Pregnancy adverse events with immune checkpoint inhibitors in monotherapy and combination therapy in cancer: a disproportionality analysis.

Background: Although immune checkpoint inhibitors (ICIs) have transformed cancer treatment, their potential to disrupt maternal-foetal immune tolerance raises important safety concerns during pregnancy. This study used global pharmacovigilance data to compare pregnancy-related adverse events (PRAEs) following ICI monotherapy vs combination therapy. Methods: A cohort based case-noncase disproportionality analysis was conducted, using VigiBase®, the WHO's global Individual Case Safety Report database through January 21, 2025. ICI exposure was classified as monotherapy or combination therapy. Cases were defined as pregnancy reports including at least one PRAE from the nine predefined pregnancy-related adverse event categories (premature birth, abortion/stillbirth, gestational age or birth weight abnormalities, congenital anomalies, neurodevelopmental disorders, neonatal respiratory events, eclampsia, delivery complications, and other pregnancy-related adverse events), while noncases were defined as pregnancy reports with ICI exposure that did not include the specific PRAE category under analysis, although they may have included other reported adverse events. Reporting odds ratios (RORs) and 95% CIs were estimated to compare PRAE reporting between combination and monotherapy exposures. Multivariable Firth logistic regression was used to calculate adjusted RORs, controlling for reporter qualification and report completeness score. Generalised estimating equations with a binomial distribution were applied to account for clustering of multiple adverse events within the same pregnancy. Levels of significance are unadjusted for multiple testing. Findings: 337 case reports were initially retrieved from VigiBase, of which 164 met the inclusion criteria. Of these, 22 (13%) involved combination ICI therapy and 142 (87%) monotherapy exposure. Overall, 72 (43.9%) of 164 reported at least one PRAE, with a significantly higher frequency among combination therapy cases compared with monotherapy (17 [77.3%] of 22 vs 55 [38.7%] of 142; p < 0.001). Premature delivery was the most common pregnancy-related adverse event across all subjects, occurring in (14 [63.6%] of 22) of the combination therapy group and (23 [16.2%] of 142) of the monotherapy group (p < 0.001). Gestational or weight abnormalities followed, occurring in (4 [18.2%] of 22) and (7 [4.9%] of 142) of the combination therapy and Monotherapy groups, respectively (p = 0.04). In multivariable analyses adjusted for reporter qualification and completeness score, combination therapy remained strongly associated with foetal and neonatal complications, particularly premature birth (adjusted ROR 9.10, 95% CI 3.38-24.55). Reports with higher completeness scores were significantly more likely to include adverse pregnancy outcomes across several categories. Findings were consistent in generalised estimating equations models, where combination therapy showed a twofold higher population-averaged risk of any PRAE (ROR 2.26, 95% CI 1.39-3.68; p < 0.001). Interpretation: ICI combination therapy was associated with a higher reporting of PRAEs compared with monotherapy, particularly premature delivery and gestational or foetal growth abnormalities. Funding: This study received no external funding.