studies evaluating tocilizumab in pregnancy and lactation for COVID-19 and other indications. Literature on pharmacokinetics and reproductive/fetal safety of monoclonal antibodies in general was also sought. US FDA and EMA guidance for the industry and regulatory approval documents were reviewed. Content Published data on tocilizumab in pregnancy includes 610 cases (n=20 with COVID-19) together with 7 mother-infant breastfeeding pairs. Higher rates of spontaneous abortion and premature birth have been reported compared to the general population, but multiple confounding variables limit interpretation. There is little data on tocilizumab exposure in the second and third trimesters when transplacental transport is highest. The effects of tocilizumab on the developing immune system are unclear. Pregnant patients with COVID-19 who received tocilizumab were often critically ill and corticosteroid use was uncommon. Neonatal follow-up was limited. Tocilizumab appears to be compatible with breastfeeding. Implications Although the available data do not raise serious safety signals, they have significant limitations and are not sufficient to delineate the complete spectrum of potential adverse outcomes that may be associated with tocilizumab exposure during pregnancy and lactation. Diligent follow-up and documentation of pregnancy outcomes will be important moving forward. A more effective regulatory framework to ensure equitable inclusion of pregnant people in research is clearly needed.

Diagnosis and management of covid-19 in pregnancy

“…In the limited data for the use of tocilizumab in pregnant patients with covid-19, administration is most frequently in the third trimester and in all cases reported to date, the pregnancies have resulted in live births 46. Tocilizumab is excreted in very low levels in breast milk and is not considered a contraindication to breastfeeding 47…”

IL-6 and IL-8: An Overview of Their Roles in Healthy and Pathological Pregnancies

“…Therefore, applying IL-6-reduction strategies as anti-IL-6 monoclonal Abs (mAbs) or TLR inhibitors to the treatment of PE, could shift the differentiation of naïve CD4 + T cells towards the anti-inflammatory Treg and Th2 phenotype, rather than the pro-inflammatory Th1 and Th17 one [ 219 ]. Of note, although the current data do not indicate a substantially increased malformation risk of using anti-IL-6 mAbs in pregnancy, they are insufficient to prove safety [ 220 , 221 ].…”

Pharmacological consideration of COVID-19 infection and vaccines in pregnancy

“…51 TCZ is licensed in over 75 countries for rheumatoid arthritis and related rheumatological diseases and chimeric antigen receptor T-cell therapy-associated cytokine release syndrome. 52 In a German case series, among 16 prospectively registered cases with maternal TCZ, 4 had spontaneous abortions (SAB). 53 In Hoeltzenbein et al review of pregnancy-related TCZ safety database review, among 108 reported pregnancies, 50.9% of live births, 28.7% spontaneous abortions, 20.4% of elective terminations, and three infants with congenital anomalies were reported.…”