Prescription Drug Exposures During Pregnancy and Risk of Nonsyndromic Craniosynostosis

ObjectivesThis study examined the association between maternal pharmacological exposures and nonsyndromic craniosynostosis (NSC).Design and MethodsIn 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.Patients10,470 pregnancies affected by NSC and 10,470 control pregnancies.Main Outcome MeasureAdjusted 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.ResultsAmong 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]).ConclusionsOur 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.