Is Tocilizumab (Interleukin-6 receptor antagonist) recommended during pregnancy?

Tocilizumab Use During Pregnancy

Tocilizumab should be continued while trying to conceive but discontinued immediately once pregnancy is confirmed, unless severe life- or organ-threatening maternal disease requires continuation. 1

Primary Recommendation

The American College of Rheumatology (2020) provides a conditional recommendation to continue tocilizumab while a woman is trying to conceive, but to discontinue the medication at the time of the first positive pregnancy test. 1 This represents the standard approach for non-TNF inhibitor biologics containing an IgG construct.

Rationale for Discontinuation

• Placental transfer timing: Tocilizumab, as an IgG-based monoclonal antibody, does not cross the placenta in significant concentrations until the second trimester, making periconception and early first-trimester exposure relatively lower risk. 1

• Limited safety data: There are insufficient data to establish the complete safety profile of tocilizumab throughout pregnancy, with only limited human pregnancy experience available. 2, 3, 4

• Fetal immune system concerns: The FDA label warns that monoclonal antibodies like tocilizumab are actively transported across the placenta during the third trimester and may affect immune response in the in utero exposed infant. 2

Exception: Severe Maternal Disease

If rheumatic disease cannot be controlled with pregnancy-compatible medications, continuation of tocilizumab may be considered when severe life- or organ-threatening maternal disease warrants it. 1 This decision requires:

• Careful discussion with the patient about potential risks versus risks of uncontrolled disease 1
• Recognition that uncontrolled rheumatic disease is associated with adverse pregnancy outcomes including preterm delivery, low birth weight, and small for gestational age infants 2
• Understanding that the neonate will have drug exposure if treatment continues into later pregnancy 1

Available Safety Data

General Population Data

• A global safety database analysis of 288 pregnancies with known outcomes showed: 60.6% live births, 21.7% spontaneous abortions, 17.2% elective terminations, and 4.5% malformation rate. 4
• An increased rate of preterm birth (31.2%) was observed compared to the general population. 4
• A German pharmacovigilance study of 16 maternal exposures found no congenital malformations, though one spontaneous abortion was complicated by hydrops fetalis of unknown origin. 5

COVID-19 Specific Data

• In pregnant women with severe COVID-19,12 pregnancies treated with tocilizumab resulted in all live births with normal somatometric values and favorable evolution. 6
• Hepatotoxicity (2 patients) and cytomegalovirus reactivation (1 patient, also on corticosteroids) were observed, classified as possibly related to tocilizumab. 6

Clinical Management Algorithm

If inadvertent exposure occurs:

1. Do not recommend elective termination based on tocilizumab exposure alone 5, 4
2. Offer detailed prenatal ultrasound for fetal assessment 5
3. Counsel about available safety data including the lack of substantially increased malformation risk in reported cases 4

If continuation is necessary:

1. Document severe, uncontrolled maternal disease that cannot be managed with pregnancy-compatible alternatives 1
2. Discuss risks and benefits including potential fetal immune system effects 2
3. Plan neonatal follow-up including consideration of delaying live vaccines if third-trimester exposure occurred 1

Important Caveats

• Avoid live vaccines in exposed infants: If tocilizumab continues during pregnancy, live vaccinations (including BCG) should be postponed for the infant for the first 12 months. 1

• Breastfeeding compatibility: Tocilizumab is conditionally recommended as compatible with breastfeeding, as large monoclonal antibodies have minimal transfer into breast milk and poor oral bioavailability. 1

• Paternal exposure: No increased risks for adverse pregnancy outcomes were observed after paternal tocilizumab exposure in 13 pregnancies. 4

• Drug interactions: The FDA warns that tocilizumab may affect CYP450 enzyme activity, potentially decreasing effectiveness of oral contraceptives, which is relevant for pregnancy planning. 2