Prescription Drug Exposures During Pregnancy and Risk of Nonsyndromic Craniosynostosis

Objectives This study examined the association between maternal pharmacological exposures and nonsyndromic craniosynostosis (NSC). Design and M ethods In this retrospective database study, all pregnancies affected by NSC were identified in the Epic Cosmos database and matched 1:1 to control pregnancies for case-control analysis. In hypothesis-driven analysis, associations between NSC and first- or second-trimester medication exposures with prior evidence of association were estimated. In exploratory analysis, all first- and second-trimester medication exposures were compared, and those that remained significant after correction for multiple comparisons with an odds ratio >2 were retained. All significant exposures were reevaluated in sibling-controlled models to isolate within-family risk. Patients 10,470 pregnancies affected by NSC and 10,470 control pregnancies. Main O utcome M easure Adjusted odds ratios (aORs) estimating the association between candidate medication exposures and NSC in case-control analysis; within-family risk of NSC in sibling-controlled analysis. Results Among medications with prior evidence, exogenous thyroid hormones (aOR: 1.25 [95% CI: 1.07, 1.47]) and selective serotonin reuptake inhibitors (SSRIs) (aOR: 1.31 [95% CI: 1.17, 1.46]) were significantly associated with NSC. Exploratory analysis revealed topiramate (aOR: 2.29 [95% CI: 1.50, 3.49]) and hydroxychloroquine (aOR: 5.42 [95% CI: 2.08, 14.12]) as significant. However, in sibling-controlled analysis, only topiramate remained significantly associated with NSC (aOR: 1.42 [95% CI: 1.10, 1.81]). Conclusions Our findings identify topiramate as a potential teratogen for craniosynostosis. The modest association and null sibling effect for SSRIs do not support discontinuation during pregnancy. Associations with thyroid hormones suggest a complex interplay between thyroid function and suture development.