Pharmacovigilance analysis of immune checkpoint inhibitor-related reproductive adverse effects based on the FDA adverse event reporting system

Abstract

This study aims to investigate the adverse effects of immune checkpoint inhibitors (ICIs) on the female and male reproductive systems. In the FDA Adverse Event Reporting System (FAERS) database, adverse reactions under the "Reproductive system and breast disorders" category in the System Organ Classes were included, covering a period from January 1, 2015, to June 30, 2023. We identified 133,512 patients treated with ICIs. Immune checkpoint inhibitor-related reproductive adverse effects (irRAEs) were reported in 568 (0.43%) patients. Spermatogenesis abnormality (ROR025 = 7.91) had the highest signal strength associated with ICI use in males. Genital tract fistula was the only significant irRAE (ROR025 = 2.72) in females. PD-1 inhibitors pose greater risk than CTLA-4 inhibitors (OR = 1.65 [1.05-2.79], p = 0.045). Gynecologic cancers in females (OR = 3.77 [2.82-4.99], p < 0.0001) and urogenital cancers in males (OR = 1.56 [1.17-2.06], p = 0.0018) carried the highest risk compared to other cancers. Additional targeted drugs (OR = 2.32 [1.76-3.02], p < 0.0001), particularly lenvatinib (OR = 3.50 [2.48-4.94], p < 0.0001) and cabozantinib (OR = 3.71 [1.96-7.03], p < 0.0001) significantly increased the risk for females. Additional use of chemotherapy drugs was associated with a significant reduction in the risk for males (OR = 0.65 [0.42-0.96], p = 0.042) except for doxorubicin (OR = 2.58 [1.22-5.47], p = 0.013) and cyclophosphamide (OR = 2.36 [1.05-5.29], p = 0.038). This study demonstrates that ICIs could potentially lead to a wide range of adverse effects in the reproductive system in both males and females.

Keywords: Female genital system; Immune checkpoint inhibitor; Male genital system; Neoplasm.

Fig. 1

The most commonly reported immune checkpoint inhibitor-related reproductive adverse effects (irRAEs) in female and male patients. In females, vaginal hemorrhage, pelvic pain, and genital tract fistulas were the most frequent irRAEs, while in males, the most commonly reported irRAEs were gynecomastia, prostatitis, benign prostatic hyperplasia, erectile dysfunction, and prostatomegaly.

Fig. 2

The lower limits of the 95% confidence intervals (CI) for the reporting odds ratio (ROR) calculations. ROR calculations were conducted for preferred terms with at least three reports. The lower limit of the 95% CI for the ROR exceeding 1 was considered significant, highlighting key drug-adverse reaction associations.

Fig. 3

The incidences of immune checkpoint inhibitor-related reproductive adverse effects (irRAEs) in patients treated with immune checkpoint inhibitor (ICI) monotherapy, including anti-PD-1, anti-PD-L1, and anti-CTLA-4 (ipilimumab) agents, as well as dual ICI therapy.