Informing Patients With Cancer About the Potential Impact of Immunotherapy on Pregnancy

Informing Patients With Cancer About the Potential Impact of Immunotherapy on Pregnancy

Diagnosis of cancer during pregnancy, as well as pregnancy arising during cancer treatment, is not common. Oncology nurses have good knowledge of teratogenic effects of chemotherapy and the potential of fetal malformations. The approval of pembrolizumab (Keytruda) in 2014 opened a new chapter of cancer therapy with immune checkpoint inhibitors (ICIs). It is generally recommended to avoid administration of ICIs during pregnancy. Oncology nurses play crucial roles educating patients about treatment, side effects, and fertility, in addition to potential effects on pregnancy and fetus.

ICIs are utilized in treatment of various cancer types and widely used for treatment of women of reproductive age. The potential adverse effects of ICIs on pregnancy require a thorough and careful approach. The American Society of Clinical Oncology (ASCO) and the European Society of Medical Oncology state that ICIs should be avoided during pregnancy and treatment should be postponed until after delivery. The FDA classifies anti-PD-1 immunotherapy (e.g., pembrolizumab) as category D, which means that there is enough evidence that they can cause harm to fetus. Medications which target CTLA-4 (e.g., ipilimumab [Yervoy]) are classified as category C; animal studies have data of harm to fetus, but there is not enough information about harmful impact on human fetus. In cases when ICIs are administered during pregnancy, it is recommended to monitor pregnancy closely for complications.

Cancer and pregnancy have similarities in immunological response and utilize similar immune check point pathways to block immune system. During pregnancy, the immune system of the mother experiences some changes to accept the fetus and prevent rejection, which is an essential part of successful pregnancy. The fetus presents paternal antigens which are recognized by the maternal immune system as foreign. The maternal immune system encounters significant changes to accept the fetus. When a regulatory mechanism is activated, it facilitates immunological tolerance of the fetus. If a regulatory mechanism is not turned on, the activated immune response can lead to fetal malformation or spontaneous termination of pregnancy.

Several types of checkpoint proteins are involved in immune-regulatory process during pregnancy: PD-1, CTLA-4, and TIM-3. PD-1 expression is elevated during pregnancy, and the PD-1/PD-L1 pathway plays an important role in maintaining immune tolerance and protecting the fetus from maternal immune response. Different types of immune cells are involved in the activation of regulatory mechanisms including dendritic cells, regulatory T cells, and innate lymphoid cells.

Cancer cells utilize PD-1/PD-L1 pathway; the PD-1 protein is expressed on T cells, and normal tissue cells express PD-L1 protein. PD-L1 is present on many healthy cells such as the heart, lung, spleen, and placenta. When PD-L1 binds to PD-1 on T cells, it sends a message to the immune system that it is a normal cell and stops the immune system from attacking its own cells. Cancer cells utilize this mechanism by expressing the PD-L1 protein on the surface, and the immune system is not able to recognize cancer cells and destroy them. ICIs reactivate T cells and guide the immune system in recognizing cancer cells. Administration of ICIs during pregnancy can lead to alterations in PD-1 expression and dysregulation of PD-1/PD-L1 pathway, which can lead to an immune activation against the fetus and preterm labor.

Literature provides controversial information about administration of ICIs during pregnancy. Most of the knowledge comes from pre-clinical data. Literature reviews of ICIs during pregnancy shows that pregnancy was associated with increased risk of complications, miscarriage, premature birth, intrauterine growth retardation, HELLP syndrome, and low fetal heart rate. Even though there are cases of full-term delivery of a healthy child, literature also describes cases of transplacental metastasis. Managing adverse events related to ICIs can impact the fetus. The use of steroids for during pregnancy can affect fetal development, impact glucose metabolism, and lead to gestational diabetes, premature labor, placental insufficiency, and changes in postnatal immunity.

The discussion of pregnancy after immunotherapy treatment for cancer is a complex topic and requires a multidisciplinary approach. General guidelines are very broad, ranging between 6 months and up to 5 years after completion of treatment. Multiple personal factors are taken into consideration: age, general health and/or comorbidities, cancer type and stage, response to treatment, and risk of disease recurrence. Emotional state and ability to cope with fear of recurrence is equally important.

Oncology nurses play a crucial role in educating patients about the implications of immunotherapy on fertility and pregnancy, as there may be a possible harmful impact on the mother and fetus. They provide essential education to patients and families about risks and benefits of treatment, potential impact on pregnancy, closely monitor and assess for side effects, and offer emotional support. It is essential to discuss fertility preservation before initiating treatment, in addition to the importance of contraception to prevent pregnancy.

ICIs have significantly improved treatment outcomes and survival among patients. ICIs are widely used in treatment of different types of cancers and among women of childbearing age. It is imperative to take into consideration the impact it can have on pregnancy and fetus, and discuss birth control options during treatment to prevent pregnancy. Information about the impact of immunotherapy on pregnancy and fetus is limited due to ethical issues. Current knowledge gives enough evidence that ICIs can have a negative impact on pregnancy and fetus.

References

1. Andrikopoulou A, Korakiti AM, Apostolidou K, Dimopoulos MA, Zagouri F. Immune checkpoint inhibitor administration during pregnancy: a case series. ESMO Open. 2021;6(5):100262. doi:10.1016/j.esmoop.2021.100262
2. Oktay K, Harvey BE, Partridge AH, et al. Fertility Preservation in Patients With Cancer: ASCO Clinical Practice Guideline Update. J Clin Oncol. 2018;36(19):1994-2001. doi:10.1200/JCO.2018.78.1914
3. Shan Q, Lu H. Immune Checkpoint Inhibitors in Special Populations. Technol Cancer Res Treat. 2021;20:15330338211036526. doi:10.1177/15330338211036526
4. Silvestris E, D'Oronzo S, Petracca EA, et al. Fertility Preservation in the Era of Immuno-Oncology: Lights and Shadows. J Pers Med. 2024;14(4):431. Published 2024 Apr 19. doi:10.3390/jpm14040431
5. Than NG, Hahn S, Rossi SW, Szekeres-Bartho J. Editorial: Fetal-Maternal Immune Interactions in Pregnancy. Front Immunol. 2019;10:2729. Published 2019 Nov 27. doi:10.3389/fimmu.2019.02729
6. Tsuda S, Nakashima A, Shima T, Saito S. New Paradigm in the Role of Regulatory T Cells During Pregnancy. Front Immunol. 2019;10:573. Published 2019 Mar 26. doi:10.3389/fimmu.2019.00573