Abstract
Objective
Infertility treatments using ovulation induction drugs lack comparative real‐world safety evidence, particularly for less common but serious adverse events (AEs). This study aimed to systematically compare the safety profiles of five ovulation induction agents—letrozole, clomiphene, leuprolide, chorionic gonadotropin, and menotropins—using a large pharmacovigilance database.
Methods
A disproportionality analysis was conducted using the FDA adverse event reporting system (FAERS) database from 2004Q1 to 2025Q1. Two signal detection algorithms, the reporting odds ratio (ROR) and the Bayesian confidence propagation neural network (BCPNN), were applied. Weibull distribution modeling was used to characterize time‐to‐onset patterns. Only AEs meeting positive thresholds in both algorithms were considered signals.
Results
A total of 984 AE reports were identified. Ovarian hyperstimulation syndrome was the most frequent AE for chorionic gonadotropin, letrozole, and menotropins; visual disturbances predominated for clomiphene; and headache and hot flush were common for leuprolide. Beyond labeled AEs, novel signals were detected: Letrozole was associated with suicidal ideation and mania; leuprolide with depression and migraine; and clomiphene with ovarian cancer. Time‐to‐onset analysis showed that most AEs occurred within the first 30 days, with a Weibull shape parameter
β
Conclusion
Each ovulation induction drug exhibits a distinct safety profile, with the highest risk period being the first month of treatment. This study provides the first systematic head‐to‐head comparison of five agents using dual signal detection and temporal modeling, revealing previously underrecognized psychiatric and oncologic signals that warrant prospective validation.