Impact of immune checkpoint inhibitors on pregnancy: current evidence and future directions

Cancer treatment has dramatically improved with the introduction of immune checkpoint inhibitors (ICIs). They are now common treatments for individuals of reproductive age, an important consideration when treating pregnant patients. Cancer in pregnancy is rare and guidelines available for ICI use during gestation are based on pre-clinical studies, single human case reports and spontaneous report databases. The immune pathways including PD-1 and PD-L1/PD-L2 and CTLA-4 provide critical immune inhibitory checkpoints at the maternal-fetal interface. These pathways support immune tolerance during implantation and the development of the placenta. Experimental animal studies demonstrated that inhibiting these immune pathways will result in increased frequency of adverse events such as spontaneous abortions and premature births. Human placental transfer of ICIs across the placenta is minimal in early gestation and increases in later gestation, coinciding with less exposure to developing organs during organogenesis and more exposure closer to term. There are now seventeen documented cases in the literature describing pregnant patients treated with ICIs. Most neonates developed normally in infancy, while there are a few documented cases of suspected neonatal immune-mediated complications. Experts including regulatory agencies and oncology professional organisations advise against the use of ICIs in pregnancy unless their use is critical to the survival of the patient and there is no safer alternative. Patient counselling regarding the risks of using ICIs during pregnancy, postpartum or both, involves a multidisciplinary team and requires shared decision making regarding maternal health, infant follow-up and standardised documentation for understanding potential delayed effects on neonate immunity as well as providing accurate information for future counselling.