Immune checkpoint inhibitors did not increase the risk of pregnancy abnormalities

Analysis of reports from the World Health Organization's global pharmacovigilance database has shown that the use of immune checkpoint inhibitors used for tumor therapy is not associated with increased reports of specific adverse pregnancy outcomes, fetal or neonatal abnormalities when compared with exposure to other antitumor drugs. Previously, the use of this class of drugs in pregnant women has been associated with a high risk of adverse fetal effects. The analysis is published in JAMA Network Open.

Pregnancy during active tumor treatment is a rare situation, occurring in 0.1 percent of pregnancies and 0.07-0.1 percent of all malignancies. The therapeutic management of pregnant women with cancer remains particularly challenging because it affects both mother and fetus. Immune checkpoint inhibitors (ICTIs) are widely used to treat a variety of malignancies. They are usually highly effective monoclonal antibodies targeting cytotoxic T-lymphocyte associated antigen 4 (CTLA-4), programmed cell death receptor 1 (PD-1) and its ligand.

However, ICTIs may decrease immune tolerance, potentially increasing the risk of immune-related side effects, including the development of autoimmunity. These side effects may reflect on the complex mechanism of maternal and fetal immune tolerance during pregnancy. In particular, expression of immune checkpoints (especially PD1) on T cells at the mother-child interface increases as pregnancy progresses and appears to prevent fetal immune rejection.

A team of scientists led by Paul Gougis of the University of Paris Cité analyzed all reports mentioning pregnancy-related conditions and anticancer drugs registered in the World Health Organization's international pharmacovigilance database as of June 26, 2022. A total of 3558 reports were included in the analysis, of which 91 reported exposure to ICTIs and the remainder to other antineoplastic drugs. The average age of the participants was 28.7 years. The most commonly diagnosed tumor types were breast cancer and chronic myeloid leukemia. The ICTI group used monoclonal antibodies against PD1, a mixture of antibodies against PD1 and CTLA4, antibodies against CTLA4, and several others.

Adverse outcomes for pregnancy, fetus, or newborn were described in 38 reports in the ICTI group (41.8 percent) and in 1,980 reports in the other anticancer drug group (57.1 percent) (relative risk 0.54). In an analysis of different regimens for the treatment of ICTI, the incidence of preterm birth was significantly overestimated with the combination of anti-PD1 and anti-CTLA4 compared with other anticancer drugs (p < 0.001). In the multivariate analysis, after adjusting for year, country, patient age, and tumor type, there was no statistically significant increased risk for all pregnancy and perinatal outcomes except miscarriage.

Overall, the researchers interpret the findings as evidence that the use of ICTI during pregnancy appears to be better tolerated than previously thought. However, due to possible rare immune-related neonatal side effects, the use of anti-PD1 or anti-PD-L1 plus anti-CTLA4 combinations should be avoided in pregnant women if possible.