Aim: To assess the risk of major congenital malformations following first-trimester PSE exposure. Methods: A population-based retrospective cohort study was conducted on pregnancies of women aged 15-49 years, insured by Clalit Health Services in southern Israel, who gave birth or had elective pregnancy terminations due to suspected fetal malformation at Soroka Medical Center (1999-2017). The study focused on the drug Clarinase (120 mg PSE, 5 mg loratadine). Multivariate negative binomial regression models were used to evaluate the risk for major congenital malformations, adjusting for potential confounders. Results: Of 251,543 pregnancies, 313 (0.12%) were exposed to Clarinase in the first trimester. PSE exposure was not associated with major congenital malformations overall (adjusted Relative Risk [aRR] = 0.90, 95% CI 0.558-1.45; p=0.66) or by organ system (cardiovascular: aRR = 0.938, p=0.841; central nervous: aRR = 0.618, p=0.633; musculoskeletal: aRR = 1.800, p=0.155; gastrointestinal: aRR = 1.013, p=0.990; genitourinary: aRR = 0.704, p=0.547). Conclusion: First-trimester PSE exposure was not associated with major congenital malformations, either overall or by organ system.